L-Glutamate

evidence_access

Primary abstract

experimental_model

Same rat perfusion study.

limitations

Not clinical ulcer prevention.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Barrier and vascular endpoints differed.

primary_references

Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same rat perfusion study. · source_derived_draft · unverified_draft

## monosodium-glutamate-duodenal-mucus Barrier and vascular endpoints differed. Glutamate increased rat duodenal mucus thickness without increasing measured blood flow. Model: Same rat perfusion study. Limitations: Not clinical ulcer prevention. Evidence access: Primary abstract Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

evidence_access

Primary abstract

experimental_model

Anesthetized-rat perfusion, 0.1–10 mM.

limitations

Local preparation; not blood alkalinization.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A luminal amino acid changed cellular acid-base handling.

primary_references

Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anesthetized-rat perfusion, 0.1–10 mM. · source_derived_draft · unverified_draft

## monosodium-glutamate-duodenal-ph A luminal amino acid changed cellular acid-base handling. Luminal L-glutamate increased epithelial pH in rat duodenum. Model: Anesthetized-rat perfusion, 0.1–10 mM. Limitations: Local preparation; not blood alkalinization. Evidence access: Primary abstract Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

evidence_access

Primary abstract

experimental_model

T1R receptor molecular assays and computational model.

limitations

A supported binding model, not a directly observed ligand-bound structure in this paper.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Glutamate and its enhancer are not assigned the same binding site.

primary_references

Molecular mechanism for the umami taste synergism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19104071/ · DOI 10.1073/pnas.0810174106

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 74–80

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · T1R receptor molecular assays and computational model. · source_derived_draft · unverified_draft

## monosodium-glutamate-umami-binding-model Glutamate and its enhancer are not assigned the same binding site. Receptor chimeras, mutagenesis and modeling support glutamate binding near the hinge of the T1R1 Venus-flytrap domain. Model: T1R receptor molecular assays and computational model. Limitations: A supported binding model, not a directly observed ligand-bound structure in this paper. Evidence access: Primary abstract Molecular mechanism for the umami taste synergism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19104071/ · DOI 10.1073/pnas.0810174106

evidence_access

Primary abstract

experimental_model

Human oral 15N tracer, arterialized blood sampling for 150 minutes.

limitations

Small tracer experiment; it does not establish supplement efficacy or a universal conversion fraction.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The incoming amino nitrogen could leave the gut region in different molecules.

primary_references

Measurement of the transfer of the nitrogen moiety of intestinal lumen glutamic acid in man after oral ingestion of l-[15N]glutamic acid. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2908193/ · DOI 10.1042/cs0750499

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human oral 15N tracer, arterialized blood sampling for 150 minutes. · source_derived_draft · unverified_draft

## glutamate-dietary-nitrogen The incoming amino nitrogen could leave the gut region in different molecules. After six fasted adults ingested 100 mg nitrogen-labeled L-glutamic acid, most recovered circulating amino-acid label appeared in alanine and glutamine, with no significant amino-acid concentration changes during 150 minutes. Model: Human oral 15N tracer, arterialized blood sampling for 150 minutes. Limitations: Small tracer experiment; it does not establish supplement efficacy or a universal conversion fraction. Evidence access: Primary abstract Measurement of the transfer of the nitrogen moiety of intestinal lumen glutamic acid in man after oral ingestion of l-[15N]glutamic acid. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2908193/ · DOI 10.1042/cs0750499

evidence_access

Primary abstract

experimental_model

Neuroblastoma/primary-retina hybrid-cell culture; transport and toxicity assays.

limitations

The early paper does not genetically resolve SLC7A11; it is not an oral glutamate exposure study.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The same molecule used to build an antioxidant can obstruct another required ingredient when outside these cells.

primary_references

Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 330–336

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Neuroblastoma/primary-retina hybrid-cell culture; transport and toxicity assays. · source_derived_draft · unverified_draft

## glutamate-extracellular-cystine-block The same molecule used to build an antioxidant can obstruct another required ingredient when outside these cells. Added extracellular glutamate inhibited cystine uptake in N18-RE-105 neuronal hybrid cells, and toxicity tracked that inhibition. Model: Neuroblastoma/primary-retina hybrid-cell culture; transport and toxicity assays. Limitations: The early paper does not genetically resolve SLC7A11; it is not an oral glutamate exposure study. Evidence access: Primary abstract Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

evidence_access

Primary full text

experimental_model

Rodent synaptic-vesicle acidification assays; glutamate compared with chloride.

limitations

The preparation does not show that glutamate supplements increase human dopamine.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

One transmitter can influence storage of another through shared vesicle chemistry.

primary_references

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 314–320

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rodent synaptic-vesicle acidification assays; glutamate compared with chloride. · source_derived_draft · unverified_draft

## glutamate-glutamate-vesicle-acidification One transmitter can influence storage of another through shared vesicle chemistry. Glutamate co-entry increased vesicular acidification in the study, supporting the pH gradient used for monoamine storage. Model: Rodent synaptic-vesicle acidification assays; glutamate compared with chloride. Limitations: The preparation does not show that glutamate supplements increase human dopamine. Evidence access: Primary full text Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

evidence_access

Primary abstract

experimental_model

Human T-cell receptor expression and adhesion assays.

limitations

Antagonist support does not uniquely prove GluA3 is the sole functional subunit; no dietary immune benefit is established.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

An extracellular amino acid changed immune-cell behavior in an assay.

primary_references

Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12682273/ · DOI 10.4049/jimmunol.170.8.4362

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell receptor expression and adhesion assays. · source_derived_draft · unverified_draft

## glutamate-immune-adhesion An extracellular amino acid changed immune-cell behavior in an assay. Glutamate at 10 nM promoted integrin-mediated adhesion of tested human T cells to laminin and fibronectin; AMPA antagonists and relevant anti-integrin antibodies blocked the response. Model: Human T-cell receptor expression and adhesion assays. Limitations: Antagonist support does not uniquely prove GluA3 is the sole functional subunit; no dietary immune benefit is established. Evidence access: Primary abstract Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12682273/ · DOI 10.4049/jimmunol.170.8.4362

evidence_access

Primary abstract

experimental_model

Human T-cell chemotaxis experiments in the receptor study.

limitations

This does not establish disease causation or the direction of a clinical immune effect.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A metabolic signal interacted with a chemokine-guided movement system.

primary_references

Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12682273/ · DOI 10.4049/jimmunol.170.8.4362

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 362–368

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell chemotaxis experiments in the receptor study. · source_derived_draft · unverified_draft

## glutamate-immune-migration A metabolic signal interacted with a chemokine-guided movement system. Glutamate increased CXCR4-mediated T-cell chemotactic migration toward CXCL12 in the reported experiments. Model: Human T-cell chemotaxis experiments in the receptor study. Limitations: This does not establish disease causation or the direction of a clinical immune effect. Evidence access: Primary abstract Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12682273/ · DOI 10.4049/jimmunol.170.8.4362

evidence_access

Primary abstract

experimental_model

Heterologous expression of human taste receptors.

limitations

Taste-receptor activation does not establish a brain neurotransmitter effect.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Two receptor proteins recognize the umami signal.

primary_references

Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 42–48

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heterologous expression of human taste receptors. · source_derived_draft · unverified_draft

## glutamate-umami-receptor Two receptor proteins recognize the umami signal. Coexpressed human T1R1/T1R3 responded to L-glutamate in receptor assays. Model: Heterologous expression of human taste receptors. Limitations: Taste-receptor activation does not establish a brain neurotransmitter effect. Evidence access: Primary abstract Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199

evidence_access

Primary full text

experimental_model

Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system.

limitations

An isolated-organelle assay does not prove that oral aspartate increases thermogenesis.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

The transport cycle linked a cytosolic redox pool to mitochondrial machinery.

primary_references

The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system. · source_derived_draft · unverified_draft

## l-aspartate-brown-shuttle-redox The transport cycle linked a cytosolic redox pool to mitochondrial machinery. Isolated mouse brown-fat mitochondria reconstituted with cytosolic shuttle enzymes oxidized extramitochondrial NADH in a glutamate-dependent manner. Model: Mouse C57BL/6J brown-fat mitochondria and reconstituted enzyme system. Limitations: An isolated-organelle assay does not prove that oral aspartate increases thermogenesis. Evidence access: Primary full text The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

evidence_access

Primary full text

experimental_model

Mouse brown adipocytes with 15N-valine/leucine; cellular tracing.

limitations

Isoleucine is a connected BCAA substrate, but was not the tracer in these experiments.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

Shared BCAA chemistry carries nitrogen as well as carbon.

primary_references

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse brown adipocytes with 15N-valine/leucine; cellular tracing. · source_derived_draft · unverified_draft

## isoleucine-bcaa-nitrogen Shared BCAA chemistry carries nitrogen as well as carbon. Nitrogen-labeled valine and leucine supplied glutamate and alanine rapidly in brown-adipocyte tracing experiments. Model: Mouse brown adipocytes with 15N-valine/leucine; cellular tracing. Limitations: Isoleucine is a connected BCAA substrate, but was not the tracer in these experiments. Evidence access: Primary full text BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

evidence_span

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experimental_model

Whole-cell current reversal measurements

exposure

Ion substitution, intracellular sodium/glutamate and extracellular potassium

limitations

Stoichiometry inferred from reversal potentials; the predicted ischemic extracellular glutamate concentration is not an in-vivo result.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Mammalian GLT-1 expressed in Chinese hamster ovary cells

plain_language

Glutamate clearance uses sodium, potassium and proton gradients together.

primary_references

[sodium-p9822723] Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. (1998). https://pubmed.ncbi.nlm.nih.gov/9822723/ DOI: 10.1523/jneurosci.18-23-09620.1998

tissue_or_cell_type

Plasma membrane

transport_effect

raises Uptake of one glutamate anion with three sodium ions and one proton.

transport_pool

the expressing cell Uptake of one glutamate anion with three sodium ions and one proton.

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 369–380

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Whole-cell current reversal measurements · source_derived_draft · unverified_draft

### sodium-glt1-stoichiometry Current reversal measurements supported uptake of one glutamate anion with three sodium ions and one proton, coupled to outward movement of one potassium ion. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutamate clearance uses sodium, potassium and proton gradients together. organism: Mammalian GLT-1 expressed in Chinese hamster ovary cells tissue_or_cell_type: Plasma membrane experimental_model: Whole-cell current reversal measurements limitations: Stoichiometry inferred from reversal potentials; the predicted ischemic extracellular glutamate concentration is not an in-vivo result. exposure: Ion substitution, intracellular sodium/glutamate and extracellular potassium evidence_span: {"source_cache": "artifacts/sodium-research/9822723.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064", "start_char": 0, "end_char": 1740, "text_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064"} [sodium-p9822723] Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. (1998). https://pubmed.ncbi.nlm.nih.gov/9822723/ DOI: 10.1523/jneurosci.18-23-09620.1998

evidence_access

Primary full text; background and test samples

experimental_model

Chemical identity and ingredient design in the primary sensory study.

limitations

This is background chemistry, not a measurement of absorption or tissue delivery.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The ingredient contributes both glutamate and sodium.

primary_references

Validation of preferred salt concentration in soup based on a randomized blinded experiment in multiple regions in Japan-influence of umami (L-glutamate) on saltiness and palatability of low-salt solutions. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996813/ · DOI 10.1038/s41440-020-0397-1

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 18–24

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Chemical identity and ingredient design in the primary sensory study. · source_derived_draft · unverified_draft

## monosodium-glutamate-salt-identity The ingredient contributes both glutamate and sodium. MSG is the sodium salt of L-glutamate; the sensory study treats added MSG and NaCl as separate ingredients. Model: Chemical identity and ingredient design in the primary sensory study. Limitations: This is background chemistry, not a measurement of absorption or tissue delivery. Evidence access: Primary full text; background and test samples Validation of preferred salt concentration in soup based on a randomized blinded experiment in multiple regions in Japan-influence of umami (L-glutamate) on saltiness and palatability of low-salt solutions. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996813/ · DOI 10.1038/s41440-020-0397-1

evidence_access

Primary abstract

experimental_model

Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views.

limitations

P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

A second enzyme turns the breakdown intermediate into glutamate.

primary_references

The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 102–108

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. · source_derived_draft · unverified_draft

## l-proline-aldh4-oxidation A second enzyme turns the breakdown intermediate into glutamate. ALDH4A1 catalyzes NAD+-dependent oxidation of glutamate semialdehyde to glutamate, completing the second enzymatic stage of proline catabolism. Model: Human enzyme structures and kinetics; mouse enzyme complexes supplied high-resolution ligand views. Limitations: P5C and glutamate semialdehyde interconvert; the aldehyde is the oxidation substrate. Mouse ligand structures are not relabeled as human complexes. Evidence access: Primary abstract The three-dimensional structural basis of type II hyperprolinemia. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22516612/ · DOI 10.1016/j.jmb.2012.04.010

cross_nutrient

Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme.

evidence_span

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experimental_model

Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate

exposure

Biochemical or structural assay; no dietary intervention

limitations

Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The two enzyme activities communicate while NAD is assembled.

primary_references

[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 342–354

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft

### b3-pre-nadsyn-glutaminase Human NADSYN1 glutaminase activity was measured as glutamate production; NaAD plus ATP/Mg2+ increased that activity 31-fold over glutamine alone in the reported assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two enzyme activities communicate while NAD is assembled. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 10–10 (0-based)", "start_char": 8754, "end_char": 10450, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "32dd95b3bef542cb15f227e9dd3de1ed68b6b9c8f6cda41d34daf7b6fe387ce7"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4

evidence_access

Primary abstract

experimental_model

Bovine capillary RNA, membrane protein analysis and transport kinetics; aggregate apparent Km 14 micromolar at −61 mV.

limitations

The panel is not a physical three-protein complex; transport assays do not measure whole human brain exposure after food intake.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The brain-facing barrier membrane participates in removing extracellular glutamate.

primary_references

Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10542215/ · DOI 10.1074/jbc.274.45.31891

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bovine capillary RNA, membrane protein analysis and transport kinetics; aggregate apparent Km 14 micromolar at −61 mV. · source_derived_draft · unverified_draft

## glutamate-bbb-clearance The brain-facing barrier membrane participates in removing extracellular glutamate. Bovine brain-capillary membrane preparations contained EAAT1/2/3 on the abluminal side and showed voltage- and potassium-dependent glutamate uptake. Model: Bovine capillary RNA, membrane protein analysis and transport kinetics; aggregate apparent Km 14 micromolar at −61 mV. Limitations: The panel is not a physical three-protein complex; transport assays do not measure whole human brain exposure after food intake. Evidence access: Primary abstract Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10542215/ · DOI 10.1074/jbc.274.45.31891

evidence_access

Primary abstract

experimental_model

Human crossover intravenous/nasogastric tracer infusion, 3.5 hours per route in each seven-hour study.

limitations

Splanchnic means gut plus liver region; the percentage is protocol-specific, not a fixed value for every meal or dose.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Much of an enteral tracer was handled before reaching the general circulation.

primary_references

Oxidation of glutamic acid by the splanchnic bed in humans. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7653544/ · DOI 10.1152/ajpendo.1995.269.2.E269

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 18–24

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human crossover intravenous/nasogastric tracer infusion, 3.5 hours per route in each seven-hour study. · source_derived_draft · unverified_draft

## glutamate-first-pass Much of an enteral tracer was handled before reaching the general circulation. In postabsorptive healthy adults, tracer comparisons estimated 96 ± 1% first-pass splanchnic extraction of enterally delivered glutamate. Model: Human crossover intravenous/nasogastric tracer infusion, 3.5 hours per route in each seven-hour study. Limitations: Splanchnic means gut plus liver region; the percentage is protocol-specific, not a fixed value for every meal or dose. Evidence access: Primary abstract Oxidation of glutamic acid by the splanchnic bed in humans. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7653544/ · DOI 10.1152/ajpendo.1995.269.2.E269

evidence_access

Primary abstract

experimental_model

Human [1,2-13C2]glutamate tracer and breath CO2 measurements.

limitations

Whole-body breath recovery does not identify the cell type oxidizing each molecule.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Glutamate carbon was used as fuel, not merely redistributed as amino nitrogen.

primary_references

Oxidation of glutamic acid by the splanchnic bed in humans. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7653544/ · DOI 10.1152/ajpendo.1995.269.2.E269

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human [1,2-13C2]glutamate tracer and breath CO2 measurements. · source_derived_draft · unverified_draft

## glutamate-first-pass-oxidation Glutamate carbon was used as fuel, not merely redistributed as amino nitrogen. About 78 ± 3% of enterally delivered carbon-labeled glutamate tracer was recovered as exhaled CO2 in the study. Model: Human [1,2-13C2]glutamate tracer and breath CO2 measurements. Limitations: Whole-body breath recovery does not identify the cell type oxidizing each molecule. Evidence access: Primary abstract Oxidation of glutamic acid by the splanchnic bed in humans. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7653544/ · DOI 10.1152/ajpendo.1995.269.2.E269

evidence_access

Primary abstract

experimental_model

Human-cell GLS2/p53 study; reaction identity described alongside functional experiments.

limitations

GLS2 and the distinct GLS gene are not interchangeable.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A related amino acid is an upstream source of glutamate.

primary_references

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 202–208

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell GLS2/p53 study; reaction identity described alongside functional experiments. · source_derived_draft · unverified_draft

## glutamate-gls2-production A related amino acid is an upstream source of glutamate. The primary study identifies GLS2 as a mitochondrial glutaminase hydrolyzing glutamine to glutamate. Model: Human-cell GLS2/p53 study; reaction identity described alongside functional experiments. Limitations: GLS2 and the distinct GLS gene are not interchangeable. Evidence access: Primary abstract Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

evidence_access

Primary abstract

experimental_model

Human carrier expressed in E. coli and reconstituted in phospholipid vesicles.

limitations

Glutamate/H+ cotransport and glutamate/OH− exchange are alternative descriptions in this assay; this is not the aspartate/glutamate exchanger.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Cytosolic glutamate needs a carrier to reach mitochondrial reactions.

primary_references

Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11897791/ · DOI 10.1074/jbc.M201572200

transport_effect

depends The record names the proton coupling and not which way glutamate crossed the membrane.

transport_pool

the mitochondrial matrix The record names the proton coupling and not which way glutamate crossed the membrane.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human carrier expressed in E. coli and reconstituted in phospholipid vesicles. · source_derived_draft · unverified_draft

## glutamate-mitochondrial-gc1 Cytosolic glutamate needs a carrier to reach mitochondrial reactions. Reconstituted human glutamate carrier 1 supported glutamate transport coupled to a proton gradient. Model: Human carrier expressed in E. coli and reconstituted in phospholipid vesicles. Limitations: Glutamate/H+ cotransport and glutamate/OH− exchange are alternative descriptions in this assay; this is not the aspartate/glutamate exchanger. Evidence access: Primary abstract Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11897791/ · DOI 10.1074/jbc.M201572200

evidence_access

Primary abstract

experimental_model

Recombinant human SLC25A18 compared with SLC25A22 in vesicle transport assays.

limitations

The proposed allocation to basal versus high-demand metabolism was an interpretation, not a universal tissue ranking.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A related carrier is a separate node with its own properties.

primary_references

Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11897791/ · DOI 10.1074/jbc.M201572200

transport_effect

depends The record names the proton coupling and not which way glutamate crossed the membrane.

transport_pool

the mitochondrial matrix The record names the proton coupling and not which way glutamate crossed the membrane.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human SLC25A18 compared with SLC25A22 in vesicle transport assays. · source_derived_draft · unverified_draft

## glutamate-mitochondrial-gc2 A related carrier is a separate node with its own properties. Reconstituted human glutamate carrier 2 also supported glutamate/proton-coupled transport, with kinetic and expression differences from carrier 1. Model: Recombinant human SLC25A18 compared with SLC25A22 in vesicle transport assays. Limitations: The proposed allocation to basal versus high-demand metabolism was an interpretation, not a universal tissue ranking. Evidence access: Primary abstract Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11897791/ · DOI 10.1074/jbc.M201572200

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse BAT carrier-loss and isotope/metabolite experiments.

limitations

Does not establish isoleucine supplementation as a glutathione intervention; the traced amino acids and cell context remain explicit.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

Transport and nitrogen handling can affect antioxidant production.

primary_references

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse BAT carrier-loss and isotope/metabolite experiments. · source_derived_draft · unverified_draft

## isoleucine-bcaa-glutathione Transport and nitrogen handling can affect antioxidant production. Impaired mitochondrial BCAA nitrogen flux reduced synthesis of downstream metabolites including glutathione and increased oxidative stress in the tested BAT system. Model: Mouse BAT carrier-loss and isotope/metabolite experiments. Limitations: Does not establish isoleucine supplementation as a glutathione intervention; the traced amino acids and cell context remain explicit. Evidence access: Primary full text BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

evidence_access

Primary abstract; reaction-intermediate structural study

experimental_model

Human BCAT2 intermediate structures and established reaction chemistry.

limitations

Reversible enzyme chemistry; concentration and compartment determine net flux.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

The first breakdown step passes nitrogen to another metabolite.

primary_references

Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12269802/ · DOI 10.1021/bi020221c

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 162–168

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human BCAT2 intermediate structures and established reaction chemistry. · source_derived_draft · unverified_draft

## isoleucine-bcat-reaction The first breakdown step passes nitrogen to another metabolite. Human BCAT2 transfers the isoleucine amino group through the PLP/PMP cycle, linking isoleucine/branched ketoacid interconversion to 2-oxoglutarate/glutamate. Model: Human BCAT2 intermediate structures and established reaction chemistry. Limitations: Reversible enzyme chemistry; concentration and compartment determine net flux. Evidence access: Primary abstract; reaction-intermediate structural study Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12269802/ · DOI 10.1021/bi020221c

evidence-system

Single-channel patch clamp with glutamate/NMDA agonists and extracellular Mg changes

experimental_model

Single-channel patch clamp with glutamate/NMDA agonists and extracellular Mg changes

limitations

Native channel subunits were not resolved; no nutritional intake or clinical outcome was tested.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mouse

plain_language

Magnesium restrains this excitatory current in a way that depends on membrane voltage.

primary_references

[nowak-1984-nmda] Magnesium gates glutamate-activated channels in mouse central neurones (1984). https://pubmed.ncbi.nlm.nih.gov/6320006/ DOI: 10.1038/307462a0

tissue

Cultured central neurons

tissue_or_cell_type

Cultured central neurons

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1261–1272

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-channel patch clamp with glutamate/NMDA agonists and extracellular Mg changes · source_derived_draft · unverified_draft

### magnesium-voltage-dependent-nmda-block Extracellular Mg caused voltage-dependent block of NMDA-type currents in cultured mouse neurons, stronger at hyperpolarized potentials. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium restrains this excitatory current in a way that depends on membrane voltage. organism: Mouse tissue_or_cell_type: Cultured central neurons experimental_model: Single-channel patch clamp with glutamate/NMDA agonists and extracellular Mg changes limitations: Native channel subunits were not resolved; no nutritional intake or clinical outcome was tested. evidence-system: Single-channel patch clamp with glutamate/NMDA agonists and extracellular Mg changes tissue: Cultured central neurons [nowak-1984-nmda] Magnesium gates glutamate-activated channels in mouse central neurones (1984). https://pubmed.ncbi.nlm.nih.gov/6320006/ DOI: 10.1038/307462a0

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Rat H4IIE cells; siRNA knockdown with alanine challenge.

limitations

Partial knockdown and partial attenuation do not prove ALT1 is the only contributing pathway.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

The response partly depended on processing alanine, rather than simply sensing it outside the cell.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 256–262

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat H4IIE cells; siRNA knockdown with alanine challenge. · source_derived_draft · unverified_draft

## alanine-ampk-alt1-dependence The response partly depended on processing alanine, rather than simply sensing it outside the cell. ALT1 siRNA reduced rat H4IIE ALT protein by about 77% and reduced alanine-stimulated AMPK activation by about 49%. Model: Rat H4IIE cells; siRNA knockdown with alanine challenge. Limitations: Partial knockdown and partial attenuation do not prove ALT1 is the only contributing pathway. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary full text

experimental_model

Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes.

limitations

Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Moving amino nitrogen changed the cell’s carbon pools and energy balance.

primary_references

l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 264–270

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. · source_derived_draft · unverified_draft

## alanine-ampk-pools Moving amino nitrogen changed the cell’s carbon pools and energy balance. Alanine increased the AMP/ATP ratio and glutamate while decreasing 2-oxoglutarate and other TCA intermediate pools in rat H4IIE cells. Model: Acute rat H4IIE metabolomics; AMP/ATP approximately 1.5-fold higher at 15 minutes. Limitations: Pool sizes are not flux measurements; increased ATP-consuming urea synthesis was proposed rather than directly proven. Evidence access: Primary full text l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30190193/ · DOI 10.1016/j.molmet.2018.08.002

evidence_access

Primary abstract

experimental_model

Rat clonal BRIN-BD11 beta-cell experiments.

limitations

Oligomycin broadly blocks oxidative phosphorylation; this is not a selective proof of one alanine enzyme.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Oxidative metabolism contributed to the secretory response in this cell line.

primary_references

A nuclear magnetic resonance-based demonstration of substantial oxidative L-alanine metabolism and L-alanine-enhanced glucose metabolism in a clonal pancreatic beta-cell line: metabolism of L-alanine is important to the regulation of insulin secretion. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12031957/ · DOI 10.2337/diabetes.51.6.1714

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 360–366

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat clonal BRIN-BD11 beta-cell experiments. · source_derived_draft · unverified_draft

## alanine-beta-oxidation Oxidative metabolism contributed to the secretory response in this cell line. Carbon-13 NMR detected alanine-derived glutamate and aspartate in BRIN-BD11 cells; oligomycin attenuated alanine-stimulated insulin secretion. Model: Rat clonal BRIN-BD11 beta-cell experiments. Limitations: Oligomycin broadly blocks oxidative phosphorylation; this is not a selective proof of one alanine enzyme. Evidence access: Primary abstract A nuclear magnetic resonance-based demonstration of substantial oxidative L-alanine metabolism and L-alanine-enhanced glucose metabolism in a clonal pancreatic beta-cell line: metabolism of L-alanine is important to the regulation of insulin secretion. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12031957/ · DOI 10.2337/diabetes.51.6.1714

evidence_access

Primary full text

experimental_model

Human fibroblast stable-isotope tracing under specified media conditions.

limitations

Atom contribution is not a one-step alanine-to-proline reaction; other enzymes, carbon sources and cofactors remain necessary.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

One amino acid can supply material used to make another.

primary_references

TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 520–526

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast stable-isotope tracing under specified media conditions. · source_derived_draft · unverified_draft

## alanine-fibroblast-proline One amino acid can supply material used to make another. Isotope experiments showed alanine supplying carbon and nitrogen to glutamate and proline synthesis in human lung fibroblasts, particularly during glutamine deprivation. Model: Human fibroblast stable-isotope tracing under specified media conditions. Limitations: Atom contribution is not a one-step alanine-to-proline reaction; other enzymes, carbon sources and cofactors remain necessary. Evidence access: Primary full text TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449

evidence_access

Primary full text

experimental_model

Human lung fibroblast cultures; TGF-beta 2 ng/mL and metabolic perturbations.

limitations

Medium composition matters; this is not proof that alanine intake causes lung fibrosis.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

A differentiation signal coordinates alanine production with other amino-acid metabolism.

primary_references

TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 496–502

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lung fibroblast cultures; TGF-beta 2 ng/mL and metabolic perturbations. · source_derived_draft · unverified_draft

## alanine-fibroblast-synthesis A differentiation signal coordinates alanine production with other amino-acid metabolism. TGF-beta increased alanine synthesis in normal and IPF human lung fibroblasts, with GPT2 as the principal examined synthesis enzyme regulated by the glutamine/glutamate/2-oxoglutarate axis. Model: Human lung fibroblast cultures; TGF-beta 2 ng/mL and metabolic perturbations. Limitations: Medium composition matters; this is not proof that alanine intake causes lung fibrosis. Evidence access: Primary full text TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42024472/ · DOI 10.1172/jci.insight.199449

evidence_access

Primary abstract

experimental_model

Human arteriovenous balance study; postabsorptive state and 4–6 weeks of fasting.

limitations

Exchange measurements do not identify every intracellular reaction or prove that all released alanine becomes glucose.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Muscle can send both carbon and amino nitrogen to the liver as alanine.

primary_references

Alanine: key role in gluconeogenesis. · 1970 · https://pubmed.ncbi.nlm.nih.gov/5411169/ · DOI 10.1126/science.167.3920.1003

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 16–22

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human arteriovenous balance study; postabsorptive state and 4–6 weeks of fasting. · source_derived_draft · unverified_draft

## alanine-human-forearm-liver Muscle can send both carbon and amino nitrogen to the liver as alanine. Arteriovenous measurements identified alanine as the principal amino acid released by forearm muscle and extracted by the liver in postabsorptive and prolonged-fasting subjects. Model: Human arteriovenous balance study; postabsorptive state and 4–6 weeks of fasting. Limitations: Exchange measurements do not identify every intracellular reaction or prove that all released alanine becomes glucose. Evidence access: Primary abstract Alanine: key role in gluconeogenesis. · 1970 · https://pubmed.ncbi.nlm.nih.gov/5411169/ · DOI 10.1126/science.167.3920.1003

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse liver Gpt2 genetic deletion; isotope tracing.

limitations

Does not mean GPT2 is the only route; lean knockout animals did not develop a general failure of glucose control. Correction record: Published correction adds the originally omitted disclosure that B.N.F. was a scientific advisory board member and stockholder of Cirius Therapeutics, which develops MPC inhibitors. Disclosure correction, not a data retraction. https://pmc.ncbi.nlm.nih.gov/articles/PMC9713851/

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Mitochondrial transamination can feed alanine carbon into glucose.

primary_references

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35476997/ · DOI 10.1016/j.celrep.2022.110733

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 216–222

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver Gpt2 genetic deletion; isotope tracing. · source_derived_draft · unverified_draft

## alanine-liver-gpt2-flux Mitochondrial transamination can feed alanine carbon into glucose. Hepatocyte-specific Gpt2 deletion reduced labeled alanine contribution to glucose production in mouse hepatocyte experiments. Model: Mouse liver Gpt2 genetic deletion; isotope tracing. Limitations: Does not mean GPT2 is the only route; lean knockout animals did not develop a general failure of glucose control. Correction record: Published correction adds the originally omitted disclosure that B.N.F. was a scientific advisory board member and stockholder of Cirius Therapeutics, which develops MPC inhibitors. Disclosure correction, not a data retraction. https://pmc.ncbi.nlm.nih.gov/articles/PMC9713851/ Evidence access: Primary full text Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35476997/ · DOI 10.1016/j.celrep.2022.110733

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse neuron-specific deletion and metabolomic experiments.

limitations

The phenotype is not an ordinary dietary alanine deficiency.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Neurons require functioning synthesis machinery as well as available carbon and nitrogen.

primary_references

Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34519342/ · DOI 10.1093/hmg/ddab269

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 304–310

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse neuron-specific deletion and metabolomic experiments. · source_derived_draft · unverified_draft

## alanine-neuron-gpt2 Neurons require functioning synthesis machinery as well as available carbon and nitrogen. Neuron-specific Gpt2 deletion impaired alanine synthesis and metabolic replenishment and reproduced severe motor abnormalities and pre-weaning mortality. Model: Mouse neuron-specific deletion and metabolomic experiments. Limitations: The phenotype is not an ordinary dietary alanine deficiency. Evidence access: Primary abstract Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34519342/ · DOI 10.1093/hmg/ddab269

evidence_access

Primary full text

experimental_model

Human pancreatic cancer cultures with labeled alanine.

limitations

Tumor-cell utilization is not evidence that dietary alanine initiates cancer. Correction record: Publisher erratum corrects the second image label in Fig. 3a to hPSC-LC3 + 8988T, matching Fig. 3b; production labeling correction, not a retraction or independent study. https://www.nature.com/articles/nature19851.pdf

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

The same amino acid can supply building material and mitochondrial fuel.

primary_references

Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27509858/ · DOI 10.1038/nature19084

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 160–166

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human pancreatic cancer cultures with labeled alanine. · source_derived_draft · unverified_draft

## alanine-pdac-carbon The same amino acid can supply building material and mitochondrial fuel. Isotope tracing showed alanine carbon entering TCA intermediates, nonessential amino acids and lipid synthesis in the tested human PDAC cells. Model: Human pancreatic cancer cultures with labeled alanine. Limitations: Tumor-cell utilization is not evidence that dietary alanine initiates cancer. Correction record: Publisher erratum corrects the second image label in Fig. 3a to hPSC-LC3 + 8988T, matching Fig. 3b; production labeling correction, not a retraction or independent study. https://www.nature.com/articles/nature19851.pdf Evidence access: Primary full text Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27509858/ · DOI 10.1038/nature19084

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human PDAC flux and compartmental metabolism experiments.

limitations

Reported metabolic crisis is not a universal consequence of reduced dietary alanine.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Losing uptake can force a cell to spend other nutrients making the missing amino acid.

primary_references

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32341021/ · DOI 10.1158/2159-8290.CD-19-0959

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 192–198

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PDAC flux and compartmental metabolism experiments. · source_derived_draft · unverified_draft

## alanine-pdac-snat2-carbon-cost Losing uptake can force a cell to spend other nutrients making the missing amino acid. SLC38A2-deficient PDAC cells increased de novo alanine synthesis and passive efflux, diverting mitochondrial pyruvate and amino-nitrogen sources toward alanine production. Model: Human PDAC flux and compartmental metabolism experiments. Limitations: Reported metabolic crisis is not a universal consequence of reduced dietary alanine. Evidence access: Primary full text Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32341021/ · DOI 10.1158/2159-8290.CD-19-0959

cross_nutrient

Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions.

experimental_model

Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate.

primary_references

[b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 717–727

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures · source_derived_draft · unverified_draft

### b6-met-bcat1-leucine Human BCAT1 transfers the leucine amino group to 2-oxoglutarate, producing alpha-ketoisocaproate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions. [b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

cross_nutrient

Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions.

experimental_model

Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate.

primary_references

[b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 729–739

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures · source_derived_draft · unverified_draft

### b6-met-bcat2-leucine Human BCAT2 transfers the leucine amino group to 2-oxoglutarate, producing alpha-ketoisocaproate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions. [b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

experimental_model

Purified human cytosolic GOT1 and GPT; coupled kinetic assays

exposure

Kinetic assays at pH 7.4 and 37 C

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

This B6-dependent enzyme links amino-acid and carbon metabolism.

primary_references

[b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 741–751

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic GOT1 and GPT; coupled kinetic assays · source_derived_draft · unverified_draft

### b6-met-got1-reaction Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent enzyme links amino-acid and carbon metabolism. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human cytosolic GOT1 and GPT; coupled kinetic assays limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. exposure: Kinetic assays at pH 7.4 and 37 C [b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398

experimental_model

Purified human cytosolic GOT1 and GPT; coupled kinetic assays

exposure

Kinetic assays at pH 7.4 and 37 C

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6-dependent alanine transamination links nitrogen transfer to pyruvate metabolism.

primary_references

[b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 753–763

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic GOT1 and GPT; coupled kinetic assays · source_derived_draft · unverified_draft

### b6-met-gpt-reaction Human GPT catalyzes reversible amino transfer between alanine and 2-oxoglutarate, producing pyruvate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6-dependent alanine transamination links nitrogen transfer to pyruvate metabolism. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human cytosolic GOT1 and GPT; coupled kinetic assays limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. exposure: Kinetic assays at pH 7.4 and 37 C [b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398

experimental_model

Human GPT2 expressed in E. coli

limitations

Functional-expression evidence; this study did not quantify B6-deficiency sensitivity.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Human alanine metabolism has a separately encoded second enzyme.

primary_references

[b6-gpt2-2002] cDNA cloning, genomic structure, chromosomal mapping, and functional expression of a novel human alanine aminotransferase (2002). https://pubmed.ncbi.nlm.nih.gov/11863375/ DOI: 10.1006/geno.2002.6722

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 776–785

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human GPT2 expressed in E. coli · source_derived_draft · unverified_draft

### b6-met-gpt2-reaction Recombinant human GPT2 catalyzed alanine transamination, confirming a second human alanine aminotransferase distinct from GPT. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human alanine metabolism has a separately encoded second enzyme. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Human GPT2 expressed in E. coli limitations: Functional-expression evidence; this study did not quantify B6-deficiency sensitivity. [b6-gpt2-2002] cDNA cloning, genomic structure, chromosomal mapping, and functional expression of a novel human alanine aminotransferase (2002). https://pubmed.ncbi.nlm.nih.gov/11863375/ DOI: 10.1006/geno.2002.6722

experimental_model

Recombinant human GAD isoforms; crystallography and enzyme kinetics

exposure

Glutamate turnover in recombinant enzyme assays.

limitations

Recombinant chemistry does not establish a human supplementation response.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Activated B6 helps this enzyme make GABA.

primary_references

[fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 949–959

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GAD isoforms; crystallography and enzyme kinetics · source_derived_draft · unverified_draft

### b6-neuro-gad1-gaba PLP-bound human GAD67 catalyzes glutamate decarboxylation to GABA. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activated B6 helps this enzyme make GABA. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human GAD isoforms; crystallography and enzyme kinetics limitations: Recombinant chemistry does not establish a human supplementation response. exposure: Glutamate turnover in recombinant enzyme assays. [fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228

experimental_model

Recombinant human GAD isoforms; crystallography and enzyme kinetics

exposure

Glutamate turnover in recombinant enzyme assays.

limitations

Recombinant chemistry does not establish a human supplementation response.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

Activated B6 helps this enzyme make GABA.

primary_references

[fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 961–971

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GAD isoforms; crystallography and enzyme kinetics · source_derived_draft · unverified_draft

### b6-neuro-gad2-gaba PLP-bound human GAD65 catalyzes glutamate decarboxylation to GABA. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activated B6 helps this enzyme make GABA. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human GAD isoforms; crystallography and enzyme kinetics limitations: Recombinant chemistry does not establish a human supplementation response. exposure: Glutamate turnover in recombinant enzyme assays. [fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228

experimental_model

Recombinant human GAD isoforms; crystallography and enzyme kinetics; Human GAD65/GAD67 recombinant chimeras

exposure

Glutamate incubation and enzyme kinetics.

limitations

Loop causality is supported by structure and kinetics; cellular net GABA was not measured.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

GAD65 can switch into an inactive cofactor-free form.

primary_references

[fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228 [langendorf-2013-gad] Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3546353/ DOI: 10.1042/BSR20120111

revision_history

[{"kind": "draft-correction", "description": "Corrected released cofactor identity from PLP to PMP after checking the source; not a scientific conflict."}]

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 973–985

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GAD isoforms; crystallography and enzyme kinetics; Human GAD65/GAD67 recombinant chimeras · source_derived_draft · unverified_draft

### b6-neuro-gad65-autoinactivation GAD65 catalytic-loop mobility favors a side reaction producing succinic semialdehyde and releasing the converted cofactor as PMP. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: GAD65 can switch into an inactive cofactor-free form. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human GAD isoforms; crystallography and enzyme kinetics; Human GAD65/GAD67 recombinant chimeras limitations: Loop causality is supported by structure and kinetics; cellular net GABA was not measured. exposure: Glutamate incubation and enzyme kinetics. revision_history: [{"kind": "draft-correction", "description": "Corrected released cofactor identity from PLP to PMP after checking the source; not a scientific conflict."}] [fenalti-2007-gad] GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop (2007). https://doi.org/10.1038/nsmb1228 DOI: 10.1038/nsmb1228 [langendorf-2013-gad] Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3546353/ DOI: 10.1042/BSR20120111

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

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experimental_model

Sustained dDAVP-induced hyponatremia followed by withdrawal and tissue measurements

exposure

14 days hyponatremia; sodium rose from 104 to 139 mmol/L over 24 hours after withdrawal

limitations

Extreme experimental correction; records tissue reaccumulation, not a safe human correction rate or direct proof of myelin injury in this study.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Rat

plain_language

Different brain solutes adapt on different timelines.

primary_references

[sodium-p8096428] Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. (1993). https://pubmed.ncbi.nlm.nih.gov/8096428/ DOI: 10.1016/0006-8993(93)91564-9

tissue_or_cell_type

Brain water, electrolytes and organic osmolytes

trigger_kind

biomarker_context Imported condition classification; unverified.

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 1032–1043

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sustained dDAVP-induced hyponatremia followed by withdrawal and tissue measurements · source_derived_draft · unverified_draft

### sodium-brain-osmolytes Most organic osmolytes required five or more days to recover; glutamate was an exception that recovered within 24 hours. Condition category: biomarker_context nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different brain solutes adapt on different timelines. organism: Rat tissue_or_cell_type: Brain water, electrolytes and organic osmolytes experimental_model: Sustained dDAVP-induced hyponatremia followed by withdrawal and tissue measurements limitations: Extreme experimental correction; records tissue reaccumulation, not a safe human correction rate or direct proof of myelin injury in this study. exposure: 14 days hyponatremia; sodium rose from 104 to 139 mmol/L over 24 hours after withdrawal evidence_span: {"source_cache": "artifacts/sodium-research/8096428.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7f7a7712c9e952343e279ae89e0d1051857c4188820819def597a430fdaf9e4c", "start_char": 0, "end_char": 1587, "text_sha256": "7f7a7712c9e952343e279ae89e0d1051857c4188820819def597a430fdaf9e4c"} [sodium-p8096428] Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. (1993). https://pubmed.ncbi.nlm.nih.gov/8096428/ DOI: 10.1016/0006-8993(93)91564-9

evidence_span

{"source_cache": "artifacts/sodium-research/9822723.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064", "start_char": 0, "end_char": 1740, "text_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064"}

experimental_model

Whole-cell current reversal measurements

exposure

Ion substitution, intracellular sodium/glutamate and extracellular potassium

limitations

Stoichiometry inferred from reversal potentials; the predicted ischemic extracellular glutamate concentration is not an in-vivo result.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Mammalian GLT-1 expressed in Chinese hamster ovary cells

plain_language

Changing the ion gradients can reverse a transporter that normally clears glutamate.

primary_references

[sodium-p9822723] Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. (1998). https://pubmed.ncbi.nlm.nih.gov/9822723/ DOI: 10.1523/jneurosci.18-23-09620.1998

tissue_or_cell_type

Plasma membrane

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 382–393

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Whole-cell current reversal measurements · source_derived_draft · unverified_draft

### sodium-glt1-reversal Increasing extracellular potassium around cells loaded with sodium and glutamate evoked an outward, blocker-sensitive reversed transport current. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the ion gradients can reverse a transporter that normally clears glutamate. organism: Mammalian GLT-1 expressed in Chinese hamster ovary cells tissue_or_cell_type: Plasma membrane experimental_model: Whole-cell current reversal measurements limitations: Stoichiometry inferred from reversal potentials; the predicted ischemic extracellular glutamate concentration is not an in-vivo result. exposure: Ion substitution, intracellular sodium/glutamate and extracellular potassium evidence_span: {"source_cache": "artifacts/sodium-research/9822723.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064", "start_char": 0, "end_char": 1740, "text_sha256": "7612750fb1528dcd6212222b248bc74a2ec7a3813f50cbe5cf8ccdadbe448064"} [sodium-p9822723] Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. (1998). https://pubmed.ncbi.nlm.nih.gov/9822723/ DOI: 10.1523/jneurosci.18-23-09620.1998

evidence_access

Primary abstract

experimental_model

Cultured rat hippocampal neurons; whole-cell patch clamp.

limitations

The inferred pore site is not a solved binding structure or measured oral human brain exposure.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Its glutamate-receptor effect depends on electrical conditions and concentration.

primary_references

Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. · 1999 · https://pubmed.ncbi.nlm.nih.gov/9918557/

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 260–266

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured rat hippocampal neurons; whole-cell patch clamp. · source_derived_draft · unverified_draft

## agmatine-sulfate-nmda-block Its glutamate-receptor effect depends on electrical conditions and concentration. Extracellular agmatine blocked NMDA currents in rat hippocampal neurons in a voltage- and concentration-dependent manner; estimated pore-site Kd was 952 micromolar at 0 mV. Model: Cultured rat hippocampal neurons; whole-cell patch clamp. Limitations: The inferred pore site is not a solved binding structure or measured oral human brain exposure. Evidence access: Primary abstract Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. · 1999 · https://pubmed.ncbi.nlm.nih.gov/9918557/

evidence_span

{"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 762, "end_char": 1092, "text_sha256": "927fa13b085700c20b578ecabc7c8c17a66ea4600b90809e3061d12bcaea3849"}

experimental_model

Human enzyme mutagenesis, kinetics and molecular dynamics

exposure

S-loop variants; established biosynthetic reactions described in the introduction

limitations

Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency.

nutrient_topic

Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study

organism

Human GSS

plain_language

The induced machinery still needs its amino-acid building blocks.

primary_references

[sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

tissue_or_cell_type

Glutathione synthesis and substrate binding

Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 840–851

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme mutagenesis, kinetics and molecular dynamics · source_derived_draft · unverified_draft

### sulforaphane-gcl-first-step Glutamate-cysteine ligase joins glutamate and cysteine to form gamma-glutamylcysteine in the first glutathione-synthesis step. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: The induced machinery still needs its amino-acid building blocks. organism: Human GSS tissue_or_cell_type: Glutathione synthesis and substrate binding experimental_model: Human enzyme mutagenesis, kinetics and molecular dynamics limitations: Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency. exposure: S-loop variants; established biosynthetic reactions described in the introduction evidence_span: {"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 762, "end_char": 1092, "text_sha256": "927fa13b085700c20b578ecabc7c8c17a66ea4600b90809e3061d12bcaea3849"} [sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract

evidence_span

State 4 respiration did not change

experimental_model

Rats fed a low-thiamine diet with pyrithiamine; intact coupled brain mitochondria isolated and assayed with defined respiratory substrates.

exposure

Low-thiamine diet plus pyrithiamine in rats

limitations

Does not demonstrate that thiamine directly forms part of the respiratory chain or that all electron-transport activity fails.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

The mitochondrial deficit depended on both substrate and respiratory state.

primary_references

[parker-1984-brain-mitochondria] Brain mitochondrial metabolism in experimental thiamine deficiency (1984). https://pubmed.ncbi.nlm.nih.gov/6493495/ DOI: 10.1212/wnl.34.11.1477

tissue_or_cell_type

Isolated brain mitochondria

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1127–1139

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats fed a low-thiamine diet with pyrithiamine; intact coupled brain mitochondria isolated and assayed with defined respiratory substrates. · source_derived_draft · unverified_draft

### thiamine-def-brain-state3-respiration Brain mitochondrial state 3 respiration fell with pyruvate/malate, 2-oxoglutarate or glutamate as substrates; state 4 respiration did not change. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mitochondrial deficit depended on both substrate and respiratory state. organism: Rattus norvegicus tissue_or_cell_type: Isolated brain mitochondria experimental_model: Rats fed a low-thiamine diet with pyrithiamine; intact coupled brain mitochondria isolated and assayed with defined respiratory substrates. limitations: Does not demonstrate that thiamine directly forms part of the respiratory chain or that all electron-transport activity fails. evidence_location: Abstract evidence_span: State 4 respiration did not change exposure: Low-thiamine diet plus pyrithiamine in rats [parker-1984-brain-mitochondria] Brain mitochondrial metabolism in experimental thiamine deficiency (1984). https://pubmed.ncbi.nlm.nih.gov/6493495/ DOI: 10.1212/wnl.34.11.1477

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Results snippet: Effects of TD conditioned media on glutamate transport; Figure 1A

evidence_span

reduced by over 70% after 24 h

experimental_model

Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors.

exposure

Thiamine-free medium plus pyrithiamine in cultured newborn-rat astrocytes

limitations

Conditioned medium is a mixture; this comparison alone cannot identify a secreted mediator or exclude carried-over medium components.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

The culture environment from depleted cells transferred a defect in glutamate removal.

primary_references

[jhala-2014-astrocyte-inflammatory-signaling] Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes. (2014). https://www.sciencedirect.com/science/article/abs/pii/S0006291X14006482 DOI: 10.1016/j.bbrc.2014.04.017

tissue_or_cell_type

Cultured astrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1297–1309

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors. · source_derived_draft · unverified_draft

### thiamine-def-conditioned-medium-uptake Medium from depleted astrocytes reduced glutamate uptake in naive recipient astrocytes by over 70% after 24 hours. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The culture environment from depleted cells transferred a defect in glutamate removal. organism: Rattus norvegicus tissue_or_cell_type: Cultured astrocytes experimental_model: Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors. limitations: Conditioned medium is a mixture; this comparison alone cannot identify a secreted mediator or exclude carried-over medium components. evidence_location: Results snippet: Effects of TD conditioned media on glutamate transport; Figure 1A evidence_span: reduced by over 70% after 24 h exposure: Thiamine-free medium plus pyrithiamine in cultured newborn-rat astrocytes [jhala-2014-astrocyte-inflammatory-signaling] Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes. (2014). https://www.sciencedirect.com/science/article/abs/pii/S0006291X14006482 DOI: 10.1016/j.bbrc.2014.04.017

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract; Results; Figure 1

evidence_span

reduced by 62%

experimental_model

Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology.

exposure

Neuropathologically identified Wernicke encephalopathy with heavy alcohol exposure

limitations

Does not isolate thiamine from alcohol effects, establish the initiating event, or directly measure uptake in living patients.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

An astrocyte glutamate transporter was reduced in the sampled diseased human cortex.

primary_references

[hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

tissue_or_cell_type

Frontal cortex

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1255–1267

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology. · source_derived_draft · unverified_draft

### thiamine-def-human-eaat1-loss Frontal-cortex EAAT1 protein was 62% lower in the five Wernicke cases than in five controls. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An astrocyte glutamate transporter was reduced in the sampled diseased human cortex. organism: Homo sapiens tissue_or_cell_type: Frontal cortex experimental_model: Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology. limitations: Does not isolate thiamine from alcohol effects, establish the initiating event, or directly measure uptake in living patients. evidence_location: Abstract; Results; Figure 1 evidence_span: reduced by 62% exposure: Neuropathologically identified Wernicke encephalopathy with heavy alcohol exposure [hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract; Results; Figure 1

evidence_span

diminished by 71%

experimental_model

Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology.

exposure

Neuropathologically identified Wernicke encephalopathy with heavy alcohol exposure

limitations

Does not isolate thiamine from alcohol effects, establish the initiating event, or directly measure uptake in living patients.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

An astrocyte glutamate transporter was reduced in the sampled diseased human cortex.

primary_references

[hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

tissue_or_cell_type

Frontal cortex

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1269–1281

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology. · source_derived_draft · unverified_draft

### thiamine-def-human-eaat2-loss Frontal-cortex EAAT2 protein was 71% lower in the five Wernicke cases than in five controls. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An astrocyte glutamate transporter was reduced in the sampled diseased human cortex. organism: Homo sapiens tissue_or_cell_type: Frontal cortex experimental_model: Human frontal-cortex autopsy samples: five male Wernicke encephalopathy cases with alcohol intake above 80 g/day versus five male controls below 20 g/day; immunoblotting and histology. limitations: Does not isolate thiamine from alcohol effects, establish the initiating event, or directly measure uptake in living patients. evidence_location: Abstract; Results; Figure 1 evidence_span: diminished by 71% exposure: Neuropathologically identified Wernicke encephalopathy with heavy alcohol exposure [hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Rat Model of TD; Results; Figures 6-7

evidence_span

NAC prevented downregulation of the transporter protein

experimental_model

Male Sprague-Dawley rats; thiamine-deficient diet plus pyrithiamine 0.5 mg/kg/day, with or without N-acetylcysteine 163 mg/kg/day intraperitoneally; day-14 symptomatic stage; pair-fed controls.

exposure

Pyrithiamine-assisted depletion with pharmacological N-acetylcysteine co-treatment

limitations

N-acetylcysteine has multiple actions; this does not prove a specific glutathione mechanism or support a human dosing recommendation.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

An antioxidant intervention preserved a glutamate transporter in this experimental model.

primary_references

[hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

tissue_or_cell_type

Medial thalamus

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1283–1295

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male Sprague-Dawley rats; thiamine-deficient diet plus pyrithiamine 0.5 mg/kg/day, with or without N-acetylcysteine 163 mg/kg/day intraperitoneally; day-14 symptomatic stage; pair-fed controls. · source_derived_draft · unverified_draft

### thiamine-def-nac-preserves-rat-eaat2 N-acetylcysteine co-treatment prevented the loss of EAAT2 protein in medial thalamus of the depleted rats. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An antioxidant intervention preserved a glutamate transporter in this experimental model. organism: Rattus norvegicus tissue_or_cell_type: Medial thalamus experimental_model: Male Sprague-Dawley rats; thiamine-deficient diet plus pyrithiamine 0.5 mg/kg/day, with or without N-acetylcysteine 163 mg/kg/day intraperitoneally; day-14 symptomatic stage; pair-fed controls. limitations: N-acetylcysteine has multiple actions; this does not prove a specific glutathione mechanism or support a human dosing recommendation. evidence_location: Rat Model of TD; Results; Figures 6-7 evidence_span: NAC prevented downregulation of the transporter protein exposure: Pyrithiamine-assisted depletion with pharmacological N-acetylcysteine co-treatment [hazell-2010-human-astrocytes] Loss of astrocytic glutamate transporters in Wernicke encephalopathy (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC3388119/ DOI: 10.1002/glia.20908

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract; NF-kappa-B inhibitor experiment

evidence_span

ameliorated the decrease in GLT-1b

experimental_model

Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors.

exposure

Thiamine-free medium plus pyrithiamine in cultured newborn-rat astrocytes

limitations

Pharmacological inhibition is not isoform-specific genetic proof; the accessible record does not establish efficacy in intact human brain.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

Suppressing the inflammatory pathway helped preserve this particular glutamate-transporter isoform.

primary_references

[jhala-2014-astrocyte-inflammatory-signaling] Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes. (2014). https://www.sciencedirect.com/science/article/abs/pii/S0006291X14006482 DOI: 10.1016/j.bbrc.2014.04.017

tissue_or_cell_type

Cultured astrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1325–1337

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors. · source_derived_draft · unverified_draft

### thiamine-def-nfkb-inhibition-glt1b NF-kappa-B inhibition attenuated GLT-1b loss in astrocytes exposed to the thiamine-disruption protocol. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Suppressing the inflammatory pathway helped preserve this particular glutamate-transporter isoform. organism: Rattus norvegicus tissue_or_cell_type: Cultured astrocytes experimental_model: Newborn-rat astrocytes differentiated with dibutyryl cAMP; thiamine-free DMEM with 5% horse serum plus 10 micromolar pyrithiamine; conditioned-medium transfer and inflammatory-pathway inhibitors. limitations: Pharmacological inhibition is not isoform-specific genetic proof; the accessible record does not establish efficacy in intact human brain. evidence_location: Abstract; NF-kappa-B inhibitor experiment evidence_span: ameliorated the decrease in GLT-1b exposure: Thiamine-free medium plus pyrithiamine in cultured newborn-rat astrocytes [jhala-2014-astrocyte-inflammatory-signaling] Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes. (2014). https://www.sciencedirect.com/science/article/abs/pii/S0006291X14006482 DOI: 10.1016/j.bbrc.2014.04.017

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Abstract

evidence_span

precedes the appearance of histological lesions

experimental_model

Awake freely moving rats with pyrithiamine-induced deficiency; microdialysis of ventral posterior medial thalamus and contralateral frontoparietal cortex, compared with pair-fed controls.

exposure

Pyrithiamine-induced deficiency within six hours of loss of righting reflexes

limitations

Microdialysis alone cannot assign increased release versus impaired uptake or prove NMDA-mediated cell death. Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

Glutamate accumulated outside cells in a vulnerable region before visible tissue lesions.

primary_references

[hazell-1993-extracellular-glutamate] Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency (1993). https://pubmed.ncbi.nlm.nih.gov/8103080/ DOI: 10.1111/j.1471-4159.1993.tb03635.x

tissue_or_cell_type

Ventral posterior medial thalamus versus frontoparietal cortex

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1141–1153

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Awake freely moving rats with pyrithiamine-induced deficiency; microdialysis of ventral posterior medial thalamus and contralateral frontoparietal cortex, compared with pair-fed controls. · source_derived_draft · unverified_draft

### thiamine-def-thalamic-extracellular-glutamate Acute symptomatic rats had thalamic dialysate glutamate of 3.37 versus 0.93 micromolar in controls, with no corresponding cortical increase. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutamate accumulated outside cells in a vulnerable region before visible tissue lesions. organism: Rattus norvegicus tissue_or_cell_type: Ventral posterior medial thalamus versus frontoparietal cortex experimental_model: Awake freely moving rats with pyrithiamine-induced deficiency; microdialysis of ventral posterior medial thalamus and contralateral frontoparietal cortex, compared with pair-fed controls. limitations: Microdialysis alone cannot assign increased release versus impaired uptake or prove NMDA-mediated cell death. Combined thiamine withdrawal and pyrithiamine exposure; not an estimate for mild dietary insufficiency or a human blood threshold. evidence_location: Abstract evidence_span: precedes the appearance of histological lesions exposure: Pyrithiamine-induced deficiency within six hours of loss of righting reflexes [hazell-1993-extracellular-glutamate] Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency (1993). https://pubmed.ncbi.nlm.nih.gov/8103080/ DOI: 10.1111/j.1471-4159.1993.tb03635.x

availability_state

nutrient_deficiency Imported condition classification; unverified.

endpoint

Diet-induced hypokalemia decreased glutamine synthetase expression throughout the mouse proximal tubule.

experimental-exposure

Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays.

experimental_model

Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays.

limitations

Expression and localization were measured; the quantitative contribution of GLUL to total flux was not isolated.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

Less ammonia-recycling enzyme was present in this compartment, potentially leaving more ammonia available for excretion.

primary_references

[verlander-2013-gs] Expression of glutamine synthetase in the mouse kidney: localization in multiple epithelial cell types and differential regulation by hypokalemia (2013). https://pubmed.ncbi.nlm.nih.gov/23804452/ DOI: 10.1152/ajprenal.00030.2013

tissue_or_cell_type

renal proximal tubule

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1028–1039

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays. · source_derived_draft · unverified_draft

### k-depletion-proximal-glul Diet-induced hypokalemia decreased glutamine synthetase expression throughout the mouse proximal tubule. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Less ammonia-recycling enzyme was present in this compartment, potentially leaving more ammonia available for excretion. organism: Mus musculus tissue_or_cell_type: renal proximal tubule experimental_model: Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays. limitations: Expression and localization were measured; the quantitative contribution of GLUL to total flux was not isolated. experimental-exposure: Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays. endpoint: Diet-induced hypokalemia decreased glutamine synthetase expression throughout the mouse proximal tubule. [verlander-2013-gs] Expression of glutamine synthetase in the mouse kidney: localization in multiple epithelial cell types and differential regulation by hypokalemia (2013). https://pubmed.ncbi.nlm.nih.gov/23804452/ DOI: 10.1152/ajprenal.00030.2013

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium deprivation changes glutamine nitrogen metabolism and sodium-coupled glutamine transport; these experiments did not manipulate dietary protein adequacy.

endpoint

Potassium deprivation increased renal phosphate-dependent glutaminase expression in the studied rats.

experimental-exposure

Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments.

experimental_model

Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments.

limitations

Dietary deprivation precedes detectable hypokalemia here; protein expression does not independently establish transport flux or quantify net bicarbonate generation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

The first glutamine-deaminating enzyme increased; glutamate and ammonium are separate products in this pathway.

primary_references

[hossain-2011-k-ammoniagenesis] Cellular and molecular basis of increased ammoniagenesis in potassium deprivation (2011). https://journals.physiology.org/doi/full/10.1152/ajprenal.00010.2011 DOI: 10.1152/ajprenal.00010.2011

tissue_or_cell_type

renal proximal tubule and whole-kidney excretion

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 986–998

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. · source_derived_draft · unverified_draft

### k-deprivation-gls Potassium deprivation increased renal phosphate-dependent glutaminase expression in the studied rats. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The first glutamine-deaminating enzyme increased; glutamate and ammonium are separate products in this pathway. organism: Rattus norvegicus tissue_or_cell_type: renal proximal tubule and whole-kidney excretion experimental_model: Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. limitations: Dietary deprivation precedes detectable hypokalemia here; protein expression does not independently establish transport flux or quantify net bicarbonate generation. cross_nutrient: Potassium deprivation changes glutamine nitrogen metabolism and sodium-coupled glutamine transport; these experiments did not manipulate dietary protein adequacy. experimental-exposure: Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. endpoint: Potassium deprivation increased renal phosphate-dependent glutaminase expression in the studied rats. [hossain-2011-k-ammoniagenesis] Cellular and molecular basis of increased ammoniagenesis in potassium deprivation (2011). https://journals.physiology.org/doi/full/10.1152/ajprenal.00010.2011 DOI: 10.1152/ajprenal.00010.2011

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium deprivation changes glutamine nitrogen metabolism and sodium-coupled glutamine transport; these experiments did not manipulate dietary protein adequacy.

endpoint

Potassium deprivation increased renal glutamate dehydrogenase expression in the studied rats.

experimental-exposure

Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments.

experimental_model

Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments.

limitations

Dietary deprivation precedes detectable hypokalemia here; protein expression does not independently establish transport flux or quantify net bicarbonate generation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

A second ammonia-producing enzyme increased; this connects glutamate nitrogen to ammonium and its carbon skeleton to 2-oxoglutarate.

primary_references

[hossain-2011-k-ammoniagenesis] Cellular and molecular basis of increased ammoniagenesis in potassium deprivation (2011). https://journals.physiology.org/doi/full/10.1152/ajprenal.00010.2011 DOI: 10.1152/ajprenal.00010.2011

tissue_or_cell_type

renal proximal tubule and whole-kidney excretion

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1000–1012

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. · source_derived_draft · unverified_draft

### k-deprivation-glud1 Potassium deprivation increased renal glutamate dehydrogenase expression in the studied rats. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second ammonia-producing enzyme increased; this connects glutamate nitrogen to ammonium and its carbon skeleton to 2-oxoglutarate. organism: Rattus norvegicus tissue_or_cell_type: renal proximal tubule and whole-kidney excretion experimental_model: Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. limitations: Dietary deprivation precedes detectable hypokalemia here; protein expression does not independently establish transport flux or quantify net bicarbonate generation. cross_nutrient: Potassium deprivation changes glutamine nitrogen metabolism and sodium-coupled glutamine transport; these experiments did not manipulate dietary protein adequacy. experimental-exposure: Rats on control or potassium-deficient diets for up to 6 days; NH4Cl co-loading and NRK52E/LLC-PK1 cell experiments. endpoint: Potassium deprivation increased renal glutamate dehydrogenase expression in the studied rats. [hossain-2011-k-ammoniagenesis] Cellular and molecular basis of increased ammoniagenesis in potassium deprivation (2011). https://journals.physiology.org/doi/full/10.1152/ajprenal.00010.2011 DOI: 10.1152/ajprenal.00010.2011

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Rat pharmacological blockade.

limitations

Subunits and an exclusive linear pathway are not established by the accessed abstract.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A serotonin receptor relays part of the gut signal.

primary_references

Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 162–168

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pharmacological blockade. · source_derived_draft · unverified_draft

## monosodium-glutamate-5ht3-gate A serotonin receptor relays part of the gut signal. Blocking 5-HT3 receptors prevented the rat gastric vagal response to luminal glutamate. Model: Rat pharmacological blockade. Limitations: Subunits and an exclusive linear pathway are not established by the accessed abstract. Evidence access: Primary abstract Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

evidence_access

Primary abstract

experimental_model

Fasted capsule challenges with three control days and spirometry.

limitations

Small study; does not establish universal absence of reactions or identify an immune mechanism.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Time-matched baseline variation changed interpretation of a lung-function fall.

primary_references

The effects of monosodium glutamate in adults with asthma who perceive themselves to be monosodium glutamate-intolerant. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9648703/ · DOI 10.1016/s0091-6749(98)70305-7

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 274–280

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fasted capsule challenges with three control days and spirometry. · source_derived_draft · unverified_draft

## monosodium-glutamate-asthma-challenge Time-matched baseline variation changed interpretation of a lung-function fall. A blinded crossover in twelve adults reporting MSG-associated asthma found no definite immediate or late asthmatic reaction to 1 g or 5 g MSG versus lactose placebo. Model: Fasted capsule challenges with three control days and spirometry. Limitations: Small study; does not establish universal absence of reactions or identify an immune mechanism. Evidence access: Primary abstract The effects of monosodium glutamate in adults with asthma who perceive themselves to be monosodium glutamate-intolerant. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9648703/ · DOI 10.1016/s0091-6749(98)70305-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse taste-bud knockout physiology.

limitations

The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A cell can detect a stimulus yet fail to transmit its message.

primary_references

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse taste-bud knockout physiology. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm1-release A cell can detect a stimulus yet fail to transmit its message. Calhm1 knockout reduced taste-evoked ATP release without eliminating taste-cell excitability to the stimuli. Model: Mouse taste-bud knockout physiology. Limitations: The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit. Evidence access: Primary abstract CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906

evidence_access

Primary abstract

experimental_model

Heterologous channel experiments and mouse taste-cell physiology.

limitations

Functional coassembly is recorded without treating the historical proposed stoichiometry as a universal structural assignment.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Two separately stored subunits form the output channel.

primary_references

CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heterologous channel experiments and mouse taste-cell physiology. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm3-channel Two separately stored subunits form the output channel. CALHM3 coassembly with CALHM1 conferred rapid voltage-dependent ATP-release-channel gating; the study connected this complex to type II taste-cell physiology. Model: Heterologous channel experiments and mouse taste-cell physiology. Limitations: Functional coassembly is recorded without treating the historical proposed stoichiometry as a universal structural assignment. Evidence access: Primary abstract CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse knockout experiments.

limitations

Shares investigators with the CALHM1 study; no human deficiency threshold follows.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Intact upstream sensing cannot compensate for a missing release channel.

primary_references

CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout experiments. · source_derived_draft · unverified_draft

## monosodium-glutamate-calhm3-loss Intact upstream sensing cannot compensate for a missing release channel. Calhm3 deletion abolished taste-evoked ATP release and disrupted GPCR-mediated taste perception in mice. Model: Mouse knockout experiments. Limitations: Shares investigators with the CALHM1 study; no human deficiency threshold follows. Evidence access: Primary abstract CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043

evidence_access

Primary abstract

experimental_model

Within-study meal comparisons.

limitations

Not a contradiction caused by different chemical identities.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The positive protein-meal result did not generalize to all liquids.

primary_references

Monosodium L-glutamate added to a high-energy, high-protein liquid diet promotes gastric emptying. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19056566/ · DOI 10.3945/ajcn.2008.26180

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 226–232

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Within-study meal comparisons. · source_derived_draft · unverified_draft

## monosodium-glutamate-carbohydrate-emptying-null The positive protein-meal result did not generalize to all liquids. The same study found no significant MSG effect for carbohydrate-rich liquid or water meals in nine men. Model: Within-study meal comparisons. Limitations: Not a contradiction caused by different chemical identities. Evidence access: Primary abstract Monosodium L-glutamate added to a high-energy, high-protein liquid diet promotes gastric emptying. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19056566/ · DOI 10.3945/ajcn.2008.26180

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human high-dose oral loading, with versus without carbohydrate.

limitations

Small acute study; not a fixed conversion fraction for foods or a brain measurement.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Carbohydrate changed how much glutamate appeared in blood.

primary_references

Effect of carbohydrate on plasma and erythrocyte glutamate levels in humans ingesting large doses of monosodium L-glutamate in water. · 1983 · https://pubmed.ncbi.nlm.nih.gov/6133445/ · DOI 10.1093/ajcn/37.6.961

trigger_kind

biomarker_context Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human high-dose oral loading, with versus without carbohydrate. · source_derived_draft · unverified_draft

## monosodium-glutamate-carbohydrate-exposure Carbohydrate changed how much glutamate appeared in blood. In eight adults receiving 150 mg/kg MSG in water, adding 1.1 g/kg hydrolyzed corn starch lowered mean peak plasma glutamate from 59.4 to 7.18 micromol/dL. Model: Human high-dose oral loading, with versus without carbohydrate. Limitations: Small acute study; not a fixed conversion fraction for foods or a brain measurement. Evidence access: Primary abstract Effect of carbohydrate on plasma and erythrocyte glutamate levels in humans ingesting large doses of monosodium L-glutamate in water. · 1983 · https://pubmed.ncbi.nlm.nih.gov/6133445/ · DOI 10.1093/ajcn/37.6.961

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Transgenic rescue in Plcb2-deficient mice.

limitations

This defines cell-specific routing in the model, not a nutritional intervention.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Putting back machinery in the wrong cell type does not restore every signal.

primary_references

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Transgenic rescue in Plcb2-deficient mice. · source_derived_draft · unverified_draft

## monosodium-glutamate-cell-specific-rescue Putting back machinery in the wrong cell type does not restore every signal. Restoring Plcb2 only in bitter-receptor cells rescued bitter responses but not sweet or amino-acid responses. Model: Transgenic rescue in Plcb2-deficient mice. Limitations: This defines cell-specific routing in the model, not a nutritional intervention. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Rat pharmacological perturbations.

limitations

No human food–drug interaction magnitude was tested.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Mediator synthesis and afferent function constrain the response.

primary_references

Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 210–216

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pharmacological perturbations. · source_derived_draft · unverified_draft

## monosodium-glutamate-duodenal-cox-gate Mediator synthesis and afferent function constrain the response. Indomethacin or capsaicin pretreatment reduced glutamate-associated mucus and pH responses. Model: Rat pharmacological perturbations. Limitations: No human food–drug interaction magnitude was tested. Evidence access: Primary abstract Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

evidence_access

Primary abstract

experimental_model

Rat duodenum pharmacology.

limitations

Not a genetic demonstration of exclusive receptor mediation.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Receptor probes help locate a step.

primary_references

Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat duodenum pharmacology. · source_derived_draft · unverified_draft

## monosodium-glutamate-duodenal-grm4 Receptor probes help locate a step. mGluR4 agonists mimicked and an antagonist inhibited glutamate-associated pH and mucus responses. Model: Rat duodenum pharmacology. Limitations: Not a genetic demonstration of exclusive receptor mediation. Evidence access: Primary abstract Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

evidence_access

Primary abstract

experimental_model

Rat perfusion; IMP 0.1 mM.

limitations

T1R involvement was inferred; not proved by receptor deletion.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The two-compound interaction also reached a gut endpoint.

primary_references

Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 202–208

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat perfusion; IMP 0.1 mM. · source_derived_draft · unverified_draft

## monosodium-glutamate-duodenal-imp The two-compound interaction also reached a gut endpoint. Glutamate plus IMP enhanced bicarbonate secretion in rat duodenum. Model: Rat perfusion; IMP 0.1 mM. Limitations: T1R involvement was inferred; not proved by receptor deletion. Evidence access: Primary abstract Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19643955/ · DOI 10.1152/ajpgi.90605.2008

evidence_access

Primary abstract

experimental_model

Same nine-person acute study.

limitations

No diabetes-treatment efficacy or durable metabolic benefit was tested.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A measured glucose effect does not by itself reveal the enzyme responsible.

primary_references

Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same nine-person acute study. · source_derived_draft · unverified_draft

## monosodium-glutamate-glucose-response A measured glucose effect does not by itself reveal the enzyme responsible. The MSG-plus-carbohydrate condition had lower peak serum glucose than carbohydrate alone, 5.50 versus 7.69 mmol/L. Model: Same nine-person acute study. Limitations: No diabetes-treatment efficacy or durable metabolic benefit was tested. Evidence access: Primary abstract Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

evidence_access

Primary abstract

experimental_model

Same mutagenesis/chimera/model study.

limitations

Do not extrapolate taste synergy to a general systemic metabolic benefit.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

IMP can amplify a glutamate signal through a different receptor contact.

primary_references

Molecular mechanism for the umami taste synergism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19104071/ · DOI 10.1073/pnas.0810174106

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same mutagenesis/chimera/model study. · source_derived_draft · unverified_draft

## monosodium-glutamate-imp-cooperation IMP can amplify a glutamate signal through a different receptor contact. The cooperative model places a 5-prime-ribonucleotide at an adjacent opening-side site, stabilizing the closed glutamate-bound receptor conformation. Model: Same mutagenesis/chimera/model study. Limitations: Do not extrapolate taste synergy to a general systemic metabolic benefit. Evidence access: Primary abstract Molecular mechanism for the umami taste synergism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19104071/ · DOI 10.1073/pnas.0810174106

evidence_access

Primary abstract

experimental_model

Multicenter blinded crossover; positive response required at least two listed symptoms within two hours.

limitations

Self-selected group and acute bolus; molecular cause was not identified.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The initial challenge showed more symptoms after MSG than placebo.

primary_references

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11080723/ · DOI 10.1067/mai.2000.110794

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 258–264

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Multicenter blinded crossover; positive response required at least two listed symptoms within two hours. · source_derived_draft · unverified_draft

## monosodium-glutamate-initial-symptoms The initial challenge showed more symptoms after MSG than placebo. In 130 self-reported MSG-reactive volunteers given 5 g without food, 50 responded to MSG only, 17 to placebo only and 19 to both. Model: Multicenter blinded crossover; positive response required at least two listed symptoms within two hours. Limitations: Self-selected group and acute bolus; molecular cause was not identified. Evidence access: Primary abstract Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11080723/ · DOI 10.1067/mai.2000.110794

evidence_access

Primary abstract

experimental_model

Same nine men; C-peptide interpretation.

limitations

This does not identify responder genotypes or a direct insulin-receptor target.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The average and individual responses tell different parts of the story.

primary_references

Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same nine men; C-peptide interpretation. · source_derived_draft · unverified_draft

## monosodium-glutamate-insulin-heterogeneity The average and individual responses tell different parts of the story. C-peptide-based insulin secretion did not differ on average: four participants increased and five decreased in the MSG-plus-carbohydrate condition. Model: Same nine men; C-peptide interpretation. Limitations: This does not identify responder genotypes or a direct insulin-receptor target. Evidence access: Primary abstract Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

evidence_access

Primary full text; results and disclosures

experimental_model

Same ten-person MRI experiment; subgroup analyses.

limitations

Responder selection and small analyzable subset limit inference. Paper reports umami-research funding and software-company author affiliations.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A selected subgroup can suggest a mechanism without establishing a population effect.

primary_references

Gastric emptying and duodenal motility upon intake of a liquid meal with monosodium glutamate in healthy subjects. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24744869/ · DOI 10.1002/phy2.187

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 242–248

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same ten-person MRI experiment; subgroup analyses. · source_derived_draft · unverified_draft

## monosodium-glutamate-mri-responder-analysis A selected subgroup can suggest a mechanism without establishing a population effect. Eight participants had faster emptying with MSG; two slowed. Duodenal wall-motion analysis in four of the eight showed increased motility. Model: Same ten-person MRI experiment; subgroup analyses. Limitations: Responder selection and small analyzable subset limit inference. Paper reports umami-research funding and software-company author affiliations. Evidence access: Primary full text; results and disclosures Gastric emptying and duodenal motility upon intake of a liquid meal with monosodium glutamate in healthy subjects. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24744869/ · DOI 10.1002/phy2.187

evidence_access

Primary full text; results

experimental_model

200 kcal/200 mL meal; serial MRI.

limitations

Different meal and measurement from the breath-test study.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The whole-cohort test must stay visible.

primary_references

Gastric emptying and duodenal motility upon intake of a liquid meal with monosodium glutamate in healthy subjects. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24744869/ · DOI 10.1002/phy2.187

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 234–240

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 200 kcal/200 mL meal; serial MRI. · source_derived_draft · unverified_draft

## monosodium-glutamate-mri-whole-cohort The whole-cohort test must stay visible. In ten men, 60-minute gastric residual volume did not differ significantly between mixed liquid meals with and without 0.5% MSG, P=0.45. Model: 200 kcal/200 mL meal; serial MRI. Limitations: Different meal and measurement from the breath-test study. Evidence access: Primary full text; results Gastric emptying and duodenal motility upon intake of a liquid meal with monosodium glutamate in healthy subjects. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24744869/ · DOI 10.1002/phy2.187

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Rat mucosal pharmacology.

limitations

Supports pathway ordering; not direct proof of each cell source or a human MSG–arginine interaction.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Nitric oxide and serotonin signaling interact upstream of the nerve response.

primary_references

Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat mucosal pharmacology. · source_derived_draft · unverified_draft

## monosodium-glutamate-nos-gate Nitric oxide and serotonin signaling interact upstream of the nerve response. NOS inhibition blocked glutamate-evoked vagal firing; an NO donor mimicked firing and its response was blocked by 5-HT3 antagonism. Model: Rat mucosal pharmacology. Limitations: Supports pathway ordering; not direct proof of each cell source or a human MSG–arginine interaction. Evidence access: Primary abstract Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

evidence_access

Primary abstract

experimental_model

Human sensory ratings and fMRI.

limitations

BOLD activation is not evidence that ingested glutamate crossed the blood-brain barrier.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Smell changes the perceived flavor through sensory convergence.

primary_references

Umami: a delicious flavor formed by convergence of taste and olfactory pathways in the human brain. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17432971/ · DOI 10.1111/j.1460-9568.2007.05445.x

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 146–152

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human sensory ratings and fMRI. · source_derived_draft · unverified_draft

## monosodium-glutamate-odor-convergence Smell changes the perceived flavor through sensory convergence. Glutamate taste with a consonant savory odor produced supralinear fMRI responses in medial orbitofrontal and pregenual cingulate regions, related to flavor pleasantness. Model: Human sensory ratings and fMRI. Limitations: BOLD activation is not evidence that ingested glutamate crossed the blood-brain barrier. Evidence access: Primary abstract Umami: a delicious flavor formed by convergence of taste and olfactory pathways in the human brain. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17432971/ · DOI 10.1111/j.1460-9568.2007.05445.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse knockout taste behavior and nerve assays.

limitations

Reported assay phenotype; not an MSG deficiency or a universal result at every stimulus concentration.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Recognizing the molecule requires downstream signaling machinery.

primary_references

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout taste behavior and nerve assays. · source_derived_draft · unverified_draft

## monosodium-glutamate-plcb2-loss Recognizing the molecule requires downstream signaling machinery. Plcb2 knockout abolished tested sweet, amino-acid and bitter responses while sparing sour and salty responses in the reported mouse experiments. Model: Mouse knockout taste behavior and nerve assays. Limitations: Reported assay phenotype; not an MSG deficiency or a universal result at every stimulus concentration. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

evidence_access

Primary abstract

experimental_model

13C-acetate breath-test study; 0.5% MSG.

limitations

Indirect emptying estimate; the study does not establish receptor mediation or treatment of gastroparesis.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A local digestive response depends on the accompanying food.

primary_references

Monosodium L-glutamate added to a high-energy, high-protein liquid diet promotes gastric emptying. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19056566/ · DOI 10.3945/ajcn.2008.26180

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 218–224

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 13C-acetate breath-test study; 0.5% MSG. · source_derived_draft · unverified_draft

## monosodium-glutamate-protein-emptying A local digestive response depends on the accompanying food. MSG shortened the estimated half-emptying time of a protein-rich liquid meal in ten healthy men. Model: 13C-acetate breath-test study; 0.5% MSG. Limitations: Indirect emptying estimate; the study does not establish receptor mediation or treatment of gastroparesis. Evidence access: Primary abstract Monosodium L-glutamate added to a high-energy, high-protein liquid diet promotes gastric emptying. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19056566/ · DOI 10.3945/ajcn.2008.26180

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

150 mg/kg MSG with or without hydrolyzed corn starch.

limitations

Other cells and later times were not established by this result.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A plasma change did not imply the same change in red cells.

primary_references

Effect of carbohydrate on plasma and erythrocyte glutamate levels in humans ingesting large doses of monosodium L-glutamate in water. · 1983 · https://pubmed.ncbi.nlm.nih.gov/6133445/ · DOI 10.1093/ajcn/37.6.961

trigger_kind

biomarker_context Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 150 mg/kg MSG with or without hydrolyzed corn starch. · source_derived_draft · unverified_draft

## monosodium-glutamate-red-cell-compartment A plasma change did not imply the same change in red cells. Erythrocyte glutamate and aspartate concentrations did not change in either arm of the eight-person MSG/carbohydrate experiment. Model: 150 mg/kg MSG with or without hydrolyzed corn starch. Limitations: Other cells and later times were not established by this result. Evidence access: Primary abstract Effect of carbohydrate on plasma and erythrocyte glutamate levels in humans ingesting large doses of monosodium L-glutamate in water. · 1983 · https://pubmed.ncbi.nlm.nih.gov/6133445/ · DOI 10.1093/ajcn/37.6.961

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse receptor knockout.

limitations

This result does not identify one exclusive alternative receptor or negate human T1R1/T1R3 activation.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

The main receptor is not necessarily the only detectable route.

primary_references

Detection of sweet and umami taste in the absence of taste receptor T1r3. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12869700/ · DOI 10.1126/science.1087155

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse receptor knockout. · source_derived_draft · unverified_draft

## monosodium-glutamate-residual-umami The main receptor is not necessarily the only detectable route. Tas1r3-null mice retained diminished behavioral and nerve responses to umami compounds. Model: Mouse receptor knockout. Limitations: This result does not identify one exclusive alternative receptor or negate human T1R1/T1R3 activation. Evidence access: Primary abstract Detection of sweet and umami taste in the absence of taste receptor T1r3. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12869700/ · DOI 10.1126/science.1087155

evidence_access

Primary abstract

experimental_model

Sequential retesting in the same study.

limitations

Only two people reached the food protocol, so it is not a large general test of all meals.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

An initial response and a reproducible sensitivity are different findings.

primary_references

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11080723/ · DOI 10.1067/mai.2000.110794

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 266–272

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Sequential retesting in the same study. · source_derived_draft · unverified_draft

## monosodium-glutamate-retest-inconsistency An initial response and a reproducible sensitivity are different findings. Repeated challenges did not establish consistent individual symptom patterns; the two final participants each reacted to only one of three MSG-with-food challenges. Model: Sequential retesting in the same study. Limitations: Only two people reached the food protocol, so it is not a large general test of all meals. Evidence access: Primary abstract Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11080723/ · DOI 10.1067/mai.2000.110794

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Rat gastric nutrient-sensing experiment.

limitations

Does not establish dietary tryptophan depletion from MSG or a human clinical syndrome.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A locally available mediator was required in the tested pathway.

primary_references

Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat gastric nutrient-sensing experiment. · source_derived_draft · unverified_draft

## monosodium-glutamate-serotonin-gate A locally available mediator was required in the tested pathway. Serotonin depletion blocked glutamate-evoked gastric vagal firing in rats. Model: Rat gastric nutrient-sensing experiment. Limitations: Does not establish dietary tryptophan depletion from MSG or a human clinical syndrome. Evidence access: Primary abstract Luminal amino acid sensing in the rat gastric mucosa. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16809638/ · DOI 10.1152/ajpgi.00587.2005

evidence_access

Primary full text

experimental_model

Randomized blinded tasting across nineteen Japanese regions.

limitations

MSG itself adds sodium; net reduction requires NaCl replacement. No long-term sodium intake or blood-pressure effect was measured. Three authors were Ajinomoto employees.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Flavor enhancement may help a lower-salt recipe remain acceptable.

primary_references

Validation of preferred salt concentration in soup based on a randomized blinded experiment in multiple regions in Japan-influence of umami (L-glutamate) on saltiness and palatability of low-salt solutions. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996813/ · DOI 10.1038/s41440-020-0397-1

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 250–256

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized blinded tasting across nineteen Japanese regions. · source_derived_draft · unverified_draft

## monosodium-glutamate-sodium-substitution Flavor enhancement may help a lower-salt recipe remain acceptable. In 584 participants, adding 0.3% MSG improved palatability ratings at tested 0.3%, 0.6% and 0.9% NaCl concentrations. Model: Randomized blinded tasting across nineteen Japanese regions. Limitations: MSG itself adds sodium; net reduction requires NaCl replacement. No long-term sodium intake or blood-pressure effect was measured. Three authors were Ajinomoto employees. Evidence access: Primary full text Validation of preferred salt concentration in soup based on a randomized blinded experiment in multiple regions in Japan-influence of umami (L-glutamate) on saltiness and palatability of low-salt solutions. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31996813/ · DOI 10.1038/s41440-020-0397-1

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Four-condition human acute supplementation experiment.

limitations

A high-dose loading protocol does not describe customary MSG use.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

Timing between amino acid and carbohydrate also matters.

primary_references

Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

trigger_kind

biomarker_context Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four-condition human acute supplementation experiment. · source_derived_draft · unverified_draft

## monosodium-glutamate-staggered-exposure Timing between amino acid and carbohydrate also matters. Nine men received 150 mg/kg MSG capsules 30 minutes before a drink; plasma glutamate rose about tenfold without carbohydrate and sixfold with a 75 g carbohydrate drink. Model: Four-condition human acute supplementation experiment. Limitations: A high-dose loading protocol does not describe customary MSG use. Evidence access: Primary abstract Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23750536/ · DOI 10.1017/S0007114513001633

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Randomized crossover; three women and three men.

limitations

Same research group as the starch study; small acute experiment, not independent mechanistic replication.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

A second carbohydrate changed the response at a different MSG dose.

primary_references

Effect of sucrose ingestion on plasma glutamate concentrations in humans administered monosodium L-glutamate. · 1986 · https://pubmed.ncbi.nlm.nih.gov/2870635/ · DOI 10.1093/ajcn/43.4.510

trigger_kind

biomarker_context Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 42–48

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized crossover; three women and three men. · source_derived_draft · unverified_draft

## monosodium-glutamate-sucrose-exposure A second carbohydrate changed the response at a different MSG dose. In six adults, 0.5 g/kg sucrose with consommé containing 50 mg/kg MSG reduced peak plasma glutamate from 18.1 to 5.48 micromol/dL and reduced exposure area. Model: Randomized crossover; three women and three men. Limitations: Same research group as the starch study; small acute experiment, not independent mechanistic replication. Evidence access: Primary abstract Effect of sucrose ingestion on plasma glutamate concentrations in humans administered monosodium L-glutamate. · 1986 · https://pubmed.ncbi.nlm.nih.gov/2870635/ · DOI 10.1093/ajcn/43.4.510

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse genetic loss-of-function.

limitations

Separate from human TRPM5 and from steviol-glycoside effects in other preparations.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

An ion channel is another gate after receptor recognition.

primary_references

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic loss-of-function. · source_derived_draft · unverified_draft

## monosodium-glutamate-trpm5-loss An ion channel is another gate after receptor recognition. Trpm5 knockout disrupted the same tested taste modalities in the mouse study. Model: Mouse genetic loss-of-function. Limitations: Separate from human TRPM5 and from steviol-glycoside effects in other preparations. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

evidence_access

Primary abstract

experimental_model

In vitro five-step bacterial enzyme system.

limitations

Environmental gene distribution does not quantify human intestinal flux.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

The sulfur and carbon skeleton enter separate products.

primary_references

In Vitro Reconstitution of a Five-Step Pathway for Bacterial Ergothioneine Catabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33544568/ · DOI 10.1021/acschembio.0c00968

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 272–278

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · In vitro five-step bacterial enzyme system. · source_derived_draft · unverified_draft

## ergothioneine-catabolic-products The sulfur and carbon skeleton enter separate products. The reconstituted bacterial pathway converted ergothioneine into glutamate, trimethylamine, hydrogen sulfide, carbon dioxide and ammonia. Model: In vitro five-step bacterial enzyme system. Limitations: Environmental gene distribution does not quantify human intestinal flux. Evidence access: Primary abstract In Vitro Reconstitution of a Five-Step Pathway for Bacterial Ergothioneine Catabolism. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33544568/ · DOI 10.1021/acschembio.0c00968

evidence_access

Primary full text, pathway background citing original reconstitution

experimental_model

Pathway description in the primary EgtE paper, citing the original reconstitution.

limitations

This step is cited background, not a new EgtA experiment in this paper; microbial and human pathways remain separate.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

A separately encoded enzyme prepares the sulfur donor.

primary_references

Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26149121/ · DOI 10.1038/srep11870

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 560–566

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pathway description in the primary EgtE paper, citing the original reconstitution. · source_derived_draft · unverified_draft

## ergothioneine-egta-precursor A separately encoded enzyme prepares the sulfur donor. The described Mycobacterium smegmatis pathway uses EgtA to condense glutamate and cysteine into gamma-glutamylcysteine. Model: Pathway description in the primary EgtE paper, citing the original reconstitution. Limitations: This step is cited background, not a new EgtA experiment in this paper; microbial and human pathways remain separate. Evidence access: Primary full text, pathway background citing original reconstitution Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26149121/ · DOI 10.1038/srep11870

evidence_access

Primary abstract

experimental_model

Purified full-length and truncated human enzyme expressed in E. coli.

limitations

A reversible enzyme assay is not a measurement of net in vivo flux.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

Tyrosine breakdown begins by moving its amino group.

primary_references

The narrow substrate specificity of human tyrosine aminotransferase--the enzyme deficient in tyrosinemia type II. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16640556/ · DOI 10.1111/j.1742-4658.2006.05202.x

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 204–210

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified full-length and truncated human enzyme expressed in E. coli. · source_derived_draft · unverified_draft

## l-tyrosine-tat-carbon Tyrosine breakdown begins by moving its amino group. Recombinant human TAT catalyzed reversible tyrosine transamination, with the highest activity for the tyrosine/2-oxoglutarate substrate pair. Model: Purified full-length and truncated human enzyme expressed in E. coli. Limitations: A reversible enzyme assay is not a measurement of net in vivo flux. Evidence access: Primary abstract The narrow substrate specificity of human tyrosine aminotransferase--the enzyme deficient in tyrosinemia type II. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16640556/ · DOI 10.1111/j.1742-4658.2006.05202.x

evidence_access

Primary full text

experimental_model

Recombinant human PSAT kinetics and substrate-bound crystal structures.

limitations

This is an enzyme reaction, not evidence that dietary glutamate or B6 is limiting in a particular person.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Glutamate supplies nitrogen while active B6 enables the transfer.

primary_references

L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 30–36

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human PSAT kinetics and substrate-bound crystal structures. · source_derived_draft · unverified_draft

## l-serine-psat-nitrogen Glutamate supplies nitrogen while active B6 enables the transfer. Human PSAT1 transfers nitrogen from glutamate to phosphohydroxypyruvate, producing O-phosphoserine and 2-oxoglutarate in a reversible PLP-dependent reaction. Model: Recombinant human PSAT kinetics and substrate-bound crystal structures. Limitations: This is an enzyme reaction, not evidence that dietary glutamate or B6 is limiting in a particular person. Evidence access: Primary full text L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

evidence_access

Primary full text

experimental_model

Purified human PSAT spectroscopy, substrate addition and crystallography.

limitations

PLP is recycled in catalysis; the experiment does not show one dietary B6 molecule is consumed for each serine made.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

The B6 cofactor cycles between forms as it carries amino-group chemistry.

primary_references

L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 38–44

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human PSAT spectroscopy, substrate addition and crystallography. · source_derived_draft · unverified_draft

## l-serine-psat-plp The B6 cofactor cycles between forms as it carries amino-group chemistry. Human PSAT contained a PLP internal aldimine associated with Lys200; glutamate converted the cofactor toward its pyridoxamine-phosphate state during the first half-reaction. Model: Purified human PSAT spectroscopy, substrate addition and crystallography. Limitations: PLP is recycled in catalysis; the experiment does not show one dietary B6 molecule is consumed for each serine made. Evidence access: Primary full text L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36851825/ · DOI 10.1002/pro.4609

evidence_access

Primary full text

experimental_model

Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment.

limitations

Atom tracing does not show that dietary glutamine or proline is the limiting substrate in a person. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Collagen-building cells can make their own proline from glutamine.

primary_references

Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 246–252

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment. · source_derived_draft · unverified_draft

## l-proline-collagen-carbon Collagen-building cells can make their own proline from glutamine. Carbon-13 glutamine tracing in human mammary cancer-associated fibroblasts demonstrated incorporation of newly synthesized proline into COL1A1 peptides. Model: Human fibroblast cultures; 2 mM labeled glutamine for 72 hours in the collagen-peptide experiment. Limitations: Atom tracing does not show that dietary glutamine or proline is the limiting substrate in a person. Correction record: Author correction PMID 35927357 / DOI 10.1038/s42255-022-00632-7 corrects the author surname Riero-Domingo to Riera-Domingo. It does not report a change to the experimental results. https://www.nature.com/articles/s42255-022-00632-7 Evidence access: Primary full text Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35760868/ · DOI 10.1038/s42255-022-00582-0

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cell deletion, isotope tracing and rescue experiments.

limitations

The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Proline production needs reducing power in the right compartment.

primary_references

Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 62–68

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell deletion, isotope tracing and rescue experiments. · source_derived_draft · unverified_draft

## l-proline-nadk2-proline Proline production needs reducing power in the right compartment. NADK2 deletion reduced glutamine-derived proline synthesis; mitochondrial NADP(H) was needed for the P5CS step reducing glutamate toward P5C. Model: Human cell deletion, isotope tracing and rescue experiments. Limitations: The limiting step was cofactor-dependent synthesis, not a demonstrated lack of glutamine in the diet. Evidence access: Primary full text Mitochondrial NADP(H) generation is essential for proline biosynthesis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33888598/ · DOI 10.1126/science.abd5491

evidence_access

Primary full text

experimental_model

Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline.

limitations

The ornithine experiment used conditions the authors regarded as likely nonphysiological; no universal exclusive routing rule is inferred.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Two precursor routes can feed the same product through differently placed enzymes.

primary_references

Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 38–44

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline. · source_derived_draft · unverified_draft

## l-proline-precursor-routing Two precursor routes can feed the same product through differently placed enzymes. Isotope tracing with gene silencing linked glutamine/glutamate-derived proline mainly to PYCR1/PYCR2 and ornithine-derived proline mainly to PYCRL in human melanoma cells. Model: Lu1205 cells; 1 mM labeled precursors for eight hours; ornithine labeling required omission of extracellular proline. Limitations: The ornithine experiment used conditions the authors regarded as likely nonphysiological; no universal exclusive routing rule is inferred. Evidence access: Primary full text Functional specialization in proline biosynthesis of melanoma. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23024808/ · DOI 10.1371/journal.pone.0045190

evidence_access

Primary abstract

experimental_model

Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements.

limitations

Culture preferences do not establish a universal human dietary proline requirement or AMD treatment.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

The eye support layer can turn proline into fuel intermediates for its neighbors.

primary_references

Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28615447/ · DOI 10.1074/jbc.M117.788422

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 302–308

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements. · source_derived_draft · unverified_draft

## l-proline-rpe-carbon The eye support layer can turn proline into fuel intermediates for its neighbors. Cultured human fetal RPE consumed proline preferentially among the measured nutrients and used its carbon in the TCA cycle and reductive citrate synthesis, with preferential apical citrate export. Model: Polarized human fetal RPE culture, carbon-13 tracing and metabolite measurements. Limitations: Culture preferences do not establish a universal human dietary proline requirement or AMD treatment. Evidence access: Primary abstract Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28615447/ · DOI 10.1074/jbc.M117.788422

evidence_access

Primary final published full text, replacing the earlier preprint

experimental_model

Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours.

limitations

Atom transfer involves multiple enzymes; this is not thirteen direct proline-conversion reactions.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Proline supplies nitrogen as well as carbon to the retinal support system.

primary_references

Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 326–332

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours. · source_derived_draft · unverified_draft

## l-proline-rpe-nitrogen Proline supplies nitrogen as well as carbon to the retinal support system. Human RPE used nitrogen from labeled proline to synthesize and export thirteen amino acids, including glutamate, aspartate, glutamine, alanine and serine. Model: Human RPE matured for 20 weeks; 1 mM nitrogen-15 proline, sampling at 24 and 48 hours. Limitations: Atom transfer involves multiple enzymes; this is not thirteen direct proline-conversion reactions. Evidence access: Primary final published full text, replacing the earlier preprint Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary final published full text

experimental_model

Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing.

limitations

Mouse compartmental transfer is not proof that oral proline prevents human retinal degeneration.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

The retina depends on processing in a neighboring support tissue.

primary_references

Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 334–340

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing. · source_derived_draft · unverified_draft

## l-proline-rpe-retina-nitrogen The retina depends on processing in a neighboring support tissue. Prodh loss blocked proline nitrogen utilization by mouse RPE and diminished delivery of proline-derived amino-acid nitrogen to the retina. Model: Mouse Prodh mutant tissue and isotope-transfer experiments, supported by coculture and in-vivo tracing. Limitations: Mouse compartmental transfer is not proof that oral proline prevents human retinal degeneration. Evidence access: Primary final published full text Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37741457/ · DOI 10.1016/j.jbc.2023.105275

evidence_access

Primary abstract

experimental_model

TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study.

limitations

No dietary dose or general antifibrotic benefit is inferred.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

Activated matrix-producing cells can use proline synthesis to handle metabolic demand.

primary_references

Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 366–372

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. · source_derived_draft · unverified_draft

## l-proline-tgfb-proline Activated matrix-producing cells can use proline synthesis to handle metabolic demand. TGF-beta induced glutamine-derived proline synthesis in a Smad4-dependent fibroblast program; manipulations of mitochondrial redox potential or ATP production changed that synthesis. Model: TGF-beta-stimulated fibroblast experiments; primary abstract, with mouse NIH3T3 model identified in the primary study. Limitations: No dietary dose or general antifibrotic benefit is inferred. Evidence access: Primary abstract Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32134147/ · DOI 10.15252/embj.2019103334

evidence_access

Primary full text

experimental_model

Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar.

limitations

Not a dietary deficiency experiment or evidence of systemic metal removal.

nutrient_topic

Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin

plain_language

Protection depended on the way oxidative stress was induced.

primary_references

Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 152–158

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar. · source_derived_draft · unverified_draft

## fisetin-metal-gsh-protection Protection depended on the way oxidative stress was induced. At 5 micromolar, fisetin limited iron- or copper-potentiated glutathione loss and cell death in glutamate-challenged mouse HT22 cells. Model: Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar. Limitations: Not a dietary deficiency experiment or evidence of systemic metal removal. Evidence access: Primary full text Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113

evidence_access

Primary abstract

experimental_model

Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions.

limitations

Millimolar experimental kinetics are not physiological brain concentrations.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A receptor channel can also provide an entry route.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 446–452

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions. · source_derived_draft · unverified_draft

## spermidine-nmda-entry A receptor channel can also provide an entry route. Spermidine permeated activated GluN1/GluN2A and GluN1/GluN2B channels; reported Km values were 2.2 and 2.7 mM. Model: Receptors expressed in Xenopus oocytes and HEK293 cells; isotonic extracellular solutions. Limitations: Millimolar experimental kinetics are not physiological brain concentrations. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_access

Primary abstract

experimental_model

Heterologous receptor transport assays.

limitations

Requirement is for receptor activation, not evidence for an oral supplement combination.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Other amino acids gate this entry route.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 454–460

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heterologous receptor transport assays. · source_derived_draft · unverified_draft

## spermidine-nmda-ligands Other amino acids gate this entry route. Spermidine uptake through the tested NMDA receptors required glycine and glutamate. Model: Heterologous receptor transport assays. Limitations: Requirement is for receptor activation, not evidence for an oral supplement combination. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_span

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experimental_model

Radiotracer uptake in synaptosomes and cultured neural cells

exposure

Theanine 0.1-10 millimolar in uptake assays; sustained 10 millimolar for glutamate release

limitations

High cell concentrations; 10 mM is far above the approximately 25 micromolar plasma peak in the separate human 100 mg study. Different cells from the system L screen; no claim all routes are sodium-dependent.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Rat neurons and astroglia

plain_language

A high-concentration cell result is preserved without presenting it as a proven effect of an ordinary oral dose.

primary_references

[theanine-p18293419] Theanine, an ingredient of green tea, inhibits [3H]glutamine transport in neurons and astroglia in rat brain. (2008). https://pubmed.ncbi.nlm.nih.gov/18293419/ DOI: 10.1002/jnr.21637

tissue_or_cell_type

Glutamine transport and extracellular glutamate

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 263–274

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiotracer uptake in synaptosomes and cultured neural cells · source_derived_draft · unverified_draft

### theanine-glutamate-release Sustained 10 mM theanine lowered extracellular glutamate released from cultured neurons. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A high-concentration cell result is preserved without presenting it as a proven effect of an ordinary oral dose. organism: Rat neurons and astroglia tissue_or_cell_type: Glutamine transport and extracellular glutamate experimental_model: Radiotracer uptake in synaptosomes and cultured neural cells limitations: High cell concentrations; 10 mM is far above the approximately 25 micromolar plasma peak in the separate human 100 mg study. Different cells from the system L screen; no claim all routes are sodium-dependent. exposure: Theanine 0.1-10 millimolar in uptake assays; sustained 10 millimolar for glutamate release evidence_span: {"source_cache": "artifacts/theanine-research/18293419.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c94471071feadec8a04eafa7e9d53999dd9756b7f1d5dc1f351152b9b5f4b5d3", "start_char": 0, "end_char": 1751, "text_sha256": "c94471071feadec8a04eafa7e9d53999dd9756b7f1d5dc1f351152b9b5f4b5d3"} [theanine-p18293419] Theanine, an ingredient of green tea, inhibits [3H]glutamine transport in neurons and astroglia in rat brain. (2008). https://pubmed.ncbi.nlm.nih.gov/18293419/ DOI: 10.1002/jnr.21637

evidence_span

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experimental_model

Randomized crossover absorption and metabolite study

exposure

100 mg theanine as capsule or green tea; subset 50 and 200 mg

limitations

Small acute study; plasma concentration does not identify brain concentration or clinical response. Tea preparation was specific to this experiment.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Twelve healthy humans; dose-ranging subset of three

plain_language

Its breakdown products have identities separate from the ingested molecule.

primary_references

[theanine-p23096008] Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea. (2012). https://pubmed.ncbi.nlm.nih.gov/23096008/ DOI: 10.3945/jn.112.166371

tissue_or_cell_type

Plasma, erythrocytes and urine

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 133–144

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover absorption and metabolite study · source_derived_draft · unverified_draft

### theanine-human-glutamate Plasma glutamate increased after theanine ingestion, consistent with hydrolysis of the parent compound. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Its breakdown products have identities separate from the ingested molecule. organism: Twelve healthy humans; dose-ranging subset of three tissue_or_cell_type: Plasma, erythrocytes and urine experimental_model: Randomized crossover absorption and metabolite study limitations: Small acute study; plasma concentration does not identify brain concentration or clinical response. Tea preparation was specific to this experiment. exposure: 100 mg theanine as capsule or green tea; subset 50 and 200 mg evidence_span: {"source_cache": "artifacts/theanine-research/23096008.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0080959c2621f814538b812413bd295d2fdab96bc401c2ed1876fc2e1044406a", "start_char": 0, "end_char": 1696, "text_sha256": "0080959c2621f814538b812413bd295d2fdab96bc401c2ed1876fc2e1044406a"} [theanine-p23096008] Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea. (2012). https://pubmed.ncbi.nlm.nih.gov/23096008/ DOI: 10.3945/jn.112.166371

evidence_span

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experimental_model

Renal enzyme purification and substrate-specificity assays

exposure

Theanine and glutamine substrates; phosphate-dependent versus independent preparations

limitations

Assay-defined enzyme identity is not assigned to human GLS or GLS2. Rat tissue distribution does not prove the human kidney is the exclusive metabolic site.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Wistar rat tissue and purified enzyme preparations

plain_language

One renal enzyme preparation broke down theanine; it must not be confused with every glutaminase.

primary_references

[theanine-p12595072] Theanine, gamma-glutamylethylamide, is metabolized by renal phosphate-independent glutaminase. (2003). https://pubmed.ncbi.nlm.nih.gov/12595072/ DOI: 10.1016/s0304-4165(02)00504-4

tissue_or_cell_type

Kidney hydrolysis and gamma-glutamyl transfer

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 146–157

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Renal enzyme purification and substrate-specificity assays · source_derived_draft · unverified_draft

### theanine-renal-enzyme Theanine-degrading activity copurified with rat renal phosphate-independent glutaminase activity. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: One renal enzyme preparation broke down theanine; it must not be confused with every glutaminase. organism: Wistar rat tissue and purified enzyme preparations tissue_or_cell_type: Kidney hydrolysis and gamma-glutamyl transfer experimental_model: Renal enzyme purification and substrate-specificity assays limitations: Assay-defined enzyme identity is not assigned to human GLS or GLS2. Rat tissue distribution does not prove the human kidney is the exclusive metabolic site. exposure: Theanine and glutamine substrates; phosphate-dependent versus independent preparations evidence_span: {"source_cache": "artifacts/theanine-research/12595072.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8a9ae8e6ba86ea3e06440e972c30ca28685032dc3b9cd74c2d98311715c2435e", "start_char": 0, "end_char": 1324, "text_sha256": "8a9ae8e6ba86ea3e06440e972c30ca28685032dc3b9cd74c2d98311715c2435e"} [theanine-p12595072] Theanine, gamma-glutamylethylamide, is metabolized by renal phosphate-independent glutaminase. (2003). https://pubmed.ncbi.nlm.nih.gov/12595072/ DOI: 10.1016/s0304-4165(02)00504-4

evidence_span

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experimental_model

Fixed-sequence two-period oral glucose tolerance study

exposure

300 mg theanine 15 minutes before OGTT; untreated visit always first

limitations

Not a randomized treatment order. Primary glucose endpoint was negative; urinary glucose and sodium trends were not statistically significant.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

39 healthy humans

plain_language

A urinary change does not by itself establish nutritional deficiency or tissue depletion.

primary_references

[theanine-p41845544] Clinical assessment of blood glucose responses to 300-mg dose of L-theanine, an amino acid unique to green tea, in a fixed-sequence, two-period trial. (2026). https://pubmed.ncbi.nlm.nih.gov/41845544/ DOI: 10.1186/s40780-026-00562-6

tissue_or_cell_type

Blood glucose and urinary solutes

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 1251–1262

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fixed-sequence two-period oral glucose tolerance study · source_derived_draft · unverified_draft

### theanine-urinary-amino-acids Urinary glutamate, aspartate and several other amino acids increased during the theanine visit. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A urinary change does not by itself establish nutritional deficiency or tissue depletion. organism: 39 healthy humans tissue_or_cell_type: Blood glucose and urinary solutes experimental_model: Fixed-sequence two-period oral glucose tolerance study limitations: Not a randomized treatment order. Primary glucose endpoint was negative; urinary glucose and sodium trends were not statistically significant. exposure: 300 mg theanine 15 minutes before OGTT; untreated visit always first evidence_span: {"source_cache": "artifacts/theanine-research/41845544.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c52235640bebf5a00b45b96dd1af1bf1c6cc102cef6a1707711314f870b08e34", "start_char": 0, "end_char": 1980, "text_sha256": "c52235640bebf5a00b45b96dd1af1bf1c6cc102cef6a1707711314f870b08e34"} [theanine-p41845544] Clinical assessment of blood glucose responses to 300-mg dose of L-theanine, an amino acid unique to green tea, in a fixed-sequence, two-period trial. (2026). https://pubmed.ncbi.nlm.nih.gov/41845544/ DOI: 10.1186/s40780-026-00562-6

evidence_access

Primary full text

experimental_model

Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.

limitations

The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

Folate accepts a group from a histidine-derived intermediate.

primary_references

Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft

## histidine-ftcd-transfer Folate accepts a group from a histidine-derived intermediate. The formiminotransferase domain of FTCD transfers the formimino group from FIGLU to THF, producing 5-formimino-THF and glutamate. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

evidence_access

Primary full text

experimental_model

Mouse regional microdialysis.

limitations

Different regions and routes remain explicit; not a claim of globally elevated brain glutamate.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

The response depends on which brain region is measured.

primary_references

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 224–230

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse regional microdialysis. · source_derived_draft · unverified_draft

## d-aspartate-brain-glutamate The response depends on which brain region is measured. One-month 20 mM oral D-aspartate increased extracellular prefrontal glutamate; acute 500 mg/kg injection did not increase striatal glutamate. Model: Mouse regional microdialysis. Limitations: Different regions and routes remain explicit; not a claim of globally elevated brain glutamate. Evidence access: Primary full text Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Constitutive Ddo-knockout mice studied across age.

limitations

Genetic lifelong exposure is not equivalent to a short human supplement course.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Long-term loss of clearance had adverse outcomes despite some short-term signaling effects.

primary_references

d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25771393/ · DOI 10.1016/j.neurobiolaging.2015.02.003

trigger_kind

machinery_impairment Imported condition classification; unverified.

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 248–254

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Constitutive Ddo-knockout mice studied across age. · source_derived_draft · unverified_draft

## d-aspartate-chronic-loss-aging Long-term loss of clearance had adverse outcomes despite some short-term signaling effects. Persistent D-aspartate elevation after Ddo deletion accompanied increased extracellular glutamate, active caspases, reactive glia and age-dependent brain abnormalities. Model: Constitutive Ddo-knockout mice studied across age. Limitations: Genetic lifelong exposure is not equivalent to a short human supplement course. Evidence access: Primary abstract d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25771393/ · DOI 10.1016/j.neurobiolaging.2015.02.003

evidence_access

Primary abstract

experimental_model

Mouse substantia nigra pars compacta slice electrophysiology.

limitations

Antagonist-sensitive responses do not by themselves prove direct agonism at every receptor; indirect glutamate release can contribute.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Several receptor pathways contribute to the observed electrical response.

primary_references

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26707656/ · DOI 10.1016/j.neuropharm.2015.12.013

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 192–198

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse substantia nigra pars compacta slice electrophysiology. · source_derived_draft · unverified_draft

## d-aspartate-nigral-excitation Several receptor pathways contribute to the observed electrical response. D-aspartate excited mouse nigral dopamine neurons with NMDA, AMPA and metabotropic receptor-sensitive components. Model: Mouse substantia nigra pars compacta slice electrophysiology. Limitations: Antagonist-sensitive responses do not by themselves prove direct agonism at every receptor; indirect glutamate release can contribute. Evidence access: Primary abstract Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26707656/ · DOI 10.1016/j.neuropharm.2015.12.013

evidence_access

Primary full text

experimental_model

Mouse microdialysis 24 hours after the final injection.

limitations

Knockouts already differ at baseline. This does not prove the pathway mediates clinical antipsychotic efficacy.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Removing the enzyme removed this drug-associated increment in the mouse experiment.

primary_references

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 280–286

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse microdialysis 24 hours after the final injection. · source_derived_draft · unverified_draft

## d-aspartate-olanzapine-mouse-dependence Removing the enzyme removed this drug-associated increment in the mouse experiment. Four weeks of olanzapine at 5 mg/kg/day intraperitoneally increased prefrontal extracellular D-aspartate and glutamate in wild-type mice; the increments were absent in Ddo-knockout mice. Model: Mouse microdialysis 24 hours after the final injection. Limitations: Knockouts already differ at baseline. This does not prove the pathway mediates clinical antipsychotic efficacy. Evidence access: Primary full text Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

evidence_access

Primary full text

experimental_model

Rat pinealocytes and slices; electrogenic current assays.

limitations

Subtype assignment is pharmacological and supported by prior expression work, not a subtype-knockout demonstration.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Transporting the amino acid can itself change the cell voltage.

primary_references

Glutamate transporter-mediated glutamate secretion in the mammalian pineal gland. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18945893/ · DOI 10.1523/JNEUROSCI.0894-08.2008

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 152–158

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pinealocytes and slices; electrogenic current assays. · source_derived_draft · unverified_draft

## d-aspartate-pineal-current Transporting the amino acid can itself change the cell voltage. D-aspartate elicited inward transporter-associated current in isolated rat pinealocytes; pharmacology favored GLT-1-type transport over ionotropic glutamate receptors. Model: Rat pinealocytes and slices; electrogenic current assays. Limitations: Subtype assignment is pharmacological and supported by prior expression work, not a subtype-knockout demonstration. Evidence access: Primary full text Glutamate transporter-mediated glutamate secretion in the mammalian pineal gland. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18945893/ · DOI 10.1523/JNEUROSCI.0894-08.2008

evidence_access

Primary abstract

experimental_model

Rat pineal gland/pinealocyte incubation.

limitations

Not a human sleep trial or a demonstrated interaction with a melatonin supplement.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

The compound can reduce stimulated melatonin production in this tissue model.

primary_references

D-aspartate modulates melatonin synthesis in rat pinealocytes. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9682837/ · DOI 10.1016/s0304-3940(98)00414-5

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 176–182

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pineal gland/pinealocyte incubation. · source_derived_draft · unverified_draft

## d-aspartate-pineal-melatonin The compound can reduce stimulated melatonin production in this tissue model. D-aspartate inhibited norepinephrine-stimulated melatonin production in rat pineal preparations, with approximately 75 micromolar required for half-maximal inhibition. Model: Rat pineal gland/pinealocyte incubation. Limitations: Not a human sleep trial or a demonstrated interaction with a melatonin supplement. Evidence access: Primary abstract D-aspartate modulates melatonin synthesis in rat pinealocytes. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9682837/ · DOI 10.1016/s0304-3940(98)00414-5

evidence_access

Primary full text; supplementary result described in main text

experimental_model

Rat pinealocytes; HPLC and calcium/exocytosis experiments; D-form comparison reported in supplemental results.

limitations

Main figures often use L-aspartate. Direct D-aspartate binding to inhibitory metabotropic receptors was not established.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

An aspartate signal can release another signaling amino acid.

primary_references

Glutamate transporter-mediated glutamate secretion in the mammalian pineal gland. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18945893/ · DOI 10.1523/JNEUROSCI.0894-08.2008

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 168–174

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat pinealocytes; HPLC and calcium/exocytosis experiments; D-form comparison reported in supplemental results. · source_derived_draft · unverified_draft

## d-aspartate-pineal-release An aspartate signal can release another signaling amino acid. The study reported D-aspartate-evoked glutamate secretion with blocker sensitivity similar to L-aspartate, supporting calcium-dependent vesicular release downstream of transport. Model: Rat pinealocytes; HPLC and calcium/exocytosis experiments; D-form comparison reported in supplemental results. Limitations: Main figures often use L-aspartate. Direct D-aspartate binding to inhibitory metabotropic receptors was not established. Evidence access: Primary full text; supplementary result described in main text Glutamate transporter-mediated glutamate secretion in the mammalian pineal gland. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18945893/ · DOI 10.1523/JNEUROSCI.0894-08.2008

evidence_access

Primary full text

experimental_model

Mouse cortical terminals; 15 mM potassium stimulus, 10 micromolar TBOA.

limitations

This is evoked release under transporter blockade, not basal release in an intact human brain.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

Receptor-sensitive feedback changed release under an uptake-blocked assay condition.

primary_references

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 232–238

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cortical terminals; 15 mM potassium stimulus, 10 micromolar TBOA. · source_derived_draft · unverified_draft

## d-aspartate-terminal-glutamate Receptor-sensitive feedback changed release under an uptake-blocked assay condition. D-aspartate at 10 micromolar enhanced potassium-evoked glutamate release in cortical synaptosomes superfused with TBOA; NMDA, AMPA/kainate and mGlu5 antagonists attenuated or prevented the effect. Model: Mouse cortical terminals; 15 mM potassium stimulus, 10 micromolar TBOA. Limitations: This is evoked release under transporter blockade, not basal release in an intact human brain. Evidence access: Primary full text Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28393897/ · DOI 10.1038/srep46288

evidence_span

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experimental_model

Purified recombinant NAGS kinetics

exposure

Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs

limitations

Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human and mouse enzymes; human findings specified

plain_language

Arginine can feed back on the upstream nitrogen-disposal pathway.

primary_references

[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

tissue_or_cell_type

N-acetylglutamate formation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 281–292

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft

### citrulline-arginine-nags Arginine approximately doubled the activity of both tested human NAGS constructs. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine can feed back on the upstream nitrogen-disposal pathway. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

evidence_span

{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}

experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human citrin and aralar proteins

plain_language

Moving aspartate between compartments helps connect nitrogen handling and redox metabolism.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 359–370

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-aspartate Reconstituted citrin exchanged aspartate for glutamate plus a proton. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Moving aspartate between compartments helps connect nitrogen handling and redox metabolism. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_span

{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}

experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human citrin and aralar proteins

plain_language

Calcium is a regulatory signal for the transporter.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 372–383

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-calcium Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium is a regulatory signal for the transporter. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_span

{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}

experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human citrin and aralar proteins

plain_language

The same transporter participates in moving reducing equivalents between compartments.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 385–396

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-shuttle Citrin overexpression increased malate-aspartate shuttle activity in transfected human cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same transporter participates in moving reducing equivalents between compartments. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_span

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experimental_model

Purified recombinant NAGS kinetics

exposure

Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs

limitations

Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human and mouse enzymes; human findings specified

plain_language

This creates a connection to the B5-derived coenzyme-A system.

primary_references

[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

tissue_or_cell_type

N-acetylglutamate formation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 268–279

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft

### citrulline-nags-acetyl-coa Acetyl-CoA is a substrate for human NAGS-mediated N-acetylglutamate synthesis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This creates a connection to the B5-derived coenzyme-A system. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

evidence_span

{"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"}

experimental_model

Purified recombinant NAGS kinetics

exposure

Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs

limitations

Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human and mouse enzymes; human findings specified

plain_language

The activator for CPS1 has its own synthesis step.

primary_references

[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

tissue_or_cell_type

N-acetylglutamate formation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 255–266

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft

### citrulline-nags-product Recombinant human NAGS catalyzed N-acetylglutamate formation from glutamate and acetyl-CoA. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The activator for CPS1 has its own synthesis step. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

evidence_span

{"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"}

experimental_model

Recombinant enzyme crystal structure

exposure

PLP-bound enzyme structure

limitations

The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human OAT

plain_language

Vitamin B6 has a defined role in the machinery handling ornithine.

primary_references

[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583

tissue_or_cell_type

Mitochondrial ornithine transamination

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 333–344

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft

### citrulline-oat-plp Human OAT bound pyridoxal phosphate through a Schiff base to Lys292. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin B6 has a defined role in the machinery handling ornithine. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583

evidence_span

{"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"}

experimental_model

Recombinant enzyme crystal structure

exposure

PLP-bound enzyme structure

limitations

The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human OAT

plain_language

This is an ornithine-processing reaction; its direction depends on the biological setting.

primary_references

[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583

tissue_or_cell_type

Mitochondrial ornithine transamination

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 346–357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft

### citrulline-oat-reaction OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is an ornithine-processing reaction; its direction depends on the biological setting. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583

evidence_span

{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}

experimental_model

Patient genetics and recombinant variant expression

exposure

ALDH18A1 R84Q compared with wild-type isoforms

limitations

Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, two siblings and mammalian expression systems

plain_language

A niacin-derived electron donor participates upstream of citrulline.

primary_references

[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

tissue_or_cell_type

Mitochondrial P5CS and circulating amino acids

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 307–318

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft

### citrulline-p5cs-nadph P5CS requires NADPH for its reductive step in glutamate-to-P5C synthesis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A niacin-derived electron donor participates upstream of citrulline. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

evidence_span

{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}

experimental_model

Patient genetics and recombinant variant expression

exposure

ALDH18A1 R84Q compared with wild-type isoforms

limitations

Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, two siblings and mammalian expression systems

plain_language

This supplies a precursor route connected to ornithine and arginine production.

primary_references

[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

tissue_or_cell_type

Mitochondrial P5CS and circulating amino acids

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 294–305

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft

### citrulline-p5cs-reaction Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This supplies a precursor route connected to ornithine and arginine production. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

evidence_access

Primary abstract

experimental_model

Mouse permanent MCAO; separate cultured-astrocyte results are not used here to assign culture species.

limitations

Preservation does not establish direct binding to GLT-1.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Glutamate handling offered another downstream connection.

primary_references

Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20043985/ · DOI 10.1016/j.freeradbiomed.2009.12.021

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 468–474

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse permanent MCAO; separate cultured-astrocyte results are not used here to assign culture species. · source_derived_draft · unverified_draft

## carnosine-ischemia-transporter Glutamate handling offered another downstream connection. In the mouse ischemia study, carnosine treatment preserved astrocytic GLT-1 expression and decreased glutamate levels. Model: Mouse permanent MCAO; separate cultured-astrocyte results are not used here to assign culture species. Limitations: Preservation does not establish direct binding to GLT-1. Evidence access: Primary abstract Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20043985/ · DOI 10.1016/j.freeradbiomed.2009.12.021

evidence_access

Primary abstract

experimental_model

Recombinant GluR2/GluR4 assemblies expressed in HEK293 cells.

limitations

Receptor construct species is not resolved in the retrieved abstract; a human host cell does not establish a human receptor sequence. Dietary calcium or amino-acid effects were not tested.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The receptor sequence changes how much current an excitatory signal produces.

primary_references

Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. · 1997 · https://pubmed.ncbi.nlm.nih.gov/8987736/ · DOI 10.1523/JNEUROSCI.17-01-00058.1997

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 242–248

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant GluR2/GluR4 assemblies expressed in HEK293 cells. · source_derived_draft · unverified_draft

## glutamate-ampa-editing The receptor sequence changes how much current an excitatory signal produces. Unedited calcium-permeable AMPA assemblies had substantially larger unitary conductances than fully edited GluR2 channels in the recombinant assays. Model: Recombinant GluR2/GluR4 assemblies expressed in HEK293 cells. Limitations: Receptor construct species is not resolved in the retrieved abstract; a human host cell does not establish a human receptor sequence. Dietary calcium or amino-acid effects were not tested. Evidence access: Primary abstract Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. · 1997 · https://pubmed.ncbi.nlm.nih.gov/8987736/ · DOI 10.1523/JNEUROSCI.17-01-00058.1997

evidence_access

Primary abstract

experimental_model

HEK293 recombinant channel recordings with splice-variant comparisons.

limitations

An assay-specific receptor assembly is retained rather than assigning every AMPA receptor the same behavior.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Even closely related receptor variants can translate a signal differently.

primary_references

Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. · 1997 · https://pubmed.ncbi.nlm.nih.gov/8987736/ · DOI 10.1523/JNEUROSCI.17-01-00058.1997

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 250–256

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · HEK293 recombinant channel recordings with splice-variant comparisons. · source_derived_draft · unverified_draft

## glutamate-ampa-splice Even closely related receptor variants can translate a signal differently. The GluR4 flip variant conferred agonist-dependent conductance properties in the reported recombinant AMPA recordings. Model: HEK293 recombinant channel recordings with splice-variant comparisons. Limitations: An assay-specific receptor assembly is retained rather than assigning every AMPA receptor the same behavior. Evidence access: Primary abstract Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. · 1997 · https://pubmed.ncbi.nlm.nih.gov/8987736/ · DOI 10.1523/JNEUROSCI.17-01-00058.1997

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Neuronal hybrid-cell nutrient-withdrawal experiment.

limitations

The deficient precursor is cystine/cysteine supply, not glutamate; no human dietary threshold is established.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Removing the missing precursor reproduced the supply failure.

primary_references

Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 346–352

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Neuronal hybrid-cell nutrient-withdrawal experiment. · source_derived_draft · unverified_draft

## glutamate-cystine-shortage Removing the missing precursor reproduced the supply failure. Lowering culture-medium cystine mimicked glutamate-associated glutathione loss and oxidative cytotoxicity in N18-RE-105 cells. Model: Neuronal hybrid-cell nutrient-withdrawal experiment. Limitations: The deficient precursor is cystine/cysteine supply, not glutamate; no human dietary threshold is established. Evidence access: Primary abstract Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human neonatal case, primary fibroblasts and variant reconstitution/metabolomics.

limitations

Patient-derived cells and rescue constructs are not dietary supplementation experiments.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A glutamate-handling translation enzyme can affect many downstream metabolic pools.

primary_references

Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33855712/ · DOI 10.1002/jimd.12387

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 402–408

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human neonatal case, primary fibroblasts and variant reconstitution/metabolomics. · source_derived_draft · unverified_draft

## glutamate-ears2-disease-metabolism A glutamate-handling translation enzyme can affect many downstream metabolic pools. Patient fibroblasts with EARS2 p.G317C had broad metabolic abnormalities; reconstitution with wild-type versus disease variants distinguished severity-related TCA and amino-acid signatures. Model: Human neonatal case, primary fibroblasts and variant reconstitution/metabolomics. Limitations: Patient-derived cells and rescue constructs are not dietary supplementation experiments. Evidence access: Primary full text Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33855712/ · DOI 10.1002/jimd.12387

evidence_access

Primary abstract

experimental_model

Recombinant human enzyme and mitochondrial tRNA biochemistry.

limitations

This intermediate is not glutamate being correctly incorporated at glutamine codons.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A deliberately intermediate amino-acid attachment must be processed before translation.

primary_references

Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 370–376

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human enzyme and mitochondrial tRNA biochemistry. · source_derived_draft · unverified_draft

## glutamate-ears2-intermediate A deliberately intermediate amino-acid attachment must be processed before translation. Human mitochondrial glutamyl-tRNA synthetase attached glutamate to mitochondrial tRNA(Gln), generating the intermediate Glu-tRNA(Gln). Model: Recombinant human enzyme and mitochondrial tRNA biochemistry. Limitations: This intermediate is not glutamate being correctly incorporated at glutamine codons. Evidence access: Primary abstract Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

evidence_access

Primary abstract

experimental_model

Human mitochondrial tRNA binding assays.

limitations

Weak affinity supports the proposed quality-control mechanism; it does not prove absolute exclusion under every condition.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Quality control reduces entry of the unfinished intermediate into protein synthesis.

primary_references

Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 394–400

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human mitochondrial tRNA binding assays. · source_derived_draft · unverified_draft

## glutamate-elongation-quality-control Quality control reduces entry of the unfinished intermediate into protein synthesis. The glutamate-mischarged tRNA(Gln) intermediate bound mitochondrial EF-Tu weakly, supporting exclusion from translation before correction. Model: Human mitochondrial tRNA binding assays. Limitations: Weak affinity supports the proposed quality-control mechanism; it does not prove absolute exclusion under every condition. Evidence access: Primary abstract Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

evidence_access

Primary abstract

experimental_model

Neuronal hybrid-cell transport, glutathione and peroxide assays.

limitations

A specific experimental toxicity mechanism is retained without inferring normal food-related brain injury.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Oxidative injury arose through precursor supply, a different route from opening an excitatory receptor.

primary_references

Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Neuronal hybrid-cell transport, glutathione and peroxide assays. · source_derived_draft · unverified_draft

## glutamate-extracellular-gsh-loss Oxidative injury arose through precursor supply, a different route from opening an excitatory receptor. Extracellular glutamate exposure lowered glutathione and increased intracellular peroxides in N18-RE-105 cells alongside inhibited cystine uptake. Model: Neuronal hybrid-cell transport, glutathione and peroxide assays. Limitations: A specific experimental toxicity mechanism is retained without inferring normal food-related brain injury. Evidence access: Primary abstract Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2576375/ · DOI 10.1016/0896-6273(89)90043-3

evidence_access

Primary full text

experimental_model

Anesthetized-rat intragastric infusion with gastric-branch vagotomy.

limitations

Nerve discharge is not direct measurement of a human hormonal or health benefit.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Cutting the sensory route interrupted the downstream reflex.

primary_references

Effects of intragastric infusion of inosine monophosphate and L: -glutamate on vagal gastric afferent activity and subsequent autonomic reflexes. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21132420/ · DOI 10.1007/s12576-010-0121-z

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 74–80

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anesthetized-rat intragastric infusion with gastric-branch vagotomy. · source_derived_draft · unverified_draft

## glutamate-gastric-reflex Cutting the sensory route interrupted the downstream reflex. MSG-evoked celiac vagal and adrenal splanchnic efferent responses were abolished by gastric vagotomy in rats. Model: Anesthetized-rat intragastric infusion with gastric-branch vagotomy. Limitations: Nerve discharge is not direct measurement of a human hormonal or health benefit. Evidence access: Primary full text Effects of intragastric infusion of inosine monophosphate and L: -glutamate on vagal gastric afferent activity and subsequent autonomic reflexes. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21132420/ · DOI 10.1007/s12576-010-0121-z

evidence_access

Primary full text

experimental_model

Anesthetized rats; 2 mL intragastric infusion at 1 mL/min, nerve discharge assessed after infusion.

limitations

MSG was the exposure; human food intake and subjective effects were not tested.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Glutamate in the stomach can signal through nerves without first acting at a brain glutamate receptor.

primary_references

Effects of intragastric infusion of inosine monophosphate and L: -glutamate on vagal gastric afferent activity and subsequent autonomic reflexes. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21132420/ · DOI 10.1007/s12576-010-0121-z

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anesthetized rats; 2 mL intragastric infusion at 1 mL/min, nerve discharge assessed after infusion. · source_derived_draft · unverified_draft

## glutamate-gastric-vagal Glutamate in the stomach can signal through nerves without first acting at a brain glutamate receptor. Intragastric 150 mM MSG increased gastric vagal afferent discharge in anesthetized rats. Model: Anesthetized rats; 2 mL intragastric infusion at 1 mL/min, nerve discharge assessed after infusion. Limitations: MSG was the exposure; human food intake and subjective effects were not tested. Evidence access: Primary full text Effects of intragastric infusion of inosine monophosphate and L: -glutamate on vagal gastric afferent activity and subsequent autonomic reflexes. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21132420/ · DOI 10.1007/s12576-010-0121-z

evidence_access

Primary abstract

experimental_model

Human recombinant mitochondrial tRNA pathway reconstitution.

limitations

Each complex subunit is separately modeled; an amino acid supplement was not the tested intervention.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A second enzyme complex converts the attached amino acid to the required one.

primary_references

Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 378–384

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant mitochondrial tRNA pathway reconstitution. · source_derived_draft · unverified_draft

## glutamate-gatcab-conversion A second enzyme complex converts the attached amino acid to the required one. Recombinant human mtGluRS and GatCAB reconstituted formation of glutaminyl-tRNA(Gln) through the glutamylated intermediate in vitro. Model: Human recombinant mitochondrial tRNA pathway reconstitution. Limitations: Each complex subunit is separately modeled; an amino acid supplement was not the tested intervention. Evidence access: Primary abstract Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human-cell siRNA against GatCAB subunits.

limitations

Knockdown establishes a machinery dependency, not dietary glutamate or glutamine deficiency.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Available amino acid cannot replace the missing processing step.

primary_references

Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 386–392

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell siRNA against GatCAB subunits. · source_derived_draft · unverified_draft

## glutamate-gatcab-loss Available amino acid cannot replace the missing processing step. Knocking down any human GatCAB subunit caused accumulation of glutamate-charged tRNA(Gln) and impaired respiration. Model: Human-cell siRNA against GatCAB subunits. Limitations: Knockdown establishes a machinery dependency, not dietary glutamate or glutamine deficiency. Evidence access: Primary abstract Biogenesis of glutaminyl-mt tRNAGln in human mitochondria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19805282/ · DOI 10.1073/pnas.0907602106

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human genetic case and recombinant transport assay.

limitations

A carrier disorder does not establish dietary glutamate deficiency or successful rescue by oral glutamate.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Enough amino acid outside mitochondria cannot guarantee transport through defective machinery.

primary_references

Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19780765/ · DOI 10.1111/j.1399-0004.2009.01236.x

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human genetic case and recombinant transport assay. · source_derived_draft · unverified_draft

## glutamate-gc1-variant Enough amino acid outside mitochondria cannot guarantee transport through defective machinery. The homozygous SLC25A22 p.G236W variant identified in a child with severe neonatal epileptic encephalopathy abolished carrier activity in vitro. Model: Human genetic case and recombinant transport assay. Limitations: A carrier disorder does not establish dietary glutamate deficiency or successful rescue by oral glutamate. Evidence access: Primary abstract Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19780765/ · DOI 10.1111/j.1399-0004.2009.01236.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human rare-disease clinical series.

limitations

This does not establish treatment futility across all regimens or justify dietary advice outside the study.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Changing a regulator or diet did not correct every downstream outcome.

primary_references

Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human rare-disease clinical series. · source_derived_draft · unverified_draft

## glutamate-gdh-ammonia-limit Changing a regulator or diet did not correct every downstream outcome. Hyperammonemia persisted despite protein/leucine restriction in the reported twelve-patient series. Model: Human rare-disease clinical series. Limitations: This does not establish treatment futility across all regimens or justify dietary advice outside the study. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

evidence_access

Primary abstract

experimental_model

Human lymphoblast enzyme assays from eight unrelated affected children and controls.

limitations

GTP regulation is not evidence that dietary purines or glutamate normalize the disease.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

An energy-related nucleotide restrains glutamate oxidation.

primary_references

Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lymphoblast enzyme assays from eight unrelated affected children and controls. · source_derived_draft · unverified_draft

## glutamate-gdh-gtp-control An energy-related nucleotide restrains glutamate oxidation. Human GLUD1 activity was inhibited by GTP; patient-derived regulatory variants showed reduced sensitivity to that inhibition. Model: Human lymphoblast enzyme assays from eight unrelated affected children and controls. Limitations: GTP regulation is not evidence that dietary purines or glutamate normalize the disease. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient series with enzyme allostery and dietary-response observations.

limitations

Observational genotype/phenotype evidence, not a controlled general-population dietary trial.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Another amino acid regulates how glutamate is processed, but the response varies by enzyme defect.

primary_references

Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human patient series with enzyme allostery and dietary-response observations. · source_derived_draft · unverified_draft

## glutamate-gdh-leucine-context Another amino acid regulates how glutamate is processed, but the response varies by enzyme defect. Leucine activation of lymphoblast GDH varied among twelve patients with hyperinsulinism/hyperammonemia; reduced leucine sensitivity tracked failure of leucine restriction to improve glucose in four patients. Model: Human patient series with enzyme allostery and dietary-response observations. Limitations: Observational genotype/phenotype evidence, not a controlled general-population dietary trial. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

evidence_access

Primary abstract

experimental_model

Established reaction described in a primary human GLUD1 genetic/functional study.

limitations

Reaction background is distinguished from the directly measured mutant regulation; this record does not quantify tissue flux.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Removing amino nitrogen connects glutamate with the central carbon cycle.

primary_references

Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction described in a primary human GLUD1 genetic/functional study. · source_derived_draft · unverified_draft

## glutamate-gdh-oxidation Removing amino nitrogen connects glutamate with the central carbon cycle. The GLUD1 study identifies glutamate oxidation to 2-oxoglutarate as the enzyme reaction underlying its metabolic and regulatory investigation. Model: Established reaction described in a primary human GLUD1 genetic/functional study. Limitations: Reaction background is distinguished from the directly measured mutant regulation; this record does not quantify tissue flux. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human disease variant expressed in nonhuman COS7 host cells; biochemical confirmation.

limitations

Host cell species and human protein identity are distinct; no intake intervention was tested.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Changing the enzyme altered its response to a brake.

primary_references

Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human disease variant expressed in nonhuman COS7 host cells; biochemical confirmation. · source_derived_draft · unverified_draft

## glutamate-gdh-regulatory-variants Changing the enzyme altered its response to a brake. Expressing a patient GLUD1 mutant in COS7 cells reproduced reduced GTP inhibition observed in the patient lymphoblasts. Model: Human disease variant expressed in nonhuman COS7 host cells; biochemical confirmation. Limitations: Host cell species and human protein identity are distinct; no intake intervention was tested. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9571255/ · DOI 10.1056/NEJM199805073381904

evidence_access

Primary abstract

experimental_model

Human-cell GLS2 expression/perturbation study.

limitations

The effect depends on cell context; it is not a clinical energy claim.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The generated carbon skeleton can support mitochondrial metabolism.

primary_references

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell GLS2 expression/perturbation study. · source_derived_draft · unverified_draft

## glutamate-gls2-energy The generated carbon skeleton can support mitochondrial metabolism. GLS2 manipulation linked increased glutamate and 2-oxoglutarate production with increased respiration and ATP generation in the tested human cells. Model: Human-cell GLS2 expression/perturbation study. Limitations: The effect depends on cell context; it is not a clinical energy claim. Evidence access: Primary abstract Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

evidence_access

Primary abstract

experimental_model

Human-cell GLS2/p53 and oxidative-stress experiments.

limitations

Cysteine, glycine and synthesis machinery remain necessary; glutamate is not established as the universal limiting substrate.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The same supply route fed antioxidant chemistry as well as energy metabolism.

primary_references

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell GLS2/p53 and oxidative-stress experiments. · source_derived_draft · unverified_draft

## glutamate-gls2-gsh The same supply route fed antioxidant chemistry as well as energy metabolism. Increasing GLS2 supported higher reduced-glutathione levels, lower reactive oxygen species and protection from peroxide-induced apoptosis in the reported cell experiments. Model: Human-cell GLS2/p53 and oxidative-stress experiments. Limitations: Cysteine, glycine and synthesis machinery remain necessary; glutamate is not established as the universal limiting substrate. Evidence access: Primary abstract Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse whole-body transporter knockout and acute cortical injury.

limitations

Developmental gene deletion is not ordinary variation in dietary glutamate.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Failure to clear a transmitter can be harmful even though the molecule is normally essential.

primary_references

Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9180080/ · DOI 10.1126/science.276.5319.1699

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse whole-body transporter knockout and acute cortical injury. · source_derived_draft · unverified_draft

## glutamate-glt1-deletion Failure to clear a transmitter can be harmful even though the molecule is normally essential. Homozygous Slc1a2/GLT-1 deletion in mice caused lethal spontaneous seizures and increased susceptibility to cortical injury, with elevated residual glutamate. Model: Mouse whole-body transporter knockout and acute cortical injury. Limitations: Developmental gene deletion is not ordinary variation in dietary glutamate. Evidence access: Primary abstract Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9180080/ · DOI 10.1126/science.276.5319.1699

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two unrelated newborns, patient lymphocytes and mutant expression in COS7 cells.

limitations

This is congenital glutamine-synthesis failure, not evidence of inadequate dietary glutamate.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A synthesis defect can prevent conversion of one available amino acid into another.

primary_references

Congenital glutamine deficiency with glutamine synthetase mutations. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16267323/ · DOI 10.1056/NEJMoa050456

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two unrelated newborns, patient lymphocytes and mutant expression in COS7 cells. · source_derived_draft · unverified_draft

## glutamate-glul-human-loss A synthesis defect can prevent conversion of one available amino acid into another. Two infants with homozygous GLUL mutations had profoundly low glutamine and severe neonatal disease; variant expression assays showed reduced enzyme activity. Model: Two unrelated newborns, patient lymphocytes and mutant expression in COS7 cells. Limitations: This is congenital glutamine-synthesis failure, not evidence of inadequate dietary glutamate. Evidence access: Primary abstract Congenital glutamine deficiency with glutamine synthetase mutations. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16267323/ · DOI 10.1056/NEJMoa050456

evidence_access

Primary full text

experimental_model

Mouse acute slices incubated for more than two hours; lithium matched between groups.

limitations

High bath exposure and slice conditions are explicit; do not substitute an oral ketone dose or attribute the difference to unmatched lithium.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A controlled slice experiment connected the transport finding with synaptic output.

primary_references

Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse acute slices incubated for more than two hours; lithium matched between groups. · source_derived_draft · unverified_draft

## glutamate-ketone-synaptic-response A controlled slice experiment connected the transport finding with synaptic output. Mouse hippocampal slices exposed to 10 mM lithium acetoacetate had lower miniature excitatory-current amplitude and frequency than lithium-chloride controls. Model: Mouse acute slices incubated for more than two hours; lithium matched between groups. Limitations: High bath exposure and slice conditions are explicit; do not substitute an oral ketone dose or attribute the difference to unmatched lithium. Evidence access: Primary full text Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

evidence_access

Primary abstract

experimental_model

Rat receptor cloning and functional expression study.

limitations

This does not demonstrate that oral inositol or calcium increases the response.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A glutamate receptor can trigger an internal signaling cascade instead of forming the ion pore itself.

primary_references

Sequence and expression of a metabotropic glutamate receptor. · 1991 · https://pubmed.ncbi.nlm.nih.gov/1847995/ · DOI 10.1038/349760a0

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat receptor cloning and functional expression study. · source_derived_draft · unverified_draft

## glutamate-mgr1-ip-calcium A glutamate receptor can trigger an internal signaling cascade instead of forming the ion pore itself. The cloned rat metabotropic glutamate receptor coupled receptor activation to inositol-phosphate/calcium signaling. Model: Rat receptor cloning and functional expression study. Limitations: This does not demonstrate that oral inositol or calcium increases the response. Evidence access: Primary abstract Sequence and expression of a metabotropic glutamate receptor. · 1991 · https://pubmed.ncbi.nlm.nih.gov/1847995/ · DOI 10.1038/349760a0

evidence_access

Primary abstract

experimental_model

Rat receptor cDNA expressed in heterologous cells.

limitations

Do not assign the mGluR1 calcium route to every metabotropic glutamate receptor.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A different glutamate receptor couples to a different second-messenger response.

primary_references

A family of metabotropic glutamate receptors. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1309649/ · DOI 10.1016/0896-6273(92)90118-w

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat receptor cDNA expressed in heterologous cells. · source_derived_draft · unverified_draft

## glutamate-mgr2-camp A different glutamate receptor couples to a different second-messenger response. Rat mGluR2 expressed in transfected cells inhibited forskolin-stimulated cAMP formation. Model: Rat receptor cDNA expressed in heterologous cells. Limitations: Do not assign the mGluR1 calcium route to every metabotropic glutamate receptor. Evidence access: Primary abstract A family of metabotropic glutamate receptors. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1309649/ · DOI 10.1016/0896-6273(92)90118-w

evidence_access

Primary abstract

experimental_model

Mouse cultured neurons and outside-out patch recordings.

limitations

The effect was distinct from strychnine-sensitive glycine receptors; it does not define an oral glycine or glutamate response.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

An amino acid usually associated with inhibition can assist an excitatory receptor.

primary_references

Glycine potentiates the NMDA response in cultured mouse brain neurons. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2433595/ · DOI 10.1038/325529a0

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cultured neurons and outside-out patch recordings. · source_derived_draft · unverified_draft

## glutamate-nmda-glycine An amino acid usually associated with inhibition can assist an excitatory receptor. Glycine increased opening frequency of NMDA-activated channels in cultured mouse brain neurons, with potentiation detected at 10 nM. Model: Mouse cultured neurons and outside-out patch recordings. Limitations: The effect was distinct from strychnine-sensitive glycine receptors; it does not define an oral glycine or glutamate response. Evidence access: Primary abstract Glycine potentiates the NMDA response in cultured mouse brain neurons. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2433595/ · DOI 10.1038/325529a0

evidence_access

Primary abstract

experimental_model

Human-cell p53 and GLS2 expression/perturbation assays.

limitations

A tumor-suppressor pathway is not evidence that glutamate supplementation prevents cancer.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Gene regulation changes the machinery that supplies glutamate.

primary_references

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 210–216

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell p53 and GLS2 expression/perturbation assays. · source_derived_draft · unverified_draft

## glutamate-p53-gls2 Gene regulation changes the machinery that supplies glutamate. Activating p53 increased GLS2 expression under stressed and unstressed conditions in the reported human-cell experiments. Model: Human-cell p53 and GLS2 expression/perturbation assays. Limitations: A tumor-suppressor pathway is not evidence that glutamate supplementation prevents cancer. Evidence access: Primary abstract Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20378837/ · DOI 10.1073/pnas.1001006107

evidence_access

Primary full text

experimental_model

Rat brain slices with axons transected; alternating 20 Hz and 0.2 Hz stimulation and naturalistic patterns.

limitations

This is a local experimental supply limitation, not a dietary glutamate-deficiency threshold.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A local transmitter supply can become insufficient when demand rises.

primary_references

A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat brain slices with axons transected; alternating 20 Hz and 0.2 Hz stimulation and naturalistic patterns. · source_derived_draft · unverified_draft

## glutamate-recycling-demand A local transmitter supply can become insufficient when demand rises. Repeated high-frequency stimulation of rat hippocampal and cortical terminals reduced synaptic efficacy and glutamate release; the effect depended on activity pattern. Model: Rat brain slices with axons transected; alternating 20 Hz and 0.2 Hz stimulation and naturalistic patterns. Limitations: This is a local experimental supply limitation, not a dietary glutamate-deficiency threshold. Evidence access: Primary full text A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Rat hippocampal/cortical slices with high-frequency stimulation, with or without prior enzyme inhibition.

limitations

Bath addition of glutamine is not oral L-glutamate treatment or proof of improved human cognition.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Providing a usable precursor bypassed part of the local synthesis limitation.

primary_references

A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 146–152

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat hippocampal/cortical slices with high-frequency stimulation, with or without prior enzyme inhibition. · source_derived_draft · unverified_draft

## glutamate-recycling-glutamine-rescue Providing a usable precursor bypassed part of the local synthesis limitation. Adding 500 micromolar glutamine prevented or reversed the activity-dependent loss of glutamate-mediated synaptic responses in the tested rat slices. Model: Rat hippocampal/cortical slices with high-frequency stimulation, with or without prior enzyme inhibition. Limitations: Bath addition of glutamine is not oral L-glutamate treatment or proof of improved human cognition. Evidence access: Primary full text A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Rat slice glutamine-synthetase inhibition and evoked field-potential recordings.

limitations

The inhibitor also restricts newly synthesized glutamine; recycling is not the only possible affected source.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Disabling the recycling enzyme made the local supply problem worse.

primary_references

A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat slice glutamine-synthetase inhibition and evoked field-potential recordings. · source_derived_draft · unverified_draft

## glutamate-recycling-gs-block Disabling the recycling enzyme made the local supply problem worse. Blocking glutamine synthetase with methionine sulfoximine worsened activity-dependent synaptic depression in rat hippocampal slices. Model: Rat slice glutamine-synthetase inhibition and evoked field-potential recordings. Limitations: The inhibitor also restricts newly synthesized glutamine; recycling is not the only possible affected source. Evidence access: Primary full text A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Rat hippocampal slices; matched low-frequency recording control.

limitations

This limited period of preserved function does not make glutamine synthesis dispensable.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A stored reserve can hide a supply defect when demand is low.

primary_references

A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat hippocampal slices; matched low-frequency recording control. · source_derived_draft · unverified_draft

## glutamate-recycling-low-demand A stored reserve can hide a supply defect when demand is low. At 0.2 Hz, evoked responses remained stable for 60 minutes despite prior glutamine-synthetase inhibition in the rat slice experiment. Model: Rat hippocampal slices; matched low-frequency recording control. Limitations: This limited period of preserved function does not make glutamine synthesis dispensable. Evidence access: Primary full text A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24559677/ · DOI 10.1016/j.neuron.2013.12.026

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract and primary full text

experimental_model

Rat PC12 cell knockdown and nerve-growth-factor differentiation.

limitations

Loss of enzyme function does not establish a free-glutamate dietary shortage or brain-regeneration treatment.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A glutamate-chain-adding enzyme contributed to cell shape in a differentiation model.

primary_references

TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16901895/ · DOI 10.1074/jbc.M603984200

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat PC12 cell knockdown and nerve-growth-factor differentiation. · source_derived_draft · unverified_draft

## glutamate-ttll7-neurite-loss A glutamate-chain-adding enzyme contributed to cell shape in a differentiation model. Ttll7 siRNA in rat PC12 cells reduced nerve-growth-factor-stimulated MAP2-positive neurite growth. Model: Rat PC12 cell knockdown and nerve-growth-factor differentiation. Limitations: Loss of enzyme function does not establish a free-glutamate dietary shortage or brain-regeneration treatment. Evidence access: Primary abstract and primary full text TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16901895/ · DOI 10.1074/jbc.M603984200

evidence_access

Primary abstract and full-text construct methods

experimental_model

Mouse cDNA constructs, recombinant biochemistry and human host-cell expression.

limitations

This protein modification differs from a free-glutamate receptor signal; the beta-tubulin isoform is not assigned beyond the study.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Glutamate can be added in side chains that modify a structural protein.

primary_references

TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16901895/ · DOI 10.1074/jbc.M603984200

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cDNA constructs, recombinant biochemistry and human host-cell expression. · source_derived_draft · unverified_draft

## glutamate-tubulin-glutamylation Glutamate can be added in side chains that modify a structural protein. Recombinant mouse TTLL7 favored beta-tubulin polyglutamylation in vitro and when expressed in HEK293T cells. Model: Mouse cDNA constructs, recombinant biochemistry and human host-cell expression. Limitations: This protein modification differs from a free-glutamate receptor signal; the beta-tubulin isoform is not assigned beyond the study. Evidence access: Primary abstract and full-text construct methods TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16901895/ · DOI 10.1074/jbc.M603984200

evidence_access

Primary abstract

experimental_model

Human receptor coexpression and ligand-response assays.

limitations

A measured receptor interaction, not a general metabolic or clinical synergy.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A nucleotide can enhance the response to an amino acid at a receptor.

primary_references

Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human receptor coexpression and ligand-response assays. · source_derived_draft · unverified_draft

## glutamate-umami-nucleotide A nucleotide can enhance the response to an amino acid at a receptor. 5-prime-ribonucleotides enhanced the human T1R1/T1R3 response to L-glutamate. Model: Human receptor coexpression and ligand-response assays. Limitations: A measured receptor interaction, not a general metabolic or clinical synergy. Evidence access: Primary abstract Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199

evidence_access

Primary full text

experimental_model

Human/mouse receptor chimeras and mutagenesis.

limitations

Sequence-dependent selectivity is not evidence that all mammalian umami receptors behave identically.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

The species of the receptor changes what the same ligand experiment means.

primary_references

Two distinct determinants of ligand specificity in T1R1/T1R3 (the umami taste receptor). · 2013 · https://pubmed.ncbi.nlm.nih.gov/24214976/ · DOI 10.1074/jbc.M113.494443

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human/mouse receptor chimeras and mutagenesis. · source_derived_draft · unverified_draft

## glutamate-umami-species The species of the receptor changes what the same ligand experiment means. Human/mouse receptor chimeras and point mutants mapped acidic-amino-acid selectivity to the T1R1 ligand-binding region and identified other residues that broadened mouse-type responses. Model: Human/mouse receptor chimeras and mutagenesis. Limitations: Sequence-dependent selectivity is not evidence that all mammalian umami receptors behave identically. Evidence access: Primary full text Two distinct determinants of ligand specificity in T1R1/T1R3 (the umami taste receptor). · 2013 · https://pubmed.ncbi.nlm.nih.gov/24214976/ · DOI 10.1074/jbc.M113.494443

evidence_access

Primary full text

experimental_model

Purified rat transporter; controlled chloride/acetoacetate concentrations and washout.

limitations

This mechanism alone does not establish the effects of fasting or a ketogenic diet in humans.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A metabolic fuel-related molecule altered transmitter packaging in a biochemical system.

primary_references

Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 282–288

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified rat transporter; controlled chloride/acetoacetate concentrations and washout. · source_derived_draft · unverified_draft

## glutamate-vglut2-acetoacetate A metabolic fuel-related molecule altered transmitter packaging in a biochemical system. Acetoacetate reversibly inhibited reconstituted rat VGLUT2 uptake with a chloride-dependent shift consistent with competition at allosteric regulation. Model: Purified rat transporter; controlled chloride/acetoacetate concentrations and washout. Limitations: This mechanism alone does not establish the effects of fasting or a ketogenic diet in humans. Evidence access: Primary full text Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

evidence_access

Primary full text

experimental_model

Rat VGLUT2 expressed in insect cells, purified and reconstituted; membrane-potential-driven uptake.

limitations

Chloride regulation in vesicles is not equivalent to an effect of dietary salt.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

An ion regulates whether the vesicle-loading transporter works.

primary_references

Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 274–280

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat VGLUT2 expressed in insect cells, purified and reconstituted; membrane-potential-driven uptake. · source_derived_draft · unverified_draft

## glutamate-vglut2-chloride An ion regulates whether the vesicle-loading transporter works. Chloride activated glutamate uptake by purified rat VGLUT2 in reconstituted proteoliposomes. Model: Rat VGLUT2 expressed in insect cells, purified and reconstituted; membrane-potential-driven uptake. Limitations: Chloride regulation in vesicles is not equivalent to an effect of dietary salt. Evidence access: Primary full text Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse dopamine-neuron conditional knockout, culture and brain slices.

limitations

Cell-specific deletion is not global glutamate deficiency.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A dopamine neuron can require separate machinery to release glutamate too.

primary_references

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 306–312

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse dopamine-neuron conditional knockout, culture and brain slices. · source_derived_draft · unverified_draft

## glutamate-vglut2-dopamine-neuron-release A dopamine neuron can require separate machinery to release glutamate too. Deleting Slc17a6 selectively in mouse dopamine neurons abolished their cultured glutamate release and greatly reduced excitatory output in mesoaccumbens slices. Model: Mouse dopamine-neuron conditional knockout, culture and brain slices. Limitations: Cell-specific deletion is not global glutamate deficiency. Evidence access: Primary full text Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse conditional knockout with tissue dopamine and behavioral measurements.

limitations

Multiple downstream effects coexist; this does not prove every dopamine neuron or behavior depends equally on VGLUT2.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

Removing the glutamate-loading route changed another transmitter system in a specific circuit.

primary_references

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse conditional knockout with tissue dopamine and behavioral measurements. · source_derived_draft · unverified_draft

## glutamate-vglut2-dopamine-stores Removing the glutamate-loading route changed another transmitter system in a specific circuit. Dopamine-neuron Slc17a6 deletion reduced dopamine stores in ventral-striatal projections and reduced cocaine-stimulated locomotor responses while sparing baseline motor behavior. Model: Mouse conditional knockout with tissue dopamine and behavioral measurements. Limitations: Multiple downstream effects coexist; this does not prove every dopamine neuron or behavior depends equally on VGLUT2. Evidence access: Primary full text Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20223200/ · DOI 10.1016/j.neuron.2010.02.012

evidence_access

Primary full text

experimental_model

Human VGLUT3 expressed in insect cells and reconstituted separately from rat VGLUT2.

limitations

Isoforms and species are kept distinct; no nutritional chloride threshold was tested.

nutrient_topic

L-Glutamate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Glutamate

plain_language

A human transporter isoform shares a tested regulatory input.

primary_references

Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 290–296

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human VGLUT3 expressed in insect cells and reconstituted separately from rat VGLUT2. · source_derived_draft · unverified_draft

## glutamate-vglut3-chloride A human transporter isoform shares a tested regulatory input. Purified human VGLUT3 also showed chloride-dependent glutamate transport in reconstituted vesicles. Model: Human VGLUT3 expressed in insect cells and reconstituted separately from rat VGLUT2. Limitations: Isoforms and species are kept distinct; no nutritional chloride threshold was tested. Evidence access: Primary full text Metabolic control of vesicular glutamate transport and release. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20920794/ · DOI 10.1016/j.neuron.2010.09.002

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse knockout-derived primary neurons versus wild-type littermates.

limitations

Genetic failure is not a dietary BDNF deficiency or human therapeutic test.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

The protective response required intact survival machinery.

primary_references

Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12504924/ · DOI 10.1016/s0028-3908(02)00217-4

trigger_kind

machinery_impairment Imported condition classification; unverified.

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 224–230

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout-derived primary neurons versus wild-type littermates. · source_derived_draft · unverified_draft

## lithium-bdnf-loss The protective response required intact survival machinery. Lithium failed to protect cortical neurons from Bdnf heterozygous or homozygous knockout mice against glutamate toxicity. Model: Mouse knockout-derived primary neurons versus wild-type littermates. Limitations: Genetic failure is not a dietary BDNF deficiency or human therapeutic test. Evidence access: Primary abstract Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12504924/ · DOI 10.1016/s0028-3908(02)00217-4

evidence_access

Primary abstract

experimental_model

Cortical slices and synaptosomes; concentration-response experiments.

limitations

Do not merge acute addition with chronic in-vivo treatment.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

An immediate effect can differ from long-term adaptation.

primary_references

Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9653192/ · DOI 10.1073/pnas.95.14.8363

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 232–238

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cortical slices and synaptosomes; concentration-response experiments. · source_derived_draft · unverified_draft

## lithium-glutamate-acute An immediate effect can differ from long-term adaptation. Acute lithium exposure lowered glutamate-uptake capacity in mouse cortical preparations without changing apparent substrate affinity. Model: Cortical slices and synaptosomes; concentration-response experiments. Limitations: Do not merge acute addition with chronic in-vivo treatment. Evidence access: Primary abstract Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9653192/ · DOI 10.1073/pnas.95.14.8363

evidence_access

Primary abstract

experimental_model

Mice treated in vivo, followed by synaptosome assays.

limitations

A duration-dependent difference explained in the same paper, not an unresolved contradiction.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

Longer exposure produced an opposite uptake response.

primary_references

Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9653192/ · DOI 10.1073/pnas.95.14.8363

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 240–246

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mice treated in vivo, followed by synaptosome assays. · source_derived_draft · unverified_draft

## lithium-glutamate-chronic Longer exposure produced an opposite uptake response. Chronic lithium treatment increased synaptosomal glutamate uptake in mice at a reported blood lithium level of 0.7 mM. Model: Mice treated in vivo, followed by synaptosome assays. Limitations: A duration-dependent difference explained in the same paper, not an unresolved contradiction. Evidence access: Primary abstract Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9653192/ · DOI 10.1073/pnas.95.14.8363

experimental_model

Human GLUL ligand-complex crystal structures; canine apoenzyme comparison

exposure

ADP/phosphate/Mn and ADP/phosphorylated-inhibitor/Mn complexes

limitations

Reaction identity does not determine the predominant metal in living human brain.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens protein

plain_language

GLUL combines glutamate and ammonia using ATP.

primary_references

[mn-enz-18005987] Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. (2008). https://pubmed.ncbi.nlm.nih.gov/18005987/ DOI: 10.1016/j.jmb.2007.10.029

tissue_or_cell_type

Purified GLUL

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 596–606

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human GLUL ligand-complex crystal structures; canine apoenzyme comparison · source_derived_draft · unverified_draft

### mn-enz-glul-reaction Human glutamine synthetase catalyzes ATP-coupled ligation of glutamate and ammonia to make glutamine. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: GLUL combines glutamate and ammonia using ATP. organism: Homo sapiens protein tissue_or_cell_type: Purified GLUL experimental_model: Human GLUL ligand-complex crystal structures; canine apoenzyme comparison limitations: Reaction identity does not determine the predominant metal in living human brain. exposure: ADP/phosphate/Mn and ADP/phosphorylated-inhibitor/Mn complexes [mn-enz-18005987] Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design. (2008). https://pubmed.ncbi.nlm.nih.gov/18005987/ DOI: 10.1016/j.jmb.2007.10.029

experimental_model

Human cDNA and recombinant bacterial expression; Purified recombinant human enzyme; kinetics and crystallography

limitations

AADAT also accepts other substrates; substrate breadth is not lysine-specific regulation.

organism

Homo sapiens

plain_language

AADAT removes the remaining amino group.

primary_references

[goh2002] Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT). (2002). https://pubmed.ncbi.nlm.nih.gov/12126930/ DOI: 10.1016/S1096-7192(02)00037-9 [han2008] Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2559858/ DOI: 10.1042/BSR20080085

tissue_or_cell_type

Mitochondrial lysine catabolism; human expression highest in liver in cloning study

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 114–123

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cDNA and recombinant bacterial expression; Purified recombinant human enzyme; kinetics and crystallography · source_derived_draft · unverified_draft

### aadat-transamination PLP-dependent AADAT transfers the amino group from aminoadipate to 2-oxoglutarate, generating 2-oxoadipate and glutamate. Plain language: AADAT removes the remaining amino group. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial lysine catabolism; human expression highest in liver in cloning study experimental_model: Human cDNA and recombinant bacterial expression; Purified recombinant human enzyme; kinetics and crystallography limitations: AADAT also accepts other substrates; substrate breadth is not lysine-specific regulation. [goh2002] Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT). (2002). https://pubmed.ncbi.nlm.nih.gov/12126930/ DOI: 10.1016/S1096-7192(02)00037-9 [han2008] Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2559858/ DOI: 10.1042/BSR20080085

experimental_model

Human AASS cloning, localization and familial hyperlysinemia genetics

limitations

Biochemical capacity does not quantify flux in every human tissue.

organism

Homo sapiens

plain_language

The second AASS activity opens the next lysine breakdown step.

primary_references

[sacksteder2000] Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia (2000). https://pmc.ncbi.nlm.nih.gov/articles/PMC1378037/ DOI: 10.1086/302919

tissue_or_cell_type

Mitochondrial matrix

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 84–92

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human AASS cloning, localization and familial hyperlysinemia genetics · source_derived_draft · unverified_draft

### aass-saccharopine-dehydrogenase The AASS dehydrogenase domain oxidatively cleaves saccharopine, producing alpha-aminoadipate semialdehyde and glutamate with NAD+ reduction. Plain language: The second AASS activity opens the next lysine breakdown step. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Mitochondrial matrix experimental_model: Human AASS cloning, localization and familial hyperlysinemia genetics limitations: Biochemical capacity does not quantify flux in every human tissue. [sacksteder2000] Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia (2000). https://pmc.ncbi.nlm.nih.gov/articles/PMC1378037/ DOI: 10.1086/302919

dose

Indicaxanthin 0.085-0.34 ng/neuron; glutamate challenge in selected recordings

duration

Acute firing measurements

evidence_access

Primary PubMed abstract.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

In vivo rat hippocampal single-neuron recordings

limitations

Local application bypasses oral distribution. NMDAR binding was proposed by modeling, not established by this electrophysiological observation.

nutrient_topic

Dedicated indicaxanthin chapter; original betalain family identity and shared claims preserved. · Indicaxanthin

organism

In vivo rat hippocampal single-neuron recordings

plain_language

Local indicaxanthin at 0.34 ng/neuron reduced glutamate-evoked excitation in rat hippocampal recordings.

primary_references

Indicaxanthin from Opuntia ficus-indica Crosses the Blood-Brain Barrier and Modulates Neuronal Bioelectric Activity in Rat Hippocampus at Dietary-Consistent Amounts. (2015). https://pubmed.ncbi.nlm.nih.gov/26227670/ DOI: 10.1021/acs.jafc.5b02612

route

Local microiontophoresis

tissue

Hippocampus

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 217–226

Original AI-assisted curation of thirteen additional primary studies, with twenty-six existing claims from eight studies linked unchanged. Study-specific citations and limitations retained. Not publisher full text. · supports · In vivo rat hippocampal single-neuron recordings · source_derived_draft · unverified_draft

## indicaxanthin-rat-glutamate-excitation Local indicaxanthin at 0.34 ng/neuron reduced glutamate-evoked excitation in rat hippocampal recordings. Model/species: In vivo rat hippocampal single-neuron recordings Tissue: Hippocampus Exposure: Indicaxanthin 0.085-0.34 ng/neuron; glutamate challenge in selected recordings Route: Local microiontophoresis Duration: Acute firing measurements Limits: Local application bypasses oral distribution. NMDAR binding was proposed by modeling, not established by this electrophysiological observation. Primary reference: Indicaxanthin from Opuntia ficus-indica Crosses the Blood-Brain Barrier and Modulates Neuronal Bioelectric Activity in Rat Hippocampus at Dietary-Consistent Amounts. (2015). https://pubmed.ncbi.nlm.nih.gov/26227670/ DOI: 10.1021/acs.jafc.5b02612 Access: Primary PubMed abstract.

evidence_span

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experimental_model

X-ray structures and human homology model

exposure

Glutamate/MgCl2 with or without ADP

limitations

Direct metal-site observation is yeast; the human model is an inference, not a human deficiency experiment.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Saccharomyces cerevisiae enzyme; separate human model

plain_language

Magnesium has a role beyond merely being present in the assay buffer.

primary_references

[glutathione-p19726687] Mechanistic details of glutathione biosynthesis revealed by crystal structures of Saccharomyces cerevisiae glutamate cysteine ligase. (2009). https://pubmed.ncbi.nlm.nih.gov/19726687/ DOI: 10.1074/jbc.m109.025114

tissue_or_cell_type

Purified Gsh1

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 346–357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures and human homology model · source_derived_draft · unverified_draft

### glutathione-gcl-magnesium The yeast GCL structures identified an ATP-independent magnesium coordination site associated with the enzyme’s Mg dependence. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium has a role beyond merely being present in the assay buffer. organism: Saccharomyces cerevisiae enzyme; separate human model tissue_or_cell_type: Purified Gsh1 experimental_model: X-ray structures and human homology model limitations: Direct metal-site observation is yeast; the human model is an inference, not a human deficiency experiment. exposure: Glutamate/MgCl2 with or without ADP evidence_span: {"source_cache": "artifacts/glutathione-research/19726687.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fd125689fc03eaf0ec433fd6b967eecc6c52c234e99e3717f10218c2c4b97625", "start_char": 0, "end_char": 1461, "text_sha256": "fd125689fc03eaf0ec433fd6b967eecc6c52c234e99e3717f10218c2c4b97625"} [glutathione-p19726687] Mechanistic details of glutathione biosynthesis revealed by crystal structures of Saccharomyces cerevisiae glutamate cysteine ligase. (2009). https://pubmed.ncbi.nlm.nih.gov/19726687/ DOI: 10.1074/jbc.m109.025114

evidence_span

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experimental_model

Human xCT expression and oxidative-stress response

exposure

hxCTb with 4F2hc; diethyl maleate challenge

limitations

Sodium independence belongs to this transporter; other cysteine-entry routes differ.

nutrient_topic

Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH

organism

Human transporter; Xenopus expression host

plain_language

The precursor-entry route depends on two transporter subunits.

primary_references

[glutathione-p11406111] Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. (2001). https://pubmed.ncbi.nlm.nih.gov/11406111/ DOI: 10.1016/s0005-2736(01)00338-8

tissue_or_cell_type

Oocyte membranes and human U87 glioma cells

transport_effect

depends The record names the cystine/glutamate exchange pair and the 4F2hc requirement, not which way cystine crossed.

transport_pool

the cytosol across the plasma membrane The record names the cystine/glutamate exchange pair and the 4F2hc requirement, not which way cystine crossed.

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 736–747

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human xCT expression and oxidative-stress response · source_derived_draft · unverified_draft

### glutathione-xct-cystine Human hxCTb required 4F2hc for sodium-independent cystine/glutamate transport in oocytes. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: The precursor-entry route depends on two transporter subunits. organism: Human transporter; Xenopus expression host tissue_or_cell_type: Oocyte membranes and human U87 glioma cells experimental_model: Human xCT expression and oxidative-stress response limitations: Sodium independence belongs to this transporter; other cysteine-entry routes differ. exposure: hxCTb with 4F2hc; diethyl maleate challenge evidence_span: {"source_cache": "artifacts/glutathione-research/11406111.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc", "start_char": 0, "end_char": 1364, "text_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc"} [glutathione-p11406111] Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. (2001). https://pubmed.ncbi.nlm.nih.gov/11406111/ DOI: 10.1016/s0005-2736(01)00338-8

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells

exposure

Micromolar sulfite exposure

limitations

Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake.

nutrient_topic

Molybdenum research collection; topical membership is not evidence of a direct dietary effect. · Molybdenum

organism

Rattus norvegicus tissue; rodent cell lines

plain_language

A sulfur-metabolism disturbance can interrupt a separate fuel-processing enzyme.

primary_references

[mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

tissue_or_cell_type

Mitochondrial glutamate oxidation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Molybdenum: cofactor assembly, sulfur metabolism and nutrient interactions (2026-09-17) · lines 1366–1377

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells · source_derived_draft · unverified_draft

### mo-sulfite-gdh Sulfite inhibited rat-brain glutamate dehydrogenase and reduced glutamate-supported NADH production. Condition category: machinery_impairment nutrient_topic: Molybdenum research collection; topical membership is not evidence of a direct dietary effect. plain_language: A sulfur-metabolism disturbance can interrupt a separate fuel-processing enzyme. organism: Rattus norvegicus tissue; rodent cell lines tissue_or_cell_type: Mitochondrial glutamate oxidation experimental_model: Rat brain mitochondria/extracts, purified enzyme and Neuro-2a/PC12 cells limitations: Experimental substrate dependence; not a measurement of these effects in people with ordinary low molybdenum intake. exposure: Micromolar sulfite exposure evidence_span: {"source_cache": "artifacts/molybdenum-research/15273247.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279", "start_char": 0, "end_char": 1606, "text_sha256": "d2f73a9ca41e4d51b85d3a66ada08511055ce6ff7462beb0e7eaf21aadf37279"} [mo-p15273247] A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. (2004). https://pubmed.ncbi.nlm.nih.gov/15273247/ DOI: 10.1074/jbc.m402759200

evidence_access

Primary full text

experimental_model

Human SLC25A12 structural analysis.

limitations

The transport domain itself was not captured in a complete transport cycle.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A12 structural analysis. · source_derived_draft · unverified_draft

## l-aspartate-aralar-calcium-site The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature. Calcium-bound human aralar regulatory-domain structures likewise identified EF-hand 2 as the calcium-binding site. Model: Human SLC25A12 structural analysis. Limitations: The transport domain itself was not captured in a complete transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_access

Primary full text

experimental_model

Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework.

limitations

A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Making asparagine needs both aspartate and a nitrogen donor, plus energy.

primary_references

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. · source_derived_draft · unverified_draft

## l-aspartate-asns-reaction Making asparagine needs both aspartate and a nitrogen donor, plus energy. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry. Model: Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. Limitations: A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

evidence_access

Primary full text

experimental_model

Human citrin/aralar domain structures and structural model.

limitations

The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Calcium binding can change access to the transport machinery.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human citrin/aralar domain structures and structural model. · source_derived_draft · unverified_draft

## l-aspartate-carrier-vestibule Calcium binding can change access to the transport machinery. Calcium-associated movement of the mobile regulatory domain opened a vestibule in regulatory-domain structures; the authors proposed that this controls substrate access. Model: Human citrin/aralar domain structures and structural model. Limitations: The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_access

Primary full text

experimental_model

Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures.

limitations

Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Several similarly named structural motifs do not mean several equivalent calcium switches.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. · source_derived_draft · unverified_draft

## l-aspartate-citrin-calcium-site Several similarly named structural motifs do not mean several equivalent calcium switches. Human citrin regulatory-domain structures resolved calcium at EF-hand 2; the other EF-hand motifs were not all calcium-binding sites. Model: Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. Limitations: Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Isolated liver mitochondria from genetically modified mice.

limitations

Small ex vivo flux increment; not human therapeutic efficacy.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

A measurable transport rescue did not amount to proof of complete disease correction.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated liver mitochondria from genetically modified mice. · source_derived_draft · unverified_draft

## l-aspartate-citrin-shuttle-rescue A measurable transport rescue did not amount to proof of complete disease correction. Liver-specific transgenic aralar expression increased residual shuttle activity in citrin-null mouse mitochondria by approximately 4–6 nmol per mg protein per minute. Model: Isolated liver mitochondria from genetically modified mice. Limitations: Small ex vivo flux increment; not human therapeutic efficacy. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

evidence_access

Primary full text

experimental_model

Human cancer cultures and xenografts in immunodeficient mice.

limitations

Not every tumor expresses this transporter, and this is not evidence that ordinary intake initiates cancer. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Uptake partly bypassed a synthesis bottleneck in the tested tumors.

primary_references

Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cultures and xenografts in immunodeficient mice. · source_derived_draft · unverified_draft

## l-aspartate-eaat1-hypoxia Uptake partly bypassed a synthesis bottleneck in the tested tumors. Increasing SLC1A3-mediated uptake supplied aspartate for nucleotide synthesis and improved proliferation under low oxygen and growth in tumor xenograft models. Model: Human cancer cultures and xenografts in immunodeficient mice. Limitations: Not every tumor expresses this transporter, and this is not evidence that ordinary intake initiates cancer. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/ Evidence access: Primary full text Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges.

limitations

SLC1A3 also transports glutamate; effects are model-specific rather than an oral supplementation result. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Transport capacity determines whether a cell can use the aspartate available outside it.

primary_references

Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 74–80

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges. · source_derived_draft · unverified_draft

## l-aspartate-eaat1-respiration Transport capacity determines whether a cell can use the aspartate available outside it. SLC1A3 manipulation changed aspartate import and cancer-cell sensitivity to respiratory inhibitors. Model: Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges. Limitations: SLC1A3 also transports glutamate; effects are model-specific rather than an oral supplementation result. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/ Evidence access: Primary full text Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition.

limitations

Direction is conditional, not an intrinsic one-way label for GOT1.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

A reversible enzyme can run in a different direction when the cell’s redox state changes.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. · source_derived_draft · unverified_draft

## l-aspartate-got1-reversal A reversible enzyme can run in a different direction when the cell’s redox state changes. Under electron-transport-chain inhibition, human GOT1 supported cytosolic aspartate synthesis rather than its usual aspartate-consuming shuttle direction. Model: Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. Limitations: Direction is conditional, not an intrinsic one-way label for GOT1. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

evidence_access

Primary abstract and primary methods/figure text

experimental_model

Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry.

limitations

Host-cell species is not the enzyme species; no dietary brain-delivery effect was tested.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Aspartate-derived NAA can feed a second, glutamate-containing product.

primary_references

Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 370–376

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry. · source_derived_draft · unverified_draft

## l-aspartate-naa-naag-supply Aspartate-derived NAA can feed a second, glutamate-containing product. Coexpressing mouse Nat8l and Rimklb in CHO-K1 or HEK293T cells enabled NAAG production from the NAA-synthesis pathway. Model: Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry. Limitations: Host-cell species is not the enzyme species; no dietary brain-delivery effect was tested. Evidence access: Primary abstract and primary methods/figure text Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

evidence_access

Primary abstract and primary methods/figure text

experimental_model

Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments.

limitations

This is NAA transport, not proof that NaDC3 transports free L-aspartate in the tested assay.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Transport of the intermediate can gate the next synthesis step.

primary_references

Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 378–384

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments. · source_derived_draft · unverified_draft

## l-aspartate-naag-import-route Transport of the intermediate can gate the next synthesis step. Coexpression of the mouse NaDC3 transporter with Rimklb enabled supplied NAA to support NAAG synthesis in heterologous cells. Model: Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments. Limitations: This is NAA transport, not proof that NaDC3 transports free L-aspartate in the tested assay. Evidence access: Primary abstract and primary methods/figure text Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

evidence_access

Primary full text

experimental_model

Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons.

limitations

Not a universal rank of potency or toxicity across all NMDA receptor subtypes.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Two agonists at the same receptor can produce different signal durations.

primary_references

Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 402–408

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons. · source_derived_draft · unverified_draft

## l-aspartate-nmda-deactivation Two agonists at the same receptor can produce different signal durations. L-aspartate-evoked GluN1/GluN2D currents deactivated faster than L-glutamate-evoked currents under matched recording conditions. Model: Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons. Limitations: Not a universal rank of potency or toxicity across all NMDA receptor subtypes. Evidence access: Primary full text Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse HY15549-centered CRISPR screens and knockout comparisons.

limitations

Do not assign all ETC-inhibitor findings to tumor hypoxia or all culture dependencies to animal tumors.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Low oxygen and a respiratory-chain drug were not identical metabolic conditions.

primary_references

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 242–248

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse HY15549-centered CRISPR screens and knockout comparisons. · source_derived_draft · unverified_draft

## l-aspartate-pdac-got2-hypoxia Low oxygen and a respiratory-chain drug were not identical metabolic conditions. Got2 knockout impaired mouse PDAC-cell growth at 0.5% oxygen more strongly than under normoxia; ETC inhibitor exposure instead exposed a distinct Got1 dependency. Model: Mouse HY15549-centered CRISPR screens and knockout comparisons. Limitations: Do not assign all ETC-inhibitor findings to tumor hypoxia or all culture dependencies to animal tumors. Evidence access: Primary full text Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human Jurkat-centered genetic and metabolic experiments.

limitations

Pyruvate is not a universally effective rescue for every respiratory or transaminase defect.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Providing an electron acceptor did not bypass the need for functioning synthesis machinery.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human Jurkat-centered genetic and metabolic experiments. · source_derived_draft · unverified_draft

## l-aspartate-pyruvate-got1-gate Providing an electron acceptor did not bypass the need for functioning synthesis machinery. GOT1 loss prevented pyruvate from rescuing aspartate synthesis and proliferation during ETC dysfunction. Model: Human Jurkat-centered genetic and metabolic experiments. Limitations: Pyruvate is not a universally effective rescue for every respiratory or transaminase defect. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human families and functional characterization of disease-associated human transporter variants.

limitations

Gene-related renal handling is not evidence of an ordinary dietary deficiency; neurological associations do not establish one mechanism.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

A transporter defect can cause nutrient loss even when intake is adequate.

primary_references

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human families and functional characterization of disease-associated human transporter variants. · source_derived_draft · unverified_draft

## l-aspartate-renal-gene-loss A transporter defect can cause nutrient loss even when intake is adequate. Human recessive SLC1A1 R445W and I395del variants were identified in dicarboxylic aminoaciduria with urinary glutamate and aspartate loss. Model: Human families and functional characterization of disease-associated human transporter variants. Limitations: Gene-related renal handling is not evidence of an ordinary dietary deficiency; neurological associations do not establish one mechanism. Evidence access: Primary abstract Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human constructs in heterologous functional assays and canine MDCK cells.

limitations

The accessed abstract reports glutamate/cysteine assays; do not mislabel them as direct aspartate uptake measurements.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Having a transporter gene is insufficient if the protein fails to reach the membrane.

primary_references

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 42–48

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human constructs in heterologous functional assays and canine MDCK cells. · source_derived_draft · unverified_draft

## l-aspartate-renal-trafficking Having a transporter gene is insufficient if the protein fails to reach the membrane. The disease-associated human SLC1A1 variants showed near-absent cell-surface expression in a canine kidney cell model, with impaired glutamate and cysteine transport in functional assays. Model: Human constructs in heterologous functional assays and canine MDCK cells. Limitations: The accessed abstract reports glutamate/cysteine assays; do not mislabel them as direct aspartate uptake measurements. Evidence access: Primary abstract Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse OT-I CD8 cells, shRNA and Listeria infection.

limitations

Knockdown affects related metabolic functions as well; do not attribute all outcomes only to the aspartate pool.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Internal synthesis machinery supported the expanding immune population.

primary_references

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38809979/ · DOI 10.1126/sciadv.adj1431

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 282–288

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse OT-I CD8 cells, shRNA and Listeria infection. · source_derived_draft · unverified_draft

## l-aspartate-tcell-got1-expansion Internal synthesis machinery supported the expanding immune population. Got1 knockdown reduced glutamine-derived aspartate and impaired effector CD8 T-cell expansion in the mouse infection model. Model: Mouse OT-I CD8 cells, shRNA and Listeria infection. Limitations: Knockdown affects related metabolic functions as well; do not attribute all outcomes only to the aspartate pool. Evidence access: Primary full text 13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38809979/ · DOI 10.1126/sciadv.adj1431

experimental_model

Partially purified human jejunal brush-border enzyme

exposure

Radiolabeled synthetic folate polyglutamates in enzyme incubations

limitations

Ex-vivo digestion, not a meal bioavailability measurement.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Food folate tails are shortened before absorption.

primary_references

[reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0

tissue_or_cell_type

Jejunal brush border

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 82–92

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human jejunal brush-border enzyme · source_derived_draft · unverified_draft

### folate-brush-border-deconjugation Partially purified human jejunal brush-border folate hydrolase progressively removed glutamates, producing predominantly monoglutamate after 120 minutes. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Food folate tails are shortened before absorption. organism: Homo sapiens tissue_or_cell_type: Jejunal brush border experimental_model: Partially purified human jejunal brush-border enzyme limitations: Ex-vivo digestion, not a meal bioavailability measurement. exposure: Radiolabeled synthetic folate polyglutamates in enzyme incubations [reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0

experimental_model

Purified human cytosolic FPGS expressed in bacteria

exposure

Comparative substrate enzyme assays

limitations

Does not establish net DHF pool size in human tissues.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens protein expressed in Escherichia coli

plain_language

Polyglutamate tails can be attached before DHF is reduced.

primary_references

[chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

tissue_or_cell_type

Purified enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 267–277

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic FPGS expressed in bacteria · source_derived_draft · unverified_draft

### folate-fpgs-dhf-substrate Dihydrofolate was also an effective substrate for purified human cytosolic FPGS. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Polyglutamate tails can be attached before DHF is reduced. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Purified enzyme experimental_model: Purified human cytosolic FPGS expressed in bacteria limitations: Does not establish net DHF pool size in human tissues. exposure: Comparative substrate enzyme assays [chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

experimental_model

Purified human cytosolic FPGS expressed in bacteria

exposure

Comparative substrate enzyme assays

limitations

Purified substrate preference does not quantify intact-cell flux.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens protein expressed in Escherichia coli

plain_language

FPGS adds tails that help retain usable folate.

primary_references

[chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

tissue_or_cell_type

Purified enzyme

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 255–265

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic FPGS expressed in bacteria · source_derived_draft · unverified_draft

### folate-fpgs-thf-substrate Purified human cytosolic FPGS used tetrahydrofolate as an effective substrate for polyglutamate synthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: FPGS adds tails that help retain usable folate. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Purified enzyme experimental_model: Purified human cytosolic FPGS expressed in bacteria limitations: Purified substrate preference does not quantify intact-cell flux. exposure: Comparative substrate enzyme assays [chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077

cross_nutrient

Histidine degradation supplies a folate-bound carbon group.

evidence_location

Introduction reaction definition; Figure 1 and FT-domain structural analysis.

experimental_model

Recombinant protein structure and functional analysis

exposure

Recombinant rat FTCD; FT-domain structural analysis.

limitations

Rat enzyme; no human histidine-loading response is inferred.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Rattus norvegicus

plain_language

This step brings histidine-derived carbon into folate chemistry.

primary_references

[mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327

tissue_or_cell_type

Cell-free

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1294–1306

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein structure and functional analysis · source_derived_draft · unverified_draft

### rat-ftcd-formimino-transfer The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This step brings histidine-derived carbon into folate chemistry. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein structure and functional analysis limitations: Rat enzyme; no human histidine-loading response is inferred. exposure: Recombinant rat FTCD; FT-domain structural analysis. cross_nutrient: Histidine degradation supplies a folate-bound carbon group. evidence_location: Introduction reaction definition; Figure 1 and FT-domain structural analysis. [mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327

evidence_access

Primary abstract

experimental_model

Recombinant human OAT structure and described catalytic reaction.

limitations

Reversible pathway; net flux depends on tissue and substrate conditions.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Ornithine also feeds a pathway connected to proline metabolism.

primary_references

Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 118–124

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human OAT structure and described catalytic reaction. · source_derived_draft · unverified_draft

## arg-oat-reaction Ornithine also feeds a pathway connected to proline metabolism. OAT transfers the ornithine delta-amino group to 2-oxoglutarate, producing glutamate-5-semialdehyde and glutamate. Model: Recombinant human OAT structure and described catalytic reaction. Limitations: Reversible pathway; net flux depends on tissue and substrate conditions. Evidence access: Primary abstract Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583