L-Glutamine

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

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

The competition was observed in both directions.

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 250–261

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-gln-reciprocal Glutamine inhibited theanine accumulation in rat brain synaptosomal fractions. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The competition was observed in both directions. 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

Stable-isotope whole-body and renal balance study

exposure

Perioperative intravenous alanyl-glutamine 0.5 g/kg/day

limitations

Small perioperative study; the reported doubling versus previous studies was not a concurrent randomized control comparison.

nutrient_topic

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

organism

Human, seven surgical patients

plain_language

Glutamine supplied much of the precursor carbon in this experimental setting.

primary_references

[citrulline-p25332337] Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. (2014). https://pubmed.ncbi.nlm.nih.gov/25332337/ DOI: 10.3945/ajcn.113.081547

tissue_or_cell_type

Intestinal-renal amino-acid axis

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 437–448

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope whole-body and renal balance study · source_derived_draft · unverified_draft

### citrulline-glutamine-source In glutamine-supplemented surgical patients, 91% of total citrulline turnover was attributed to glutamine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutamine supplied much of the precursor carbon in this experimental setting. organism: Human, seven surgical patients tissue_or_cell_type: Intestinal-renal amino-acid axis experimental_model: Stable-isotope whole-body and renal balance study limitations: Small perioperative study; the reported doubling versus previous studies was not a concurrent randomized control comparison. exposure: Perioperative intravenous alanyl-glutamine 0.5 g/kg/day evidence_span: {"source_cache": "artifacts/citrulline-research/25332337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0", "start_char": 0, "end_char": 1788, "text_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0"} [citrulline-p25332337] Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. (2014). https://pubmed.ncbi.nlm.nih.gov/25332337/ DOI: 10.3945/ajcn.113.081547

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

evidence_access

Primary full text

experimental_model

Mouse in vivo tracer infusions and sorted effector T cells.

limitations

Fuel use changed across infection stages; no generalized human glutamine/aspartate supplementation benefit was tested.

nutrient_topic

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

plain_language

The immune cell used one amino acid to help supply another and build nucleotides.

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

L-Aspartate: redox transfer, nitrogen partitioning 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 · Mouse in vivo tracer infusions and sorted effector T cells. · source_derived_draft · unverified_draft

## l-aspartate-tcell-glutamine-carbon The immune cell used one amino acid to help supply another and build nucleotides. Carbon-13 glutamine tracing during mouse Listeria infection showed substantial glutamine contribution to aspartate and pyrimidine synthesis in early effector CD8 T cells. Model: Mouse in vivo tracer infusions and sorted effector T cells. Limitations: Fuel use changed across infection stages; no generalized human glutamine/aspartate supplementation benefit was tested. 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

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

evidence_access

Primary abstract

experimental_model

Human proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel.

limitations

Accessed abstract does not resolve a separate isoleucine kinetic value. Shared transport is not proof that an ordinary mixed meal causes deficiency.

nutrient_topic

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

plain_language

Shared transport depends on amino acids on both sides of the membrane.

primary_references

Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

L-Isoleucine: transport, translation, catabolism 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 proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel. · source_derived_draft · unverified_draft

## isoleucine-lat1-exchange Shared transport depends on amino acids on both sides of the membrane. Human LAT1 with SLC3A2 transported large neutral amino acids and exchanged intracellular leucine or glutamine with extracellular substrates. Model: Human proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel. Limitations: Accessed abstract does not resolve a separate isoleucine kinetic value. Shared transport is not proof that an ordinary mixed meal causes deficiency. Evidence access: Primary abstract Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human stable-isotope-study sampling and treated control comparisons.

limitations

Mixed BCAA effect; dietary decisions in urea-cycle disorders require the full clinical context.

nutrient_topic

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

plain_language

A low amino-acid pool can reflect drug-related handling, not just low intake.

primary_references

New insights in nutritional management and amino acid supplementation in urea cycle disorders. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20299258/ · DOI 10.1016/j.ymgme.2010.02.019

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism 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 · Human stable-isotope-study sampling and treated control comparisons. · source_derived_draft · unverified_draft

## isoleucine-phenylbutyrate-plasma A low amino-acid pool can reflect drug-related handling, not just low intake. Sodium phenylbutyrate-treated urea-cycle-disorder patients had lower circulating BCAAs despite adequate protein intake; low steady-state BCAAs were also observed in treated controls. Model: Human stable-isotope-study sampling and treated control comparisons. Limitations: Mixed BCAA effect; dietary decisions in urea-cycle disorders require the full clinical context. Evidence access: Primary abstract New insights in nutritional management and amino acid supplementation in urea cycle disorders. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20299258/ · DOI 10.1016/j.ymgme.2010.02.019

evidence_span

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experimental_model

Network integration of transcriptomics and metabolomics with pathway inhibition in monocytes and in mice

exposure

Beta-glucan training with inhibition of glutaminolysis and cholesterol synthesis, and fumarate given alone

limitations

Fumarate reproducing the epigenetic programme on its own is the strongest part. The link runs through inhibition of a demethylase, which is not the same modification as an acetylation mark.

nutrient_topic

Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. · Beta-glucan

organism

Human cells and mouse

plain_language

A metabolite piles up and jams the enzyme that would strip the marks off, so the marks stay.

primary_references

[bg-p27866838] Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. (2016). https://pubmed.ncbi.nlm.nih.gov/27866838/ DOI: 10.1016/j.cmet.2016.10.008

tissue_or_cell_type

Monocyte

Beta-glucan: a structural family rather than an agent, what decides whether a bound glucan actually signals, the complement route that a cereal and a yeast preparation share, and the unequal human evidence behind each (2026-09-22) · lines 450–461

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Network integration of transcriptomics and metabolomics with pathway inhibition in monocytes and in mice · source_derived_draft · unverified_draft

### bg-fumarate-blocks-a-demethylase Network-level integration of transcriptomics and metabolomics data identifies glycolysis, glutaminolysis and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by beta-glucan in monocytes, accumulation of fumarate due to glutamine replenishment of the TCA cycle integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases, fumarate itself induced an epigenetic program similar to beta-glucan-induced trained immunity, and inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by beta-glucan. Condition category: normal nutrient_topic: Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. plain_language: A metabolite piles up and jams the enzyme that would strip the marks off, so the marks stay. organism: Human cells and mouse tissue_or_cell_type: Monocyte experimental_model: Network integration of transcriptomics and metabolomics with pathway inhibition in monocytes and in mice limitations: Fumarate reproducing the epigenetic programme on its own is the strongest part. The link runs through inhibition of a demethylase, which is not the same modification as an acetylation mark. exposure: Beta-glucan training with inhibition of glutaminolysis and cholesterol synthesis, and fumarate given alone evidence_span: {"source_cache": "artifacts/glucan-research/27866838.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c67ca385f9dd5e9e97432aa9141a594b7121acca8eea6eba3d0738fed75deba8", "start_char": 0, "end_char": 1031, "text_sha256": "c67ca385f9dd5e9e97432aa9141a594b7121acca8eea6eba3d0738fed75deba8"} [bg-p27866838] Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. (2016). https://pubmed.ncbi.nlm.nih.gov/27866838/ DOI: 10.1016/j.cmet.2016.10.008

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 full text

experimental_model

Normal and IPF human lung fibroblast transporter experiments.

limitations

Dual transport does not by itself prove clinically relevant competition at ordinary plasma concentrations.

nutrient_topic

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

plain_language

A shared importer links access to two amino acids.

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 504–510

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Normal and IPF human lung fibroblast transporter experiments. · source_derived_draft · unverified_draft

## alanine-fibroblast-transporter A shared importer links access to two amino acids. SLC38A2 mediated alanine and glutamine uptake in human lung fibroblasts and increased with TGF-beta exposure or alanine deprivation. Model: Normal and IPF human lung fibroblast transporter experiments. Limitations: Dual transport does not by itself prove clinically relevant competition at ordinary plasma concentrations. 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

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium depletion changes mitochondrial glutamine nitrogen metabolism; enzyme capacity and substrate entry need separate accounting.

endpoint

Renal mitochondria from potassium-depleted rats produced more ammonia during glutamine-metabolism assays after three days of potassium-free feeding.

experimental-exposure

Rats on potassium-free diet with renal mitochondrial and cortical-tubule ammonia assays during depletion and potassium refeeding.

experimental_model

Rats on potassium-free diet with renal mitochondrial and cortical-tubule ammonia assays during depletion and potassium refeeding.

limitations

Isolated mitochondrial assay, not whole-body bicarbonate balance. Glutaminase activity rose earlier than ammonia flux; mitochondrial glutamine entry was proposed as a limiting step.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The kidney adaptation included greater ammonia production, beyond changes in enzyme abundance.

primary_references

[sastrasinh-1986-mitochondrial-ammonia] Renal mitochondrial glutamine metabolism during K+ depletion (1986). https://pubmed.ncbi.nlm.nih.gov/3963205/ DOI: 10.1152/ajprenal.1986.250.4.F667

tissue_or_cell_type

renal mitochondria

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1041–1053

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats on potassium-free diet with renal mitochondrial and cortical-tubule ammonia assays during depletion and potassium refeeding. · source_derived_draft · unverified_draft

### k-depletion-increases-mitochondrial-ammonia Renal mitochondria from potassium-depleted rats produced more ammonia during glutamine-metabolism assays after three days of potassium-free feeding. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidney adaptation included greater ammonia production, beyond changes in enzyme abundance. organism: Rattus norvegicus tissue_or_cell_type: renal mitochondria experimental_model: Rats on potassium-free diet with renal mitochondrial and cortical-tubule ammonia assays during depletion and potassium refeeding. limitations: Isolated mitochondrial assay, not whole-body bicarbonate balance. Glutaminase activity rose earlier than ammonia flux; mitochondrial glutamine entry was proposed as a limiting step. cross_nutrient: Potassium depletion changes mitochondrial glutamine nitrogen metabolism; enzyme capacity and substrate entry need separate accounting. experimental-exposure: Rats on potassium-free diet with renal mitochondrial and cortical-tubule ammonia assays during depletion and potassium refeeding. endpoint: Renal mitochondria from potassium-depleted rats produced more ammonia during glutamine-metabolism assays after three days of potassium-free feeding. [sastrasinh-1986-mitochondrial-ammonia] Renal mitochondrial glutamine metabolism during K+ depletion (1986). https://pubmed.ncbi.nlm.nih.gov/3963205/ DOI: 10.1152/ajprenal.1986.250.4.F667

availability_state

nutrient_deficiency Imported condition classification; unverified.

endpoint

The same hypokalemic diet increased glutamine synthetase expression in type A intercalated cells.

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

Cell-specific regulation is not a contradiction of the proximal-tubule result; neither establishes net flux in an intact human kidney.

nutrient_topic

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

organism

Mus musculus

plain_language

Different kidney cells adjusted the same ammonia-recycling enzyme in opposite directions.

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

type A intercalated cells of cortical and outer medullary collecting duct

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1055–1066

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-intercalated-glul The same hypokalemic diet increased glutamine synthetase expression in type A intercalated cells. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different kidney cells adjusted the same ammonia-recycling enzyme in opposite directions. organism: Mus musculus tissue_or_cell_type: type A intercalated cells of cortical and outer medullary collecting duct experimental_model: Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays. limitations: Cell-specific regulation is not a contradiction of the proximal-tubule result; neither establishes net flux in an intact human kidney. experimental-exposure: Mice fed a nominally potassium-free diet for 12 days; renal immunolabeling and protein/RNA assays. endpoint: The same hypokalemic diet increased glutamine synthetase expression in type A intercalated cells. [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.

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-deficient feeding increased urinary ammonium excretion before detectable hypokalemia 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 kidney changed nitrogen and acid excretion before blood potassium fell.

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 958–970

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-early-ammonium Potassium-deficient feeding increased urinary ammonium excretion before detectable hypokalemia 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 kidney changed nitrogen and acid excretion before blood potassium fell. 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-deficient feeding increased urinary ammonium excretion before detectable hypokalemia 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 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 SNAT3/SN1 expression in the rat time course.

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

More glutamine transporter was detected in the kidney, supporting substrate delivery to the ammonia 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 972–984

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-snat3 Potassium deprivation increased renal SNAT3/SN1 expression in the rat time course. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: More glutamine transporter was detected in the kidney, supporting substrate delivery to the ammonia 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 SNAT3/SN1 expression in the rat time course. [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

evidence_access

Primary full text

experimental_model

Human/mouse metabolomics study; established conjugation route described in primary full text.

limitations

This is not a purified conjugating-enzyme kinetic experiment and does not show clinically meaningful glutamine or glycine depletion.

nutrient_topic

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

plain_language

Host amino acids help turn a bacterial product into circulating metabolites.

primary_references

A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 358–364

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human/mouse metabolomics study; established conjugation route described in primary full text. · source_derived_draft · unverified_draft

## l-phenylalanine-host-conjugation Host amino acids help turn a bacterial product into circulating metabolites. Host conjugation of microbially derived phenylacetate with glutamine produces PAGln, the predominant human conjugate in the study; glycine conjugation produces PAGly, predominant in mice. Model: Human/mouse metabolomics study; established conjugation route described in primary full text. Limitations: This is not a purified conjugating-enzyme kinetic experiment and does not show clinically meaningful glutamine or glycine depletion. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016

evidence_access

Primary abstract

experimental_model

Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected.

limitations

This is an exchange assay, not a direct human brain-uptake trial.

nutrient_topic

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

plain_language

Transport depends on a partner protein and amino acids on both sides of the membrane.

primary_references

Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 42–48

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. · source_derived_draft · unverified_draft

## tryptophan-lat1-partner Transport depends on a partner protein and amino acids on both sides of the membrane. Human LAT1 coexpressed with human SLC3A2/4F2hc in Xenopus oocytes transported large neutral amino acids; extracellular substrates exchanged intracellular leucine and glutamine. Model: Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. Limitations: This is an exchange assay, not a direct human brain-uptake trial. Evidence access: Primary abstract Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences.

limitations

This is a tumor-associated fibroblast model, not a trial of ordinary wound healing. 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

Endogenous synthesis can limit matrix production in activated fibroblasts.

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences. · source_derived_draft · unverified_draft

## l-proline-collagen-pycr1 Endogenous synthesis can limit matrix production in activated fibroblasts. Reducing PYCR1 in human mammary cancer-associated fibroblasts lowered proline supply for collagen production and decreased collagen deposition. Model: Human CAF knockdown and matrix measurements; xenograft experiments separately examined tumor consequences. Limitations: This is a tumor-associated fibroblast model, not a trial of ordinary wound healing. 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 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_span

{"source_cache": "artifacts/theanine-research/34037653.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c792377afacbf5a17e93e4675a4a28ee6849d0288bfc09ad53a2377a0bb982b1", "start_char": 0, "end_char": 1786, "text_sha256": "c792377afacbf5a17e93e4675a4a28ee6849d0288bfc09ad53a2377a0bb982b1"}

experimental_model

Receptor interaction and pathway assays

exposure

Theanine; normal versus experimental stress conditions

limitations

Preclinical CB1-binding claim requires independent confirmation at human exposures; signaling direction differed between normal and stressed rats. No equivalence to cannabinoid drugs inferred.

nutrient_topic

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

organism

Normal and E44813-stressed rats

plain_language

Receptor signaling connects to the enzyme that makes glutamine; the direction depends on context.

primary_references

[theanine-p34037653] L-Theanine regulates glutamine metabolism and immune function by binding to cannabinoid receptor 1. (2021). https://pubmed.ncbi.nlm.nih.gov/34037653/ DOI: 10.1039/d1fo00505g

tissue_or_cell_type

CB1-associated immune and glutamine regulation

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 484–495

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor interaction and pathway assays · source_derived_draft · unverified_draft

### theanine-cb1-gs The authors linked CB1 antagonism to ERK-dependent regulation of glutamine synthetase in rats, with different ERK responses in normal and stressed conditions. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Receptor signaling connects to the enzyme that makes glutamine; the direction depends on context. organism: Normal and E44813-stressed rats tissue_or_cell_type: CB1-associated immune and glutamine regulation experimental_model: Receptor interaction and pathway assays limitations: Preclinical CB1-binding claim requires independent confirmation at human exposures; signaling direction differed between normal and stressed rats. No equivalence to cannabinoid drugs inferred. exposure: Theanine; normal versus experimental stress conditions evidence_span: {"source_cache": "artifacts/theanine-research/34037653.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c792377afacbf5a17e93e4675a4a28ee6849d0288bfc09ad53a2377a0bb982b1", "start_char": 0, "end_char": 1786, "text_sha256": "c792377afacbf5a17e93e4675a4a28ee6849d0288bfc09ad53a2377a0bb982b1"} [theanine-p34037653] L-Theanine regulates glutamine metabolism and immune function by binding to cannabinoid receptor 1. (2021). https://pubmed.ncbi.nlm.nih.gov/34037653/ DOI: 10.1039/d1fo00505g

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"}

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

Competition for a precursor can alter a neurotransmitter-related metabolic pool.

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 237–248

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-gln-astroglia Theanine inhibited glutamine accumulation in cultured rat astroglia. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Competition for a precursor can alter a neurotransmitter-related metabolic pool. 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

{"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"}

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

Competition for a precursor can alter a neurotransmitter-related metabolic pool.

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 224–235

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-gln-neuron Theanine inhibited glutamine accumulation in cultured rat neurons. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Competition for a precursor can alter a neurotransmitter-related metabolic pool. 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

availability_state

machinery_impairment Imported condition classification; unverified.

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"}

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

This particular transport system required its normal ionic environment.

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 276–287

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-sodium-replacement Replacing sodium chloride with choline chloride reduced theanine and glutamine accumulation in rat brain preparations. Condition category: machinery_impairment nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This particular transport system required its normal ionic environment. 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_access

Primary abstract

experimental_model

Human SiHa extracts and purified recombinant human LAT1 in proteoliposomes.

limitations

In-vitro exchange does not establish whole-body competition or supplement ratios.

nutrient_topic

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

plain_language

The transporter exchanges substrates, so both sides of the membrane matter.

primary_references

LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004

transport_effect

depends Recorded as antiport, including exchange with internal cysteine, tyrosine or glutamine.

transport_pool

the cytosol across the plasma membrane Recorded as antiport, including exchange with internal cysteine, tyrosine or glutamine.

L-Histidine: supply, catabolism, histamine, receptors 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 SiHa extracts and purified recombinant human LAT1 in proteoliposomes. · source_derived_draft · unverified_draft

## histidine-lat1-exchange The transporter exchanges substrates, so both sides of the membrane matter. Reconstituted human LAT1 supported histidine antiport, including exchange with internal cysteine, tyrosine or glutamine; external histidine affinity exceeded internal affinity. Model: Human SiHa extracts and purified recombinant human LAT1 in proteoliposomes. Limitations: In-vitro exchange does not establish whole-body competition or supplement ratios. Evidence access: Primary abstract LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004

evidence_access

Primary abstract

experimental_model

Cloned human liver-cell SN2 in mammalian expression assays.

limitations

Transporter kinetics do not supply a dietary sodium or histidine target.

nutrient_topic

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

plain_language

A second uptake system depends on the ionic and pH environment.

primary_references

Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11243884/ · DOI 10.1006/bbrc.2001.4504

transport_effect

raises Sodium-dependent histidine transport with a measured Km of 0.6 mM.

transport_pool

the expressing cell Sodium-dependent histidine transport with a measured Km of 0.6 mM.

L-Histidine: supply, catabolism, histamine, receptors 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 · Cloned human liver-cell SN2 in mammalian expression assays. · source_derived_draft · unverified_draft

## histidine-sn2-uptake A second uptake system depends on the ionic and pH environment. Expressed human SN2 transported histidine with sodium dependence and strong pH sensitivity; the measured histidine Km was 0.6 +/- 0.1 mM. Model: Cloned human liver-cell SN2 in mammalian expression assays. Limitations: Transporter kinetics do not supply a dietary sodium or histidine target. Evidence access: Primary abstract Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11243884/ · DOI 10.1006/bbrc.2001.4504

cross_nutrient

Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway.

evidence_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}

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 deamidated route finishes by making NAD+ through NADSYN1.

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 328–340

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-amidation Purified human NADSYN1 catalyzed ATP-dependent NAD+ production from nicotinic acid adenine dinucleotide in glutamine-supported assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The deamidated route finishes by making NAD+ through NADSYN1. 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 supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [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_span

{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}

experimental_model

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

exposure

Biochemical or structural assay; no dietary intervention

limitations

Assay substrate efficiency does not show that free ammonia replaces glutamine physiologically or justify ammonia exposure.

nutrient_topic

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

organism

Homo sapiens

plain_language

Human NADSYN1 can use either tested nitrogen source in vitro.

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 356–367

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-ammonia Purified human NADSYN1 also supported NAD+ formation with free ammonia; its reported catalytic efficiencies for glutamine and ammonia were similar, 0.45 and 0.49 per second per millimolar. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human NADSYN1 can use either tested nitrogen source in vitro. 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: Assay substrate efficiency does not show that free ammonia replaces glutamine physiologically or justify ammonia exposure. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [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

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"}

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

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

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

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

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 218–224

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 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

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

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

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 ASNS 1.85-angstrom structure and comparison with mechanistic data.

limitations

Structural interpretation is distinguished from measuring every transient chemical intermediate in intact cells. 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

The enzyme coordinates two reactions rather than attaching free glutamine directly to aspartate.

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 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human ASNS 1.85-angstrom structure and comparison with mechanistic data. · source_derived_draft · unverified_draft

## l-aspartate-asns-two-sites The enzyme coordinates two reactions rather than attaching free glutamine directly to aspartate. The human ASNS structure separates glutamine-processing and ATP-dependent synthetase domains, with an internal path supporting nitrogen transfer toward activated aspartate. Model: Human ASNS 1.85-angstrom structure and comparison with mechanistic data. Limitations: Structural interpretation is distinguished from measuring every transient chemical intermediate in intact cells. 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 HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing.

limitations

This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity.

nutrient_topic

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

plain_language

Growth signals can accelerate use of aspartate for nucleotide production.

primary_references

Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

L-Aspartate: redox transfer, nitrogen partitioning 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 · Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. · source_derived_draft · unverified_draft

## l-aspartate-cad-s6k1 Growth signals can accelerate use of aspartate for nucleotide production. S6K1 directly phosphorylated CAD at Ser1859, connecting mTORC1 signaling to increased de novo pyrimidine synthesis. Model: Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. Limitations: This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity. Evidence access: Primary full text Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse Got1-deficient T-cell and chronic-infection experiments.

limitations

Experimental rescue does not establish a human dosing strategy or replacement for intact immunity.

nutrient_topic

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

plain_language

Supplying the nitrogen acceptor let the cells dispose of the ammonia that had built up.

primary_references

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning 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 Got1-deficient T-cell and chronic-infection experiments. · source_derived_draft · unverified_draft

## l-aspartate-tcell-akg-rescue Restoring a missing nitrogen-accepting metabolite helped recover function. 2-Oxoglutarate supplementation promoted ammonia assimilation and restored antiviral responses in Got1-deficient T-cell experiments. Model: Mouse Got1-deficient T-cell and chronic-infection experiments. Limitations: Experimental rescue does not establish a human dosing strategy or replacement for intact immunity. Evidence access: Primary abstract The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse Got1-deficient T-cell and chronic-infection experiments.

limitations

Experimental rescue does not establish a human dosing strategy or replacement for intact immunity.

nutrient_topic

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

plain_language

Restoring a missing nitrogen-accepting metabolite helped recover function.

primary_references

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning 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 Got1-deficient T-cell and chronic-infection experiments. · source_derived_draft · unverified_draft

## l-aspartate-tcell-akg-rescue Restoring a missing nitrogen-accepting metabolite helped recover function. 2-Oxoglutarate supplementation promoted ammonia assimilation and restored antiviral responses in Got1-deficient T-cell experiments. Model: Mouse Got1-deficient T-cell and chronic-infection experiments. Limitations: Experimental rescue does not establish a human dosing strategy or replacement for intact immunity. Evidence access: Primary abstract The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse T-cell-specific gene deletion and chronic LCMV infection.

limitations

This is a cell-state-specific mechanism, not a universal definition of malate–aspartate shuttle function.

nutrient_topic

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

plain_language

The transaminase also helped manage the nitrogen released while using glutamine.

primary_references

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 298–304

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse T-cell-specific gene deletion and chronic LCMV infection. · source_derived_draft · unverified_draft

## l-aspartate-tcell-ammonia The transaminase also helped manage the nitrogen released while using glutamine. Got1 deficiency lowered 2-oxoglutarate production from glutamine metabolism and caused toxic ammonia accumulation in mouse CD8 T cells during chronic infection. Model: Mouse T-cell-specific gene deletion and chronic LCMV infection. Limitations: This is a cell-state-specific mechanism, not a universal definition of malate–aspartate shuttle function. Evidence access: Primary abstract The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37813964/ · DOI 10.1038/s41590-023-01636-5

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