L-Aspartate

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mammalian cell-culture respiration perturbation and rescue.

limitations

Cell-culture rescue does not establish oral aspartate delivery or therapeutic efficacy in people.

nutrient_topic

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

plain_language

Supplying the missing product can bypass a biosynthetic bottleneck.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 212–218

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mammalian cell-culture respiration perturbation and rescue. · source_derived_draft · unverified_draft

## nad-plus-aspartate-rescue Supplying the missing product can bypass a biosynthetic bottleneck. Aspartate supplementation rescued proliferation of the tested respiration-deficient cells. Model: Mammalian cell-culture respiration perturbation and rescue. Limitations: Cell-culture rescue does not establish oral aspartate delivery or therapeutic efficacy in people. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

evidence_span

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experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

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

organism

Human ASS1

plain_language

Aspartate supplies part of the molecule built at this step.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 138–149

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-aspartate Aspartate is a substrate of human ASS1 and was resolved with citrulline in the enzyme structure. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Aspartate supplies part of the molecule built at this step. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_access

Primary abstract

experimental_model

Eight infants, gestational age 26–34 weeks; enteral and intravenous stable-isotope tracer protocol.

limitations

Do not substitute the paper title’s almost all for 100%, or extrapolate this percentage to healthy adults.

nutrient_topic

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

plain_language

Much of the ingested amino acid was handled before reaching the wider circulation.

primary_references

Almost all enteral aspartate is taken up in first-pass metabolism in enterally fed preterm infants. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20022677/ · DOI 10.1016/j.clnu.2009.11.008

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 18–24

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Eight infants, gestational age 26–34 weeks; enteral and intravenous stable-isotope tracer protocol. · source_derived_draft · unverified_draft

## l-aspartate-infant-first-pass Much of the ingested amino acid was handled before reaching the wider circulation. Dual-isotope tracing in eight enterally fed preterm infants measured splanchnic first-pass aspartate uptake of 77 ± 15%. Model: Eight infants, gestational age 26–34 weeks; enteral and intravenous stable-isotope tracer protocol. Limitations: Do not substitute the paper title’s almost all for 100%, or extrapolate this percentage to healthy adults. Evidence access: Primary abstract Almost all enteral aspartate is taken up in first-pass metabolism in enterally fed preterm infants. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20022677/ · DOI 10.1016/j.clnu.2009.11.008

evidence_access

Primary abstract

experimental_model

Same eight preterm infants; carbon-13 recovery in breath.

limitations

The denominator is label used in first pass, not necessarily the entire administered dose; no adult efficacy inference.

nutrient_topic

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

plain_language

The tracing supports extensive use of the carbon skeleton for energy metabolism.

primary_references

Almost all enteral aspartate is taken up in first-pass metabolism in enterally fed preterm infants. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20022677/ · DOI 10.1016/j.clnu.2009.11.008

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same eight preterm infants; carbon-13 recovery in breath. · source_derived_draft · unverified_draft

## l-aspartate-infant-oxidation The tracing supports extensive use of the carbon skeleton for energy metabolism. About 80 ± 9% of labeled aspartate carbon used in first-pass metabolism was recovered in expired carbon dioxide. Model: Same eight preterm infants; carbon-13 recovery in breath. Limitations: The denominator is label used in first pass, not necessarily the entire administered dose; no adult efficacy inference. Evidence access: Primary abstract Almost all enteral aspartate is taken up in first-pass metabolism in enterally fed preterm infants. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20022677/ · DOI 10.1016/j.clnu.2009.11.008

evidence_access

Primary full text

experimental_model

Rat receptor constructs; 1-second 1 mM agonist pulse with 0.05 mM glycine.

limitations

This does not demonstrate brain entry, cognitive benefit or excitotoxicity after oral intake.

nutrient_topic

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

plain_language

L-aspartate can act at a receptor in a controlled electrophysiology experiment.

primary_references

Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 394–400

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat receptor constructs; 1-second 1 mM agonist pulse with 0.05 mM glycine. · source_derived_draft · unverified_draft

## l-aspartate-nmda-agonism L-aspartate can act at a receptor in a controlled electrophysiology experiment. L-aspartate evoked currents from recombinant rat GluN1/GluN2D receptors expressed in HEK293 cells when glycine was present. Model: Rat receptor constructs; 1-second 1 mM agonist pulse with 0.05 mM glycine. Limitations: This does not demonstrate brain entry, cognitive benefit or excitotoxicity after oral intake. Evidence access: Primary full text Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

evidence_access

Primary full text

experimental_model

Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons.

limitations

Not a universal rank of potency or toxicity across all NMDA receptor subtypes.

nutrient_topic

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

plain_language

Two agonists at the same receptor can produce different signal durations.

primary_references

Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 402–408

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons. · source_derived_draft · unverified_draft

## l-aspartate-nmda-deactivation Two agonists at the same receptor can produce different signal durations. L-aspartate-evoked GluN1/GluN2D currents deactivated faster than L-glutamate-evoked currents under matched recording conditions. Model: Rat recombinant receptors in HEK293 cells; voltage-clamp and structural comparisons. Limitations: Not a universal rank of potency or toxicity across all NMDA receptor subtypes. Evidence access: Primary full text Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21522138/ · DOI 10.1038/ncomms1295

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate.

limitations

The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery.

nutrient_topic

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

plain_language

Restoring one substrate repaired some nucleotide steps without repairing all of them.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. · source_derived_draft · unverified_draft

## l-aspartate-purine-rescue Restoring one substrate repaired some nucleotide steps without repairing all of them. Aspartate supplementation relieved IMP accumulation and restored AMP and SAICAR pools in respiration-impaired 143B cells, while GMP did not similarly recover. Model: Human 143B cytochrome-b-mutant cells; metabolomics after high extracellular aspartate. Limitations: The GMP branch also depends on redox chemistry; high culture supplementation does not establish oral delivery. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

evidence_access

Primary abstract and primary figure descriptions

experimental_model

Proliferating-cell perturbation and tracer study, including human NSCLC models.

limitations

Substrate availability in cell models is not evidence for benefits of oral L-aspartate.

nutrient_topic

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

plain_language

Aspartate demand for building material can compete with its participation in redox transfer.

primary_references

Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 226–232

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Proliferating-cell perturbation and tracer study, including human NSCLC models. · source_derived_draft · unverified_draft

## l-aspartate-shuttle-aspartate-availability Aspartate demand for building material can compete with its participation in redox transfer. Increasing aspartate availability enhanced malate–aspartate shuttle use and mitochondrial metabolism of glucose-derived pyruvate in proliferating cell experiments. Model: Proliferating-cell perturbation and tracer study, including human NSCLC models. Limitations: Substrate availability in cell models is not evidence for benefits of oral L-aspartate. Evidence access: Primary abstract and primary figure descriptions Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse CD8 culture; Got1 knockdown with/without medium aspartate.

limitations

Conditional auxotrophy is not a demonstrated human dietary deficiency.

nutrient_topic

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

plain_language

Cells depended more on external supply when synthesis was impaired.

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

nutrient_deficiency Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 290–296

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse CD8 culture; Got1 knockdown with/without medium aspartate. · source_derived_draft · unverified_draft

## l-aspartate-tcell-external-gate Cells depended more on external supply when synthesis was impaired. Removing extracellular aspartate selectively reduced proliferation of Got1-silenced mouse CD8 cells, whereas control cells better tolerated its removal and viability was unchanged. Model: Mouse CD8 culture; Got1 knockdown with/without medium aspartate. Limitations: Conditional auxotrophy is not a demonstrated human dietary deficiency. 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

Purified human cytosolic GOT1 and GPT; coupled kinetic assays

exposure

Kinetic assays at pH 7.4 and 37 C

limitations

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

nutrient_topic

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

organism

Homo sapiens

plain_language

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

primary_references

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

tissue_or_cell_type

Purified recombinant protein; no intact tissue

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Cultured proliferating mammalian cells with impaired respiration.

limitations

ATP is not generally dispensable; this experiment isolates an electron-acceptor bottleneck in supplied culture conditions.

nutrient_topic

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

plain_language

Respiration supports building material by restoring electron acceptors, as well as producing ATP.

primary_references

Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 204–210

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured proliferating mammalian cells with impaired respiration. · source_derived_draft · unverified_draft

## nad-plus-electron-acceptor-aspartate Respiration supports building material by restoring electron acceptors, as well as producing ATP. Respiration-deficient proliferating cells became limited in aspartate synthesis; alpha-ketobutyrate restored proliferation as an electron acceptor without supplying carbon or ATP. Model: Cultured proliferating mammalian cells with impaired respiration. Limitations: ATP is not generally dispensable; this experiment isolates an electron-acceptor bottleneck in supplied culture conditions. Evidence access: Primary full text Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232225/ · DOI 10.1016/j.cell.2015.07.017

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human cancer-cell perturbations, metabolic analysis and disease-related comparisons.

limitations

The finding does not mean reducing nitrogen disposal is beneficial; it is a tumor-model mechanism.

nutrient_topic

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

plain_language

Using less aspartate for arginine synthesis can leave more for nucleotide synthesis.

primary_references

Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26560030/ · DOI 10.1038/nature15529

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell perturbations, metabolic analysis and disease-related comparisons. · source_derived_draft · unverified_draft

## l-aspartate-ass1-diversion Using less aspartate for arginine synthesis can leave more for nucleotide synthesis. Reduced ASS1 activity increased cytosolic aspartate availability and CAD-dependent pyrimidine synthesis in the studied cancer models. Model: Human cancer-cell perturbations, metabolic analysis and disease-related comparisons. Limitations: The finding does not mean reducing nitrogen disposal is beneficial; it is a tumor-model mechanism. Evidence access: Primary abstract Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26560030/ · DOI 10.1038/nature15529

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition.

limitations

Direction is conditional, not an intrinsic one-way label for GOT1.

nutrient_topic

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

plain_language

A reversible enzyme can run in a different direction when the cell’s redox state changes.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. · source_derived_draft · unverified_draft

## l-aspartate-got1-reversal A reversible enzyme can run in a different direction when the cell’s redox state changes. Under electron-transport-chain inhibition, human GOT1 supported cytosolic aspartate synthesis rather than its usual aspartate-consuming shuttle direction. Model: Human proliferating cell models; genetic screen and metabolic tracing during ETC inhibition. Limitations: Direction is conditional, not an intrinsic one-way label for GOT1. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

evidence_access

Primary 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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Liver-specific Pcx-knockout mice

exposure

Genetic deletion of hepatic pyruvate carboxylase

limitations

Genetic enzyme deletion is not a dietary biotin experiment. Cross-nutrient implications identify pathway dependence rather than a proven supplement response.

nutrient_topic

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

organism

Mus musculus

plain_language

Loss of carbon replenishment also constrained nitrogen disposal.

primary_references

[b7-p31006591] Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. (2019). https://pubmed.ncbi.nlm.nih.gov/31006591/ DOI: 10.1016/j.cmet.2019.03.014

tissue_or_cell_type

Liver and systemic metabolism

trigger_kind

machinery_impairment Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 858–869

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific Pcx-knockout mice · source_derived_draft · unverified_draft

### b7-pc-null-aspartate Liver-specific Pcx deletion depleted aspartate and impaired urea-cycle function, with hyperammonemia. Condition category: machinery_impairment nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of carbon replenishment also constrained nitrogen disposal. organism: Mus musculus tissue_or_cell_type: Liver and systemic metabolism experimental_model: Liver-specific Pcx-knockout mice limitations: Genetic enzyme deletion is not a dietary biotin experiment. Cross-nutrient implications identify pathway dependence rather than a proven supplement response. exposure: Genetic deletion of hepatic pyruvate carboxylase evidence_span: {"source_cache": "artifacts/biotin-research/31006591.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e", "start_char": 0, "end_char": 1141, "text_sha256": "0dcedbfac623863bd4ae86ed1bb97cef0ef56bd417bd0d49507ef47d16af7b4e"} [b7-p31006591] Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. (2019). https://pubmed.ncbi.nlm.nih.gov/31006591/ DOI: 10.1016/j.cmet.2019.03.014

evidence_access

Primary abstract

experimental_model

Rat clonal BRIN-BD11 beta-cell experiments.

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_span

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experimental_model

Cancer cells in varied culture environments with complex I inhibitors

exposure

Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply

limitations

Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human and mouse cancer cells

plain_language

The real shortage is the carrier the chain recycles and the amino acid that depends on it.

primary_references

[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006

tissue_or_cell_type

Cancer cells in culture and in vivo

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 710–721

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer cells in varied culture environments with complex I inhibitors · source_derived_draft · unverified_draft

### metformin-nad-aspartate The anti-proliferative effect of metformin was due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis, because complex I supports proliferation by regenerating NAD+. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The real shortage is the carrier the chain recycles and the amino acid that depends on it. organism: Human and mouse cancer cells tissue_or_cell_type: Cancer cells in culture and in vivo experimental_model: Cancer cells in varied culture environments with complex I inhibitors limitations: Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property. exposure: Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply evidence_span: {"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"} [metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006

evidence_access

Primary full text

experimental_model

Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.

limitations

Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues.

nutrient_topic

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

plain_language

Available nutrients can change the effect of an inhibitor on the same pathway.

primary_references

Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 220–226

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. · source_derived_draft · unverified_draft

## nad-plus-pyruvate-metformin Available nutrients can change the effect of an inhibitor on the same pathway. Pyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells. Model: Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. Limitations: Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues. Evidence access: Primary full text Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006

evidence_span

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experimental_model

Fixed-sequence two-period oral glucose tolerance study

exposure

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

limitations

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

nutrient_topic

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

organism

39 healthy humans

plain_language

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

primary_references

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

tissue_or_cell_type

Blood glucose and urinary solutes

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

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

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

evidence_access

Primary full text

experimental_model

Rat pinealocytes and slices; electrogenic current assays.

limitations

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

nutrient_topic

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

plain_language

Transporting the amino acid can itself change the cell voltage.

primary_references

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse frontal cortex, hippocampus and striatum; cerebellum unaffected.

limitations

Association supported a production hypothesis; it did not independently identify the complete biosynthetic pathway.

nutrient_topic

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

plain_language

A smaller pool was not explained by higher measured breakdown or lower L-aspartate.

primary_references

Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23439386/ · DOI 10.1016/j.neuint.2013.02.015

trigger_kind

machinery_impairment Imported condition classification; unverified.

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 48–54

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse frontal cortex, hippocampus and striatum; cerebellum unaffected. · source_derived_draft · unverified_draft

## d-aspartate-srr-loss-ddo-control A smaller pool was not explained by higher measured breakdown or lower L-aspartate. Srr-knockout mouse forebrain had less D-aspartate without detected differences in DDO activity or L-aspartate concentrations. Model: Mouse frontal cortex, hippocampus and striatum; cerebellum unaffected. Limitations: Association supported a production hypothesis; it did not independently identify the complete biosynthetic pathway. Evidence access: Primary abstract Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23439386/ · DOI 10.1016/j.neuint.2013.02.015

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Srr-knockout mice; regional amino-acid measurements.

limitations

Not dietary deficiency or proof that a supplement repairs the knockout.

nutrient_topic

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

plain_language

Dependence on the same enzyme varies by tissue.

primary_references

Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

trigger_kind

machinery_impairment Imported condition classification; unverified.

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 40–46

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Srr-knockout mice; regional amino-acid measurements. · source_derived_draft · unverified_draft

## d-aspartate-srr-mouse-loss Dependence on the same enzyme varies by tissue. Srr deletion lowered D-aspartate in mouse frontal cortex and hippocampus, while cerebellum and testes were unchanged. Model: Srr-knockout mice; regional amino-acid measurements. Limitations: Not dietary deficiency or proof that a supplement repairs the knockout. Evidence access: Primary abstract Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

evidence_access

Primary abstract

experimental_model

Rat PC12 host cells; overexpressed construct species not resolved here.

limitations

Overexpression does not establish that native SRR is the sole source.

nutrient_topic

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

plain_language

Adding more racemase increased the measured D-aspartate pool.

primary_references

Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 24–30

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat PC12 host cells; overexpressed construct species not resolved here. · source_derived_draft · unverified_draft

## d-aspartate-srr-overexpression Adding more racemase increased the measured D-aspartate pool. SRR overexpression increased intracellular D-aspartate in rat PC12 cells. Model: Rat PC12 host cells; overexpressed construct species not resolved here. Limitations: Overexpression does not establish that native SRR is the sole source. Evidence access: Primary abstract Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

evidence_access

Primary abstract

experimental_model

Recombinant mammalian enzyme; protein species not resolved in the accessed abstract.

limitations

Do not substitute a specific human enzyme identity or infer rates in intact human tissues.

nutrient_topic

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

plain_language

An enzyme best known for serine can also change aspartate chirality.

primary_references

Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 16–22

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant mammalian enzyme; protein species not resolved in the accessed abstract. · source_derived_draft · unverified_draft

## d-aspartate-srr-racemization An enzyme best known for serine can also change aspartate chirality. Purified mammalian serine racemase catalyzed aspartate racemization in the reported two-base reaction mechanism. Model: Recombinant mammalian enzyme; protein species not resolved in the accessed abstract. Limitations: Do not substitute a specific human enzyme identity or infer rates in intact human tissues. Evidence access: Primary abstract Serine racemase is involved in d-aspartate biosynthesis. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27387750/ · DOI 10.1093/jb/mvw043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Ddo-knockout mouse nigral neuron transporter-blocker experiments.

limitations

A protective adaptation is an interpretation; human transporter failure and dietary consequences were not tested.

nutrient_topic

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

plain_language

Uptake can buffer excitation when breakdown is impaired.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 208–214

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ddo-knockout mouse nigral neuron transporter-blocker experiments. · source_derived_draft · unverified_draft

## d-aspartate-uptake-buffer Uptake can buffer excitation when breakdown is impaired. EAAT inhibition strongly potentiated D-aspartate-evoked, but not L-aspartate-evoked, currents in Ddo-knockout mouse neurons. Model: Ddo-knockout mouse nigral neuron transporter-blocker experiments. Limitations: A protective adaptation is an interpretation; human transporter failure and dietary consequences were not tested. Evidence access: Primary abstract Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26707656/ · DOI 10.1016/j.neuropharm.2015.12.013

evidence_span

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experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

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

organism

Human ASS1

plain_language

Arginine regeneration has an energy cost.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 151–162

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-energy The ASS1 reaction uses ATP cleavage to AMP and pyrophosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine regeneration has an energy cost. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_span

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experimental_model

Crystal structure and biochemical reaction characterization

exposure

Citrulline and aspartate bound to recombinant enzyme

limitations

Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.

nutrient_topic

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

organism

Human ASS1

plain_language

Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine.

primary_references

[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

tissue_or_cell_type

Cytosolic arginine-regeneration reaction

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 125–136

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft

### citrulline-ass1-reaction Human ASS1 combines citrulline and aspartate to form argininosuccinate in an ATP-dependent reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455

evidence_span

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experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

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

organism

Human citrin and aralar proteins

plain_language

Moving aspartate between compartments helps connect nitrogen handling and redox metabolism.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 359–370

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-aspartate Reconstituted citrin exchanged aspartate for glutamate plus a proton. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Moving aspartate between compartments helps connect nitrogen handling and redox metabolism. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_span

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experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

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

organism

Human citrin and aralar proteins

plain_language

Calcium is a regulatory signal for the transporter.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 372–383

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-calcium Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium is a regulatory signal for the transporter. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_span

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experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

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

organism

Human citrin and aralar proteins

plain_language

The same transporter participates in moving reducing equivalents between compartments.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 385–396

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-shuttle Citrin overexpression increased malate-aspartate shuttle activity in transfected human cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same transporter participates in moving reducing equivalents between compartments. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_access

Primary abstract

experimental_model

Human intestinal mucosa and red-cell lysate fractionation.

limitations

Intact dipeptide transport was proposed; the cytosolic enzyme was not molecularly identified.

nutrient_topic

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

plain_language

The amino-acid pair can be processed after reaching a different cell compartment.

primary_references

Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human intestinal mucosa and red-cell lysate fractionation. · source_derived_draft · unverified_draft

## aspartame-dipeptide-cleavage The amino-acid pair can be processed after reaching a different cell compartment. Brush-border and cytosolic preparations hydrolyzed Asp-Phe; cytosolic fractionation identified one activity peak distinct from seven previously described peptidases. Model: Human intestinal mucosa and red-cell lysate fractionation. Limitations: Intact dipeptide transport was proposed; the cytosolic enzyme was not molecularly identified. Evidence access: Primary abstract Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Same human comparison.

limitations

Plasma is not synaptic aspartate.

nutrient_topic

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

plain_language

The other amino-acid product also shows formulation effects.

primary_references

Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 98–104

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

## aspartame-formulation-aspartate The other amino-acid product also shows formulation effects. Peak plasma aspartate was higher and earlier with 3 g solution than capsules: 26.2 versus 10.4 micromol/L. Model: Same human comparison. Limitations: Plasma is not synaptic aspartate. Evidence access: Primary abstract Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7

evidence_access

Primary abstract

experimental_model

Six healthy young adults.

limitations

Normal range is protocol- and assay-dependent, not proof that no metabolism occurred.

nutrient_topic

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

plain_language

Products can be generated without a sustained high blood pool.

primary_references

Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six healthy young adults. · source_derived_draft · unverified_draft

## aspartame-repeated-metabolites Products can be generated without a sustained high blood pool. Methanol and formate remained within reported normal limits; plasma aspartate did not significantly rise in the eight-serving experiment. Model: Six healthy young adults. Limitations: Normal range is protocol- and assay-dependent, not proof that no metabolism occurred. Evidence access: Primary abstract Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x

evidence_access

Primary full text

experimental_model

Human SLC25A12 structural analysis.

limitations

The transport domain itself was not captured in a complete transport cycle.

nutrient_topic

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

plain_language

The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A12 structural analysis. · source_derived_draft · unverified_draft

## l-aspartate-aralar-calcium-site The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature. Calcium-bound human aralar regulatory-domain structures likewise identified EF-hand 2 as the calcium-binding site. Model: Human SLC25A12 structural analysis. Limitations: The transport domain itself was not captured in a complete transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_access

Primary full text

experimental_model

Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework.

limitations

A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1

nutrient_topic

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

plain_language

Making asparagine needs both aspartate and a nitrogen donor, plus energy.

primary_references

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. · source_derived_draft · unverified_draft

## l-aspartate-asns-reaction Making asparagine needs both aspartate and a nitrogen donor, plus energy. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry. Model: Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. Limitations: A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z

evidence_access

Primary full text

experimental_model

Human 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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human disorder-derived observations and experimental disease/cancer comparisons.

limitations

Neither condition is simple low dietary aspartate; do not turn cellular proliferation measures into patient cancer-risk estimates.

nutrient_topic

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

plain_language

Two defects affecting the same cycle can leave very different amounts of substrate for another pathway.

primary_references

Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26560030/ · DOI 10.1038/nature15529

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human disorder-derived observations and experimental disease/cancer comparisons. · source_derived_draft · unverified_draft

## l-aspartate-ass1-citrin-difference Two defects affecting the same cycle can leave very different amounts of substrate for another pathway. ASS1-deficient citrullinemia type I models showed greater pyrimidine synthesis and proliferation than citrin-deficient type II models, where aspartate delivery was restricted. Model: Human disorder-derived observations and experimental disease/cancer comparisons. Limitations: Neither condition is simple low dietary aspartate; do not turn cellular proliferation measures into patient cancer-risk estimates. Evidence access: Primary abstract Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26560030/ · DOI 10.1038/nature15529

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse primary brown adipocytes; approximately 80% knockdown in the reported experiment.

limitations

This does not establish human weight-loss effects or a nutrient-intake threshold.

nutrient_topic

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

plain_language

Disrupting the carrier changed fat handling in the cell.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 330–336

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse primary brown adipocytes; approximately 80% knockdown in the reported experiment. · source_derived_draft · unverified_draft

## l-aspartate-brown-aralar-lipids Disrupting the carrier changed fat handling in the cell. Aralar1 silencing in primary mouse brown adipocytes impaired norepinephrine-induced lipid mobilization and increased small lipid-droplet accumulation. Model: Mouse primary brown adipocytes; approximately 80% knockdown in the reported experiment. Limitations: This does not establish human weight-loss effects or a nutrient-intake threshold. Evidence access: Primary full text The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse primary brown adipocytes; adenoviral shRNA with metabolic assays.

limitations

Shared pathway dependence does not make the two carriers interchangeable.

nutrient_topic

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

plain_language

A second carrier in the same shuttle also affected lipid mobilization.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse primary brown adipocytes; adenoviral shRNA with metabolic assays. · source_derived_draft · unverified_draft

## l-aspartate-brown-ogc-lipids A second carrier in the same shuttle also affected lipid mobilization. Oxoglutarate-carrier silencing similarly increased small lipid droplets and impaired norepinephrine-induced lipolysis in mouse brown adipocytes. Model: Mouse primary brown adipocytes; adenoviral shRNA with metabolic assays. Limitations: Shared pathway dependence does not make the two carriers interchangeable. Evidence access: Primary full text The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Same mouse primary-cell experiments; respiration measurements.

limitations

The null result is limited to the tested conditions and does not establish that the shuttle never contributes to respiration.

nutrient_topic

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

plain_language

A lipid-storage phenotype did not imply that mitochondrial oxygen consumption had collapsed.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 346–352

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

## l-aspartate-brown-respiration-limit A lipid-storage phenotype did not imply that mitochondrial oxygen consumption had collapsed. Silencing either carrier had no apparent effect on the measured respiratory rates despite changes in lipid handling. Model: Same mouse primary-cell experiments; respiration measurements. Limitations: The null result is limited to the tested conditions and does not establish that the shuttle never contributes to respiration. Evidence access: Primary full text The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41704162/ · DOI 10.1111/febs.70461

evidence_access

Primary full text

experimental_model

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

limitations

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

nutrient_topic

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

plain_language

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

primary_references

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

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

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

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

evidence_access

Primary full text

experimental_model

Recombinant human CAD ATCase domain fused to MBP; biochemical assay.

limitations

Isolated-domain kinetics are not whole-cell nucleotide flux.

nutrient_topic

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

plain_language

Aspartate becomes part of the precursor used to build pyrimidine bases.

primary_references

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

L-Aspartate: redox transfer, nitrogen partitioning 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 · Recombinant human CAD ATCase domain fused to MBP; biochemical assay. · source_derived_draft · unverified_draft

## l-aspartate-cad-aspartate-reaction Aspartate becomes part of the precursor used to build pyrimidine bases. Purified human CAD aspartate-transcarbamylase domain converted carbamoyl phosphate and aspartate to carbamoyl-aspartate in an initial-rate assay. Model: Recombinant human CAD ATCase domain fused to MBP; biochemical assay. Limitations: Isolated-domain kinetics are not whole-cell nucleotide flux. Evidence access: Primary full text Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

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 full text

experimental_model

Mouse wild-type embryonic fibroblasts; S6K1 siRNA, 15-hour serum starvation, 100 nM insulin for six hours during RNA/DNA labeling, with pyrimidine salvage controls.

limitations

An isotope-incorporation endpoint is not a measurement of dietary aspartate efficacy.

nutrient_topic

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

plain_language

Blocking new nucleotide production differs from blocking every route for supplying nucleotides.

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 162–168

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse wild-type embryonic fibroblasts; S6K1 siRNA, 15-hour serum starvation, 100 nM insulin for six hours during RNA/DNA labeling, with pyrimidine salvage controls. · source_derived_draft · unverified_draft

## l-aspartate-cad-s6k1-flux Blocking new nucleotide production differs from blocking every route for supplying nucleotides. S6K1 depletion blocked insulin-stimulated aspartate-carbon incorporation into RNA and DNA while sparing incorporation of supplied pyrimidines in the compared assays. Model: Mouse wild-type embryonic fibroblasts; S6K1 siRNA, 15-hour serum starvation, 100 nM insulin for six hours during RNA/DNA labeling, with pyrimidine salvage controls. Limitations: An isotope-incorporation endpoint is not a measurement of dietary aspartate efficacy. 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

evidence_access

Primary full text

experimental_model

Mouse and human liver quantitative proteomics.

limitations

Sampled expression ratios are not universal constants or proof of a clinical rescue strategy.

nutrient_topic

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

plain_language

A mouse may compensate for a missing carrier more readily than a human.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

L-Aspartate: redox transfer, nitrogen partitioning 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 · Mouse and human liver quantitative proteomics. · source_derived_draft · unverified_draft

## l-aspartate-carrier-species-expression A mouse may compensate for a missing carrier more readily than a human. Absolute proteomics found citrin/aralar molar ratios of about 7.8 in mouse liver and 397 in human liver, indicating much less endogenous aralar relative to citrin in humans. Model: Mouse and human liver quantitative proteomics. Limitations: Sampled expression ratios are not universal constants or proof of a clinical rescue strategy. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

evidence_access

Primary full text

experimental_model

Human citrin/aralar domain structures and structural model.

limitations

The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle.

nutrient_topic

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

plain_language

Calcium binding can change access to the transport machinery.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human citrin/aralar domain structures and structural model. · source_derived_draft · unverified_draft

## l-aspartate-carrier-vestibule Calcium binding can change access to the transport machinery. Calcium-associated movement of the mobile regulatory domain opened a vestibule in regulatory-domain structures; the authors proposed that this controls substrate access. Model: Human citrin/aralar domain structures and structural model. Limitations: The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse Slc25a13-null hepatocytes with exogenous aralar expression.

limitations

Gene-expression rescue is not proof that oral aspartate or calcium corrects human citrin deficiency.

nutrient_topic

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

plain_language

A related carrier can substitute for part of the missing transport function in this model.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse Slc25a13-null hepatocytes with exogenous aralar expression. · source_derived_draft · unverified_draft

## l-aspartate-citrin-aralar-rescue A related carrier can substitute for part of the missing transport function in this model. Exogenous aralar expression reversed the increased NADH/NAD+ ratio in hepatocytes from citrin-null mice. Model: Mouse Slc25a13-null hepatocytes with exogenous aralar expression. Limitations: Gene-expression rescue is not proof that oral aspartate or calcium corrects human citrin deficiency. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

evidence_access

Primary full text

experimental_model

Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures.

limitations

Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency.

nutrient_topic

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

plain_language

Several similarly named structural motifs do not mean several equivalent calcium switches.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. · source_derived_draft · unverified_draft

## l-aspartate-citrin-calcium-site Several similarly named structural motifs do not mean several equivalent calcium switches. Human citrin regulatory-domain structures resolved calcium at EF-hand 2; the other EF-hand motifs were not all calcium-binding sites. Model: Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. Limitations: Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Isolated liver mitochondria from genetically modified mice.

limitations

Small ex vivo flux increment; not human therapeutic efficacy.

nutrient_topic

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

plain_language

A measurable transport rescue did not amount to proof of complete disease correction.

primary_references

Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated liver mitochondria from genetically modified mice. · source_derived_draft · unverified_draft

## l-aspartate-citrin-shuttle-rescue A measurable transport rescue did not amount to proof of complete disease correction. Liver-specific transgenic aralar expression increased residual shuttle activity in citrin-null mouse mitochondria by approximately 4–6 nmol per mg protein per minute. Model: Isolated liver mitochondria from genetically modified mice. Limitations: Small ex vivo flux increment; not human therapeutic efficacy. Evidence access: Primary full text Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36967723/ · DOI 10.1016/j.ymgmr.2023.100967

evidence_access

Primary full text

experimental_model

Human recombinant cytosolic enzyme structural study.

limitations

Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling.

nutrient_topic

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

plain_language

Aspartate must be placed on the correct transfer RNA to enter proteins.

primary_references

Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant cytosolic enzyme structural study. · source_derived_draft · unverified_draft

## l-aspartate-dars1-translation Aspartate must be placed on the correct transfer RNA to enter proteins. Human cytosolic DARS1 catalyzes attachment of aspartate to its cognate tRNA; its 2.25-angstrom homodimer structure defines the cytosolic enzyme separately from mitochondrial DARS2. Model: Human recombinant cytosolic enzyme structural study. Limitations: Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling. Evidence access: Primary full text Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306

evidence_access

Primary full text

experimental_model

Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry.

limitations

Bacterial structural comparison is not a human aspartate-deficiency model or proof of supplement rescue.

nutrient_topic

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

plain_language

Mitochondrial translation has its own aspartate-handling machinery.

primary_references

Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA synthetase from bacterial homolog with same 3D architecture. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23275545/ · DOI 10.1093/nar/gks1322

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 362–368

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry. · source_derived_draft · unverified_draft

## l-aspartate-dars2-compartment Mitochondrial translation has its own aspartate-handling machinery. Human mitochondrial aspartyl-tRNA synthetase showed a broader catalytic groove and distinct tRNA-binding thermodynamics compared with its bacterial structural homologue. Model: Purified human mitochondrial DARS2, crystallography and isothermal titration calorimetry. Limitations: Bacterial structural comparison is not a human aspartate-deficiency model or proof of supplement rescue. Evidence access: Primary full text Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA synthetase from bacterial homolog with same 3D architecture. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23275545/ · DOI 10.1093/nar/gks1322

evidence_access

Primary full text

experimental_model

Human cancer cultures and xenografts in immunodeficient mice.

limitations

Not every tumor expresses this transporter, and this is not evidence that ordinary intake initiates cancer. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/

nutrient_topic

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

plain_language

Uptake partly bypassed a synthesis bottleneck in the tested tumors.

primary_references

Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cultures and xenografts in immunodeficient mice. · source_derived_draft · unverified_draft

## l-aspartate-eaat1-hypoxia Uptake partly bypassed a synthesis bottleneck in the tested tumors. Increasing SLC1A3-mediated uptake supplied aspartate for nucleotide synthesis and improved proliferation under low oxygen and growth in tumor xenograft models. Model: Human cancer cultures and xenografts in immunodeficient mice. Limitations: Not every tumor expresses this transporter, and this is not evidence that ordinary intake initiates cancer. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/ Evidence access: Primary full text Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges.

limitations

SLC1A3 also transports glutamate; effects are model-specific rather than an oral supplementation result. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/

nutrient_topic

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

plain_language

Transport capacity determines whether a cell can use the aspartate available outside it.

primary_references

Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 74–80

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges. · source_derived_draft · unverified_draft

## l-aspartate-eaat1-respiration Transport capacity determines whether a cell can use the aspartate available outside it. SLC1A3 manipulation changed aspartate import and cancer-cell sensitivity to respiratory inhibitors. Model: Human cancer-cell panels; SLC1A3 knockout/overexpression and inhibitor challenges. Limitations: SLC1A3 also transports glutamate; effects are model-specific rather than an oral supplementation result. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/ Evidence access: Primary full text Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient genetic study with functional expression characterization.

limitations

A single rare disorder is not evidence of dietary aspartate deficiency or that supplying aspartate fixes the defect.

nutrient_topic

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

plain_language

Lack of the derived metabolite can reflect faulty synthesis machinery.

primary_references

Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19807691/ · DOI 10.1042/BJ20091024

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 386–392

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human patient genetic study with functional expression characterization. · source_derived_draft · unverified_draft

## l-aspartate-human-nat8l-loss Lack of the derived metabolite can reflect faulty synthesis machinery. A homozygous 19-base-pair NAT8L deletion in a patient with absent brain NAA produced a frameshift and failure to produce a functional enzyme. Model: Human patient genetic study with functional expression characterization. Limitations: A single rare disorder is not evidence of dietary aspartate deficiency or that supplying aspartate fixes the defect. Evidence access: Primary abstract Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19807691/ · DOI 10.1042/BJ20091024

evidence_access

Primary full text

experimental_model

Human and mouse PDAC model program; human-cell HIF1A/CA9 manipulations.

limitations

CA9 is a mediator in the tested models, not a universal aspartate transporter.

nutrient_topic

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

plain_language

An oxygen-response program increased an alternative nutrient-acquisition route.

primary_references

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 266–272

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human and mouse PDAC model program; human-cell HIF1A/CA9 manipulations. · source_derived_draft · unverified_draft

## l-aspartate-hypoxia-hif-ca9 An oxygen-response program increased an alternative nutrient-acquisition route. Genetic and pharmacological experiments linked hypoxia-enhanced macropinocytosis to HIF1A and its target CA9 in KRAS-mutant PDAC models. Model: Human and mouse PDAC model program; human-cell HIF1A/CA9 manipulations. Limitations: CA9 is a mediator in the tested models, not a universal aspartate transporter. Evidence access: Primary full text Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

evidence_access

Primary abstract and primary methods/figure text

experimental_model

Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry.

limitations

Host-cell species is not the enzyme species; no dietary brain-delivery effect was tested.

nutrient_topic

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

plain_language

Aspartate-derived NAA can feed a second, glutamate-containing product.

primary_references

Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 370–376

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry. · source_derived_draft · unverified_draft

## l-aspartate-naa-naag-supply Aspartate-derived NAA can feed a second, glutamate-containing product. Coexpressing mouse Nat8l and Rimklb in CHO-K1 or HEK293T cells enabled NAAG production from the NAA-synthesis pathway. Model: Mouse-brain cDNA constructs in hamster/human cell hosts; product identified by HPLC and tandem mass spectrometry. Limitations: Host-cell species is not the enzyme species; no dietary brain-delivery effect was tested. Evidence access: Primary abstract and primary methods/figure text Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

evidence_access

Primary abstract and primary methods/figure text

experimental_model

Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments.

limitations

This is NAA transport, not proof that NaDC3 transports free L-aspartate in the tested assay.

nutrient_topic

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

plain_language

Transport of the intermediate can gate the next synthesis step.

primary_references

Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 378–384

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments. · source_derived_draft · unverified_draft

## l-aspartate-naag-import-route Transport of the intermediate can gate the next synthesis step. Coexpression of the mouse NaDC3 transporter with Rimklb enabled supplied NAA to support NAAG synthesis in heterologous cells. Model: Mouse transporter/enzyme cDNAs; CHO-K1 and HEK293T cell experiments. Limitations: This is NAA transport, not proof that NaDC3 transports free L-aspartate in the tested assay. Evidence access: Primary abstract and primary methods/figure text Molecular characterization of N-acetylaspartylglutamate synthetase. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20643647/ · DOI 10.1074/jbc.M110.111765

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse HY15549-centered CRISPR screens and knockout comparisons.

limitations

Do not assign all ETC-inhibitor findings to tumor hypoxia or all culture dependencies to animal tumors.

nutrient_topic

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

plain_language

Low oxygen and a respiratory-chain drug were not identical metabolic conditions.

primary_references

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 242–248

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse HY15549-centered CRISPR screens and knockout comparisons. · source_derived_draft · unverified_draft

## l-aspartate-pdac-got2-hypoxia Low oxygen and a respiratory-chain drug were not identical metabolic conditions. Got2 knockout impaired mouse PDAC-cell growth at 0.5% oxygen more strongly than under normoxia; ETC inhibitor exposure instead exposed a distinct Got1 dependency. Model: Mouse HY15549-centered CRISPR screens and knockout comparisons. Limitations: Do not assign all ETC-inhibitor findings to tumor hypoxia or all culture dependencies to animal tumors. Evidence access: Primary full text Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human MIA PaCa-2 cells implanted in mice; companion murine and PDX experiments.

limitations

This does not prove GOT2 is dispensable in every tumor or that it never contributes to growth.

nutrient_topic

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

plain_language

An animal tumor had alternative nutrient routes unavailable in the simplified culture.

primary_references

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 250–256

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MIA PaCa-2 cells implanted in mice; companion murine and PDX experiments. · source_derived_draft · unverified_draft

## l-aspartate-pdac-got2-invivo-limit An animal tumor had alternative nutrient routes unavailable in the simplified culture. GOT2 deletion did not reduce MIA PaCa-2 tumor size in the tested mouse xenografts, despite the synthesis dependency observed in hypoxic culture systems. Model: Human MIA PaCa-2 cells implanted in mice; companion murine and PDX experiments. Limitations: This does not prove GOT2 is dispensable in every tumor or that it never contributes to growth. Evidence access: Primary full text Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

evidence_access

Primary full text

experimental_model

Human MIA PaCa-2-centered hypoxic culture, albumin addition and macropinocytosis experiments.

limitations

This is an extracellular protein-scavenging mechanism, not evidence of direct intact dietary protein delivery to a tumor.

nutrient_topic

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

plain_language

Cells can obtain amino acids by digesting extracellular protein.

primary_references

Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 258–264

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MIA PaCa-2-centered hypoxic culture, albumin addition and macropinocytosis experiments. · source_derived_draft · unverified_draft

## l-aspartate-protein-scavenging-rescue Cells can obtain amino acids by digesting extracellular protein. Bovine albumin supplementation restored aspartate and pyrimidine-related metabolites and partly rescued hypoxic growth in the tested KRAS-mutant human PDAC cultures. Model: Human MIA PaCa-2-centered hypoxic culture, albumin addition and macropinocytosis experiments. Limitations: This is an extracellular protein-scavenging mechanism, not evidence of direct intact dietary protein delivery to a tumor. Evidence access: Primary full text Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35726024/ · DOI 10.1038/s42255-022-00583-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human Jurkat-centered genetic and metabolic experiments.

limitations

Pyruvate is not a universally effective rescue for every respiratory or transaminase defect.

nutrient_topic

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

plain_language

Providing an electron acceptor did not bypass the need for functioning synthesis machinery.

primary_references

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human Jurkat-centered genetic and metabolic experiments. · source_derived_draft · unverified_draft

## l-aspartate-pyruvate-got1-gate Providing an electron acceptor did not bypass the need for functioning synthesis machinery. GOT1 loss prevented pyruvate from rescuing aspartate synthesis and proliferation during ETC dysfunction. Model: Human Jurkat-centered genetic and metabolic experiments. Limitations: Pyruvate is not a universally effective rescue for every respiratory or transaminase defect. Evidence access: Primary full text An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26232224/ · DOI 10.1016/j.cell.2015.07.016

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human families and functional characterization of disease-associated human transporter variants.

limitations

Gene-related renal handling is not evidence of an ordinary dietary deficiency; neurological associations do not establish one mechanism.

nutrient_topic

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

plain_language

A transporter defect can cause nutrient loss even when intake is adequate.

primary_references

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human families and functional characterization of disease-associated human transporter variants. · source_derived_draft · unverified_draft

## l-aspartate-renal-gene-loss A transporter defect can cause nutrient loss even when intake is adequate. Human recessive SLC1A1 R445W and I395del variants were identified in dicarboxylic aminoaciduria with urinary glutamate and aspartate loss. Model: Human families and functional characterization of disease-associated human transporter variants. Limitations: Gene-related renal handling is not evidence of an ordinary dietary deficiency; neurological associations do not establish one mechanism. Evidence access: Primary abstract Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human constructs in heterologous functional assays and canine MDCK cells.

limitations

The accessed abstract reports glutamate/cysteine assays; do not mislabel them as direct aspartate uptake measurements.

nutrient_topic

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

plain_language

Having a transporter gene is insufficient if the protein fails to reach the membrane.

primary_references

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 42–48

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human constructs in heterologous functional assays and canine MDCK cells. · source_derived_draft · unverified_draft

## l-aspartate-renal-trafficking Having a transporter gene is insufficient if the protein fails to reach the membrane. The disease-associated human SLC1A1 variants showed near-absent cell-surface expression in a canine kidney cell model, with impaired glutamate and cysteine transport in functional assays. Model: Human constructs in heterologous functional assays and canine MDCK cells. Limitations: The accessed abstract reports glutamate/cysteine assays; do not mislabel them as direct aspartate uptake measurements. Evidence access: Primary abstract Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21123949/ · DOI 10.1172/JCI44474

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human 143B and other cell models; live aspartate biosensor and time-resolved metabolomics.

limitations

Responses are time- and model-dependent; later adaptation does not make the early block disappear.

nutrient_topic

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

plain_language

A restored metabolite concentration did not show that the cell could use it normally.

primary_references

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning 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 143B and other cell models; live aspartate biosensor and time-resolved metabolomics. · source_derived_draft · unverified_draft

## l-aspartate-sdh-aspartate-rebound A restored metabolite concentration did not show that the cell could use it normally. SDH inhibition produced early aspartate depletion followed by a rebound, while proliferation remained impaired over the compared interval. Model: Human 143B and other cell models; live aspartate biosensor and time-resolved metabolomics. Limitations: Responses are time- and model-dependent; later adaptation does not make the early block disappear. Evidence access: Primary full text Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cell genetic/pharmacological SDH perturbations; nucleotide and replication readouts.

limitations

Not a clinical treatment recommendation or proof that extra aspartate universally overcomes the competitive block.

nutrient_topic

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

plain_language

The effect propagated from metabolism into DNA replication control.

primary_references

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning 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 genetic/pharmacological SDH perturbations; nucleotide and replication readouts. · source_derived_draft · unverified_draft

## l-aspartate-sdh-pyrimidine-stress The effect propagated from metabolism into DNA replication control. SDH loss increased succinate, impaired aspartate entry into pyrimidine synthesis and produced nucleotide insufficiency with replication stress and increased ATR-inhibitor sensitivity. Model: Human cell genetic/pharmacological SDH perturbations; nucleotide and replication readouts. Limitations: Not a clinical treatment recommendation or proof that extra aspartate universally overcomes the competitive block. Evidence access: Primary full text Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract and primary figure descriptions

experimental_model

Human lung-cancer cell gene editing, metabolite ratios and carbon tracing.

limitations

A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured.

nutrient_topic

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

plain_language

Redox handling connects aspartate machinery to synthesis of another amino acid.

primary_references

Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 234–240

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. · source_derived_draft · unverified_draft

## l-aspartate-shuttle-serine-link Redox handling connects aspartate machinery to synthesis of another amino acid. Loss of shuttle components reduced pyruvate/lactate ratios and glucose-derived serine synthesis in the studied human A549 models. Model: Human lung-cancer cell gene editing, metabolite ratios and carbon tracing. Limitations: A ratio is a redox proxy, and no dietary serine/aspartate deficiency threshold was measured. Evidence access: Primary abstract and primary figure descriptions Aspartate availability drives differential engagement of the malate-aspartate shuttle. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41759528/ · DOI 10.1016/j.molcel.2026.02.004

evidence_access

Primary full text

experimental_model

Recombinant human ATCase kinetic experiments with succinate and substrate titration.

limitations

This is not proof that ordinary dietary succinate or aspartate concentrations cause the same inhibition in a person.

nutrient_topic

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

plain_language

An accumulated carbon-cycle metabolite competes with aspartate at a nucleotide-making enzyme.

primary_references

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 210–216

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human ATCase kinetic experiments with succinate and substrate titration. · source_derived_draft · unverified_draft

## l-aspartate-succinate-atcase An accumulated carbon-cycle metabolite competes with aspartate at a nucleotide-making enzyme. Succinate competitively inhibited aspartate utilization by the purified human CAD ATCase domain. Model: Recombinant human ATCase kinetic experiments with succinate and substrate titration. Limitations: This is not proof that ordinary dietary succinate or aspartate concentrations cause the same inhibition in a person. Evidence access: Primary full text Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42082831/ · DOI 10.1038/s42255-026-01524-w

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse T-cell genetic and redox-restoration experiments.

limitations

Not evidence that NAD metabolism is irrelevant in other cell states.

nutrient_topic

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

plain_language

Correcting one metabolic measurement did not fix the nitrogen-handling problem.

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 314–320

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

## l-aspartate-tcell-redox-insufficient Correcting one metabolic measurement did not fix the nitrogen-handling problem. Increasing the NAD+/NADH ratio did not restore the impaired antiviral T-cell response after Got1 loss in the tested chronic-infection setting. Model: Mouse T-cell genetic and redox-restoration experiments. Limitations: Not evidence that NAD metabolism is irrelevant in other cell states. 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

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human tumor metabolite and marker analysis.

limitations

Correlation alone cannot establish causal direction or a universal tissue threshold. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/

nutrient_topic

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

plain_language

Human tumor measurements were consistent with the oxygen-related mechanism.

primary_references

Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human tumor metabolite and marker analysis. · source_derived_draft · unverified_draft

## l-aspartate-tumor-marker-limit Human tumor measurements were consistent with the oxygen-related mechanism. Aspartate abundance in primary human tumor samples negatively correlated with hypoxia-marker expression. Model: Human tumor metabolite and marker analysis. Limitations: Correlation alone cannot establish causal direction or a universal tissue threshold. Correction record: The 2018 author correction added a missing competing-interests statement declaring no competing interests; no mechanism or data change was stated. PMID 30089842; DOI 10.1038/s41556-018-0184-2. https://pubmed.ncbi.nlm.nih.gov/30089842/ Evidence access: Primary full text Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29941933/ · DOI 10.1038/s41556-018-0118-z