L-Arginine

evidence_access

Primary abstract

experimental_model

Mouse chemical-pain assays; high-dose injected arginine.

limitations

This does not prove that normal dietary arginine negates an oral agmatine supplement or identify one exclusive target.

nutrient_topic

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

plain_language

A precursor-related nutrient changed the response in a pharmacological animal experiment.

primary_references

Mechanisms involved in the antinociception caused by agmatine in mice. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15857629/ · DOI 10.1016/j.neuropharm.2005.01.012

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 428–434

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse chemical-pain assays; high-dose injected arginine. · source_derived_draft · unverified_draft

## agmatine-sulfate-arginine-pain-interaction A precursor-related nutrient changed the response in a pharmacological animal experiment. L-arginine at 600 mg/kg intraperitoneally attenuated agmatine-associated antinociception in the mouse acetic-acid test. Model: Mouse chemical-pain assays; high-dose injected arginine. Limitations: This does not prove that normal dietary arginine negates an oral agmatine supplement or identify one exclusive target. Evidence access: Primary abstract Mechanisms involved in the antinociception caused by agmatine in mice. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15857629/ · DOI 10.1016/j.neuropharm.2005.01.012

evidence_span

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experimental_model

Purified recombinant NAGS kinetics

exposure

Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs

limitations

Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.

nutrient_topic

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

organism

Human and mouse enzymes; human findings specified

plain_language

Arginine can feed back on the upstream nitrogen-disposal pathway.

primary_references

[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

tissue_or_cell_type

N-acetylglutamate formation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 281–292

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft

### citrulline-arginine-nags Arginine approximately doubled the activity of both tested human NAGS constructs. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine can feed back on the upstream nitrogen-disposal pathway. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003

evidence_access

Primary abstract

experimental_model

Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments.

limitations

No direct change in whole-cell calcium or ATP-sensitive potassium currents was detected.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The electrical change links arginine transport to calcium entry.

primary_references

Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 310–316

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. · source_derived_draft · unverified_draft

## arg-beta-calcium The electrical change links arginine transport to calcium entry. The calcium response required depolarization and extracellular calcium. Model: Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. Limitations: No direct change in whole-cell calcium or ATP-sensitive potassium currents was detected. Evidence access: Primary abstract Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

evidence_access

Primary abstract

experimental_model

Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments.

limitations

Cell/animal mechanism; no universal human insulin response inferred. NAD(P)H autofluorescence did not show increased metabolism.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Moving a positively charged amino acid can change membrane voltage.

primary_references

Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 302–308

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. · source_derived_draft · unverified_draft

## arg-beta-current Moving a positively charged amino acid can change membrane voltage. Arginine generated an inward current carried by the amino acid; CAT2A-mediated electrogenic uptake was the proposed route. Model: Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. Limitations: Cell/animal mechanism; no universal human insulin response inferred. NAD(P)H autofluorescence did not show increased metabolism. Evidence access: Primary abstract Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

evidence_access

Primary abstract

experimental_model

Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments.

limitations

Cell/animal mechanism; no universal human insulin response inferred. NAD(P)H autofluorescence did not show increased metabolism.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A secretion effect can start at transport rather than at the final release machinery.

primary_references

Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 318–324

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. · source_derived_draft · unverified_draft

## arg-beta-insulin A secretion effect can start at transport rather than at the final release machinery. Results supported insulin stimulation through electrogenic transport; arginine did not directly enhance the measured exocytotic machinery. Model: Mouse pancreatic beta cells; electrophysiology, calcium imaging and secretion experiments. Limitations: Cell/animal mechanism; no universal human insulin response inferred. NAD(P)H autofluorescence did not show increased metabolism. Evidence access: Primary abstract Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9130159/ · DOI 10.1113/jphysiol.1997.sp021955

evidence_access

Primary abstract

experimental_model

Mammalian-cell signaling experiments and biochemical CASTOR1 binding.

limitations

Binding constant is not a human deficiency threshold.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Arginine is a signal as well as a reaction substrate.

primary_references

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 174–180

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian-cell signaling experiments and biochemical CASTOR1 binding. · source_derived_draft · unverified_draft

## arg-castor-binding Arginine is a signal as well as a reaction substrate. Arginine bound CASTOR1 with an approximate dissociation constant of 30 micromolar. Model: Mammalian-cell signaling experiments and biochemical CASTOR1 binding. Limitations: Binding constant is not a human deficiency threshold. Evidence access: Primary abstract The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

evidence_access

Primary abstract

experimental_model

Mammalian-cell signaling experiments and biochemical CASTOR1 binding.

limitations

Do not equate pathway activation with guaranteed muscle growth.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Binding releases a brake on nutrient signaling.

primary_references

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian-cell signaling experiments and biochemical CASTOR1 binding. · source_derived_draft · unverified_draft

## arg-castor-release Binding releases a brake on nutrient signaling. Arginine binding disrupted the CASTOR1–GATOR2 complex; arginine-binding capacity was needed for pathway activation. Model: Mammalian-cell signaling experiments and biochemical CASTOR1 binding. Limitations: Do not equate pathway activation with guaranteed muscle growth. Evidence access: Primary abstract The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

evidence_access

Primary abstract

experimental_model

1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis.

limitations

Structural homology to bacterial lysine sensors is not proof that lysine substitutes for arginine.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The structure explains how binding can change signaling.

primary_references

Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27487210/ · DOI 10.1038/nature19079

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis. · source_derived_draft · unverified_draft

## arg-castor-structure The structure explains how binding can change signaling. Arginine binds between two ACT domains, controlling the neighboring GATOR2-binding site. Model: 1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis. Limitations: Structural homology to bacterial lysine sensors is not proof that lysine substitutes for arginine. Evidence access: Primary abstract Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27487210/ · DOI 10.1038/nature19079

evidence_access

Primary abstract

experimental_model

Six men; 30 g intravenous arginine and GHRH/TRH comparison tests.

limitations

Not an oral muscle-building outcome.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A pharmacological infusion changed hormone release.

primary_references

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2903866/ · DOI 10.1210/jcem-67-6-1186

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 326–332

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Six men; 30 g intravenous arginine and GHRH/TRH comparison tests. · source_derived_draft · unverified_draft

## arg-gh A pharmacological infusion changed hormone release. Arginine infusion increased GH, and its combination with GHRH produced a larger response than either stimulus alone. Model: Six men; 30 g intravenous arginine and GHRH/TRH comparison tests. Limitations: Not an oral muscle-building outcome. Evidence access: Primary abstract Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2903866/ · DOI 10.1210/jcem-67-6-1186

evidence_access

Primary abstract

experimental_model

VINTAGE MI randomized post-infarction trial.

limitations

Small event count; causal molecular explanation unresolved. The trial authors advised against use following acute MI.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The clinical harm signal is retained alongside the mechanism records.

primary_references

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16391217/ · DOI 10.1001/jama.295.1.58

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 382–388

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · VINTAGE MI randomized post-infarction trial. · source_derived_draft · unverified_draft

## arg-mi-deaths The clinical harm signal is retained alongside the mechanism records. Six arginine-group participants died versus none receiving placebo; enrollment stopped for safety concerns. Model: VINTAGE MI randomized post-infarction trial. Limitations: Small event count; causal molecular explanation unresolved. The trial authors advised against use following acute MI. Evidence access: Primary abstract L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16391217/ · DOI 10.1001/jama.295.1.58

evidence_access

Primary abstract

experimental_model

153 recent STEMI patients; target 3 g three times daily versus placebo plus usual therapy.

limitations

Post-infarction setting; a biochemical NO pathway is not evidence of benefit here.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A plausible pathway did not deliver the intended clinical benefit.

primary_references

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16391217/ · DOI 10.1001/jama.295.1.58

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 374–380

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 153 recent STEMI patients; target 3 g three times daily versus placebo plus usual therapy. · source_derived_draft · unverified_draft

## arg-mi-function A plausible pathway did not deliver the intended clinical benefit. VINTAGE MI found no significant improvement in ejection fraction or vascular stiffness over six months. Model: 153 recent STEMI patients; target 3 g three times daily versus placebo plus usual therapy. Limitations: Post-infarction setting; a biochemical NO pathway is not evidence of benefit here. Evidence access: Primary abstract L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16391217/ · DOI 10.1001/jama.295.1.58

evidence_access

Primary abstract

experimental_model

Rat cerebellar NOS preparation; separated partial reactions.

limitations

Purified preparation; residual enzyme reductant supported a limited first reaction without added NADPH. This does not imply physiological NOS is NADPH independent.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Nitric-oxide production passes through a distinct intermediate.

primary_references

Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 70–76

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat cerebellar NOS preparation; separated partial reactions. · source_derived_draft · unverified_draft

## arg-nos-first Nitric-oxide production passes through a distinct intermediate. NOS converted arginine to N-hydroxyarginine in an oxygen- and calcium/calmodulin-dependent partial reaction. Model: Rat cerebellar NOS preparation; separated partial reactions. Limitations: Purified preparation; residual enzyme reductant supported a limited first reaction without added NADPH. This does not imply physiological NOS is NADPH independent. Evidence access: Primary abstract Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

evidence_access

Primary abstract

experimental_model

NO-PAIN: 133 PAD patients, 3 g/day for six months.

limitations

Endpoint-dependent pattern; not every marker necessarily decreased.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Higher blood availability did not ensure better pathway output.

primary_references

L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17592080/ · DOI 10.1161/circulationaha.106.683656

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 390–396

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · NO-PAIN: 133 PAD patients, 3 g/day for six months. · source_derived_draft · unverified_draft

## arg-pad-markers Higher blood availability did not ensure better pathway output. Plasma arginine rose, but NO-related measurements were reduced or unimproved versus placebo. Model: NO-PAIN: 133 PAD patients, 3 g/day for six months. Limitations: Endpoint-dependent pattern; not every marker necessarily decreased. Evidence access: Primary abstract L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17592080/ · DOI 10.1161/circulationaha.106.683656

evidence_access

Primary abstract

experimental_model

NO-PAIN randomized trial; treadmill claudication distance.

limitations

Does not isolate why shorter and longer studies differ.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The functional outcome did not follow the expected supplement benefit.

primary_references

L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17592080/ · DOI 10.1161/circulationaha.106.683656

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · NO-PAIN randomized trial; treadmill claudication distance. · source_derived_draft · unverified_draft

## arg-pad-walking The functional outcome did not follow the expected supplement benefit. Walking distance improved less with arginine than placebo in the six-month PAD trial. Model: NO-PAIN randomized trial; treadmill claudication distance. Limitations: Does not isolate why shorter and longer studies differ. Evidence access: Primary abstract L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17592080/ · DOI 10.1161/circulationaha.106.683656

evidence_access

Primary abstract

experimental_model

Oral 6 g, intravenous 6/30 g and placebo comparisons.

limitations

Study-specific estimate; another study using 10 g reported approximately 20%. Different dose and analysis prevent treating either as a universal constant.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The administered dose and the amount reaching circulation differ.

primary_references

L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9833603/ · DOI 10.1046/j.1365-2125.1998.00803.x

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 342–348

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Oral 6 g, intravenous 6/30 g and placebo comparisons. · source_derived_draft · unverified_draft

## arg-pk-six The administered dose and the amount reaching circulation differ. Estimated oral bioavailability was 68 ± 9% after 6 g in eight healthy men. Model: Oral 6 g, intravenous 6/30 g and placebo comparisons. Limitations: Study-specific estimate; another study using 10 g reported approximately 20%. Different dose and analysis prevent treating either as a universal constant. Evidence access: Primary abstract L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9833603/ · DOI 10.1046/j.1365-2125.1998.00803.x

evidence_access

Primary abstract

experimental_model

Ten healthy volunteers; dietary baseline-variation control and 30 g intravenous comparison.

limitations

Dose, endogenous baseline and modeling differ from the 6 g study. No mechanism resolving the difference is established here.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A second protocol produced a different exposure estimate.

primary_references

Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10215749/ · DOI 10.1046/j.1365-2125.1999.00883.x

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Ten healthy volunteers; dietary baseline-variation control and 30 g intravenous comparison. · source_derived_draft · unverified_draft

## arg-pk-ten A second protocol produced a different exposure estimate. A 10 g oral dose had approximately 20% absolute bioavailability in the crossover study. Model: Ten healthy volunteers; dietary baseline-variation control and 30 g intravenous comparison. Limitations: Dose, endogenous baseline and modeling differ from the 6 g study. No mechanism resolving the difference is established here. Evidence access: Primary abstract Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10215749/ · DOI 10.1046/j.1365-2125.1999.00883.x

evidence_access

Primary abstract

experimental_model

Healthy-volunteer pharmacokinetic study.

limitations

Do not extrapolate this pattern unchanged to kidney disease.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Route and concentration changed how arginine was removed.

primary_references

Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10215749/ · DOI 10.1046/j.1365-2125.1999.00883.x

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Healthy-volunteer pharmacokinetic study. · source_derived_draft · unverified_draft

## arg-renal-clearance Route and concentration changed how arginine was removed. Rapid early disappearance after intravenous dosing included concentration-dependent renal clearance; renal elimination was not observed after the 10 g oral dose. Model: Healthy-volunteer pharmacokinetic study. Limitations: Do not extrapolate this pattern unchanged to kidney disease. Evidence access: Primary abstract Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10215749/ · DOI 10.1046/j.1365-2125.1999.00883.x

evidence_access

Primary abstract

experimental_model

Nine men in oral lysine tests; three men in intravenous amino-acid loading tests.

limitations

Small historical experiment; no molecular transporter identified and no ordinary-meal effect size established.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Related amino acids interacted at a kidney transport step.

primary_references

A new transport interaction of dibasic amino acids and citrulline in human kidney. · 1981 · https://pubmed.ncbi.nlm.nih.gov/6797099/ · DOI 10.1620/tjem.134.55

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Nine men in oral lysine tests; three men in intravenous amino-acid loading tests. · source_derived_draft · unverified_draft

## arg-renal-competition Related amino acids interacted at a kidney transport step. Amino-acid loading experiments indicated inhibition of renal citrulline transport by arginine, lysine and ornithine. Model: Nine men in oral lysine tests; three men in intravenous amino-acid loading tests. Limitations: Small historical experiment; no molecular transporter identified and no ordinary-meal effect size established. Evidence access: Primary abstract A new transport interaction of dibasic amino acids and citrulline in human kidney. · 1981 · https://pubmed.ncbi.nlm.nih.gov/6797099/ · DOI 10.1620/tjem.134.55

evidence_access

Primary abstract

experimental_model

Human challenge tests plus rat pituitary-cell experiments.

limitations

Somatostatin suppression was inferred, not directly measured; retained as a proposed mechanism.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The proposed control point lies upstream of the pituitary response.

primary_references

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2903866/ · DOI 10.1210/jcem-67-6-1186

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human challenge tests plus rat pituitary-cell experiments. · source_derived_draft · unverified_draft

## arg-somatostatin The proposed control point lies upstream of the pituitary response. The authors inferred suppression of endogenous somatostatin from human stimulation tests and absent direct effects in rat pituitary cultures. Model: Human challenge tests plus rat pituitary-cell experiments. Limitations: Somatostatin suppression was inferred, not directly measured; retained as a proposed mechanism. Evidence access: Primary abstract Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2903866/ · DOI 10.1210/jcem-67-6-1186

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Primary human activated T cells; isotope tracing and functional assays.

limitations

The responsible enzyme was not established here; no universal human arginine-decarboxylase assignment.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A separate metabolic branch remained detectable.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 230–236

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Primary human activated T cells; isotope tracing and functional assays. · source_derived_draft · unverified_draft

## arg-tcell-agmatine A separate metabolic branch remained detectable. Arginine-derived tracer also appeared in agmatine, without suppression by the arginase inhibitor. Model: Primary human activated T cells; isotope tracing and functional assays. Limitations: The responsible enzyme was not established here; no universal human arginine-decarboxylase assignment. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Primary human activated T cells; isotope tracing and functional assays.

limitations

Flux is model-specific; not evidence of clinical wound healing.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Arginine fed more than the NO pathway.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 222–228

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Primary human activated T cells; isotope tracing and functional assays. · source_derived_draft · unverified_draft

## arg-tcell-carbon Arginine fed more than the NO pathway. Tracer carbon appeared in putrescine and proline; arginase inhibition reduced these labeled products. Model: Primary human activated T cells; isotope tracing and functional assays. Limitations: Flux is model-specific; not evidence of clinical wound healing. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Primary human activated T cells; isotope tracing and functional assays.

limitations

Not a human supplementation efficacy trial.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Availability changed cellular fuel use.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 238–244

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Primary human activated T cells; isotope tracing and functional assays. · source_derived_draft · unverified_draft

## arg-tcell-metabolism Availability changed cellular fuel use. Higher arginine shifted activated T cells toward oxidative phosphorylation. Model: Primary human activated T cells; isotope tracing and functional assays. Limitations: Not a human supplementation efficacy trial. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

evidence_access

Primary abstract

experimental_model

Eight healthy men; acute route/dose comparison.

limitations

Not evidence of a long-term cardiovascular benefit.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A vascular effect depended on the tested exposure.

primary_references

L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9833603/ · DOI 10.1046/j.1365-2125.1998.00803.x

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 366–372

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Eight healthy men; acute route/dose comparison. · source_derived_draft · unverified_draft

## arg-vascular-dose A vascular effect depended on the tested exposure. Thirty grams intravenously reduced peripheral resistance by 10.4% and blood pressure by 4.4%; 6 g orally or intravenously did not significantly change them. Model: Eight healthy men; acute route/dose comparison. Limitations: Not evidence of a long-term cardiovascular benefit. Evidence access: Primary abstract L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9833603/ · DOI 10.1046/j.1365-2125.1998.00803.x

evidence_span

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experimental_model

Recombinant human enzyme complementation and stability experiments

exposure

Wild type and Q286R, D87G, M360T or A398D variants

limitations

Reaction identity and complementation are established in enzyme systems; these variants do not describe all ASL deficiencies.

nutrient_topic

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

organism

Human ASL expressed experimentally

plain_language

The second enzyme releases arginine from the intermediate.

primary_references

[citrulline-p11747433] Mechanisms for intragenic complementation at the human argininosuccinate lyase locus. (2001). https://pubmed.ncbi.nlm.nih.gov/11747433/ DOI: 10.1021/bi011526e

tissue_or_cell_type

Argininosuccinate cleavage

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 177–188

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

### citrulline-asl-arginine Human ASL catalyzes reversible cleavage of argininosuccinate to arginine and fumarate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The second enzyme releases arginine from the intermediate. organism: Human ASL expressed experimentally tissue_or_cell_type: Argininosuccinate cleavage experimental_model: Recombinant human enzyme complementation and stability experiments limitations: Reaction identity and complementation are established in enzyme systems; these variants do not describe all ASL deficiencies. exposure: Wild type and Q286R, D87G, M360T or A398D variants evidence_span: {"source_cache": "artifacts/citrulline-research/11747433.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1", "start_char": 0, "end_char": 1617, "text_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1"} [citrulline-p11747433] Mechanisms for intragenic complementation at the human argininosuccinate lyase locus. (2001). https://pubmed.ncbi.nlm.nih.gov/11747433/ DOI: 10.1021/bi011526e

experimental_model

Recombinant human ARG2 expressed in E. coli and purified

exposure

Substrate/product kinetics

limitations

Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established.

nutrient_topic

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

organism

Homo sapiens protein

plain_language

ARG2 breaks arginine into ornithine and urea.

primary_references

[mn-enz-11370664] Expression, purification, and characterization of human type II arginase. (2001). https://pubmed.ncbi.nlm.nih.gov/11370664/ DOI: 10.1006/abbi.2001.2324

tissue_or_cell_type

Purified ARG2

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 572–582

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ARG2 expressed in E. coli and purified · source_derived_draft · unverified_draft

### mn-enz-arg2-hydrolysis Purified recombinant human ARG2 catalyzes arginine hydrolysis to ornithine and urea. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: ARG2 breaks arginine into ornithine and urea. organism: Homo sapiens protein tissue_or_cell_type: Purified ARG2 experimental_model: Recombinant human ARG2 expressed in E. coli and purified limitations: Primary experimental scope only; no human dietary threshold, clinical treatment rule, or universal metal substitution is established. exposure: Substrate/product kinetics [mn-enz-11370664] Expression, purification, and characterization of human type II arginase. (2001). https://pubmed.ncbi.nlm.nih.gov/11370664/ DOI: 10.1006/abbi.2001.2324

evidence_access

Full-text methods/results/discussion, Europe PMC PMC9217908.

experimental_model

HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake.

limitations

An expression system does not measure every tissue flux.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A membrane transporter controls entry into the cell.

primary_references

Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

transport_effect

raises Expression supported measurable uptake of arginine.

transport_pool

the expressing cell Expression supported measurable uptake of arginine.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 22–28

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. · source_derived_draft · unverified_draft

## arg-cat1 A membrane transporter controls entry into the cell. CAT1 expression supported measurable uptake of arginine in the transporter assay. Model: HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. Limitations: An expression system does not measure every tissue flux. Evidence access: Full-text methods/results/discussion, Europe PMC PMC9217908. Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

evidence_access

Primary abstract

experimental_model

Primary rat hypothalamus/brainstem cultures; uptake and transcript assays.

limitations

CAT2 transcripts were not detected; the kinetic result does not establish a human blood threshold.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Neurons used a different transporter pattern from stimulated glial cells.

primary_references

Membrane transport of neuronal nitric oxide synthase substrate L-arginine is constitutively expressed with CAT1 and 4F2hc, but not CAT2 or rBAT. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9681446/ · DOI 10.1046/j.1471-4159.1998.71020564.x

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 62–68

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Primary rat hypothalamus/brainstem cultures; uptake and transcript assays. · source_derived_draft · unverified_draft

## arg-neuronal-transport Neurons used a different transporter pattern from stimulated glial cells. Rat neuronal uptake showed a sodium-independent component consistent with CAT1, with Km 47 ± 8 micromolar. Model: Primary rat hypothalamus/brainstem cultures; uptake and transcript assays. Limitations: CAT2 transcripts were not detected; the kinetic result does not establish a human blood threshold. Evidence access: Primary abstract Membrane transport of neuronal nitric oxide synthase substrate L-arginine is constitutively expressed with CAT1 and 4F2hc, but not CAT2 or rBAT. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9681446/ · DOI 10.1046/j.1471-4159.1998.71020564.x

evidence_access

Primary full text

experimental_model

Double-blind randomized crossover in 12 healthy men; equimolar IV amino-acid boluses on separate days after an overnight fast.

limitations

A peak response is not equivalent to a significant integrated response; small male-only study.

nutrient_topic

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

plain_language

Alanine and arginine were not interchangeable glucagon signals.

primary_references

Intravenous Arginine Stimulates Glucagon Secretion More Than Equimolar Alanine, Leucine, Glutamine, and Proline in Humans. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40980546/ · DOI 10.1210/jendso/bvaf139

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 336–342

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Double-blind randomized crossover in 12 healthy men; equimolar IV amino-acid boluses on separate days after an overnight fast. · source_derived_draft · unverified_draft

## alanine-human-glucagon Alanine and arginine were not interchangeable glucagon signals. Intravenous alanine produced a minor increase in peak glucagon, whereas arginine was the strongest tested stimulus and significantly increased both peak and 30-minute incremental area. Model: Double-blind randomized crossover in 12 healthy men; equimolar IV amino-acid boluses on separate days after an overnight fast. Limitations: A peak response is not equivalent to a significant integrated response; small male-only study. Evidence access: Primary full text Intravenous Arginine Stimulates Glucagon Secretion More Than Equimolar Alanine, Leucine, Glutamine, and Proline in Humans. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40980546/ · DOI 10.1210/jendso/bvaf139

evidence_access

Primary abstract

experimental_model

Human and mouse islet perifusion; low-glucose amino-acid challenges.

limitations

Mixed-species functional observation, not a human supplementation trial; nutrient concentrations and glucose state determine interpretation.

nutrient_topic

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

plain_language

One amino acid can reduce the hormone response to another.

primary_references

Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 344–350

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human and mouse islet perifusion; low-glucose amino-acid challenges. · source_derived_draft · unverified_draft

## alanine-leucine-glucagon One amino acid can reduce the hormone response to another. Leucine suppressed alanine- and arginine-stimulated glucagon secretion in isolated human and mouse islets under the tested low-glucose conditions. Model: Human and mouse islet perifusion; low-glucose amino-acid challenges. Limitations: Mixed-species functional observation, not a human supplementation trial; nutrient concentrations and glucose state determine interpretation. Evidence access: Primary abstract Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

evidence_access

Primary abstract

experimental_model

Human protein biochemical and cell studies.

limitations

This rejects that assignment, not every possible source of mammalian agmatine.

nutrient_topic

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

plain_language

Do not assign a human agmatine-synthesis reaction to AZIN2 just because older names suggest it.

primary_references

Human ornithine decarboxylase paralogue (ODCp) is an antizyme inhibitor but not an arginine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/17900240/ · DOI 10.1042/BJ20071004

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 172–178

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human protein biochemical and cell studies. · source_derived_draft · unverified_draft

## agmatine-sulfate-azin2-identity Do not assign a human agmatine-synthesis reaction to AZIN2 just because older names suggest it. Human ODC paralogue/AZIN2 had no intrinsic arginine-decarboxylase activity in the reported experiments. Model: Human protein biochemical and cell studies. Limitations: This rejects that assignment, not every possible source of mammalian agmatine. Evidence access: Primary abstract Human ornithine decarboxylase paralogue (ODCp) is an antizyme inhibitor but not an arginine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/17900240/ · DOI 10.1042/BJ20071004

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text; Figure 4 and Figure S5

experimental_model

E. coli OP50 mutants feeding C. elegans.

limitations

This is a worm–bacterium experiment, not human gene manipulation or demonstrated clinical synergy.

nutrient_topic

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

plain_language

Bacterial production and disposal influence a host metabolic signal.

primary_references

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

trigger_kind

machinery_impairment Imported condition classification; unverified.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 404–410

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · E. coli OP50 mutants feeding C. elegans. · source_derived_draft · unverified_draft

## agmatine-sulfate-bacterial-speb Bacterial production and disposal influence a host metabolic signal. Deleting E. coli speB increased the worm acs-2 reporter response; deleting additional agmatine-production genes abolished that increase. Model: E. coli OP50 mutants feeding C. elegans. Limitations: This is a worm–bacterium experiment, not human gene manipulation or demonstrated clinical synergy. Evidence access: Primary full text; Figure 4 and Figure S5 Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

evidence_access

Primary full text; Figure 4B

experimental_model

Recombinant human enzyme assay.

limitations

No competition magnitude with glycine or taurine in a living person was established.

nutrient_topic

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

plain_language

Beta-alanine connects to the guanidino-acid network through a distinct reaction.

primary_references

Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 204–210

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

## agmatine-sulfate-gatm-beta-alanine Beta-alanine connects to the guanidino-acid network through a distinct reaction. Human GATM transferred the amidino group of arginine to beta-alanine, producing guanidinopropionate. Model: Recombinant human enzyme assay. Limitations: No competition magnitude with glycine or taurine in a living person was established. Evidence access: Primary full text; Figure 4B Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

evidence_access

Primary full text; Figure 4B

experimental_model

Purified human GATM.

limitations

Presence of this route does not prove a change in brain inhibitory neurotransmission after agmatine supplementation.

nutrient_topic

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

plain_language

The same guanidino metabolite has another possible source besides agmatine oxidation.

primary_references

Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 196–202

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

## agmatine-sulfate-gatm-gaba The same guanidino metabolite has another possible source besides agmatine oxidation. Human GATM used GABA as an amidino acceptor to form guanidinobutyrate in vitro. Model: Purified human GATM. Limitations: Presence of this route does not prove a change in brain inhibitory neurotransmission after agmatine supplementation. Evidence access: Primary full text; Figure 4B Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

evidence_access

Primary full text; Figure 4B

experimental_model

Recombinant human GATM substrate comparison.

limitations

Taurine is a secondary substrate in this assay; tissue flux and clinically important depletion were not established.

nutrient_topic

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

plain_language

Creatine-synthesis machinery also accepts a taurine-related side reaction.

primary_references

Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 188–194

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

## agmatine-sulfate-gatm-taurine Creatine-synthesis machinery also accepts a taurine-related side reaction. Purified human GATM transferred an amidino group from arginine to taurine, producing taurocyamine in vitro. Model: Recombinant human GATM substrate comparison. Limitations: Taurine is a secondary substrate in this assay; tissue flux and clinically important depletion were not established. Evidence access: Primary full text; Figure 4B Guanidino acid hydrolysis by the human enzyme annotated as agmatinase. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36543883/ · DOI 10.1038/s41598-022-26655-4

evidence_access

Primary abstract

experimental_model

Isolated rat liver mitochondria; force-flux and inhibitor analysis.

limitations

The proposed transporter was not genetically identified; no single universal agmatine carrier is asserted.

nutrient_topic

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

plain_language

Mitochondrial entry has different requirements from plasma-membrane entry.

primary_references

Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16509824/ · DOI 10.1042/BJ20060003

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 372–378

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated rat liver mitochondria; force-flux and inhibitor analysis. · source_derived_draft · unverified_draft

## agmatine-sulfate-liver-mito-transport Mitochondrial entry has different requirements from plasma-membrane entry. Agmatine entered rat liver mitochondrial matrix through membrane-potential-dependent transport; putrescine, arginine, ornithine and lysine did not inhibit uptake. Model: Isolated rat liver mitochondria; force-flux and inhibitor analysis. Limitations: The proposed transporter was not genetically identified; no single universal agmatine carrier is asserted. Evidence access: Primary abstract Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16509824/ · DOI 10.1042/BJ20060003

evidence_access

Primary abstract

experimental_model

NOS activity measured by nitrite or citrulline production; species not specified in accessed abstract.

limitations

Isolated-preparation potency does not quantify inhibition after an oral sulfate dose.

nutrient_topic

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

plain_language

An arginine-related compound can inhibit the enzyme rather than supply its product.

primary_references

Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 220–226

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · NOS activity measured by nitrite or citrulline production; species not specified in accessed abstract. · source_derived_draft · unverified_draft

## agmatine-sulfate-nos1-inhibition An arginine-related compound can inhibit the enzyme rather than supply its product. Agmatine competitively inhibited the brain-derived NOS I preparation with approximate Ki 660 micromolar and was not an NO precursor. Model: NOS activity measured by nitrite or citrulline production; species not specified in accessed abstract. Limitations: Isolated-preparation potency does not quantify inhibition after an oral sulfate dose. Evidence access: Primary abstract Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

evidence_access

Primary abstract

experimental_model

Macrophage NOS preparation; enzymatic activity assay.

limitations

This is not a universal inflammatory-cell response or a human concentration target.

nutrient_topic

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

plain_language

NOS isoforms showed different assay sensitivities.

primary_references

Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 228–234

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Macrophage NOS preparation; enzymatic activity assay. · source_derived_draft · unverified_draft

## agmatine-sulfate-nos2-inhibition NOS isoforms showed different assay sensitivities. Agmatine competitively inhibited macrophage-derived NOS II with approximate Ki 220 micromolar. Model: Macrophage NOS preparation; enzymatic activity assay. Limitations: This is not a universal inflammatory-cell response or a human concentration target. Evidence access: Primary abstract Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

evidence_access

Primary abstract

experimental_model

Endothelial NOS enzyme preparation.

limitations

This enzyme result is distinct from upstream signaling in intact endothelial cells.

nutrient_topic

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

plain_language

Direct inhibition of one isoform can require a very different concentration.

primary_references

Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 236–242

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Endothelial NOS enzyme preparation. · source_derived_draft · unverified_draft

## agmatine-sulfate-nos3-inhibition Direct inhibition of one isoform can require a very different concentration. Agmatine competitively inhibited endothelial-derived NOS III only at a much higher approximate Ki of 7.5 mM in the isoform comparison. Model: Endothelial NOS enzyme preparation. Limitations: This enzyme result is distinct from upstream signaling in intact endothelial cells. Evidence access: Primary abstract Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8645212/ · DOI 10.1042/bj3160247

evidence_access

Primary abstract

experimental_model

Human MATE1-expressing HEK293 cells.

limitations

The primary abstract groups the polyamine competitors; no individual potency rank is assigned.

nutrient_topic

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

plain_language

A shared precursor is not necessarily a transport competitor.

primary_references

OCT2 and MATE1 provide bidirectional agmatine transport. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21128598/ · DOI 10.1021/mp100180a

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 52–58

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MATE1-expressing HEK293 cells. · source_derived_draft · unverified_draft

## agmatine-sulfate-polyamine-competition A shared precursor is not necessarily a transport competitor. Polyamines inhibited MATE1-mediated agmatine transport, whereas L-arginine did not inhibit it in the tested system. Model: Human MATE1-expressing HEK293 cells. Limitations: The primary abstract groups the polyamine competitors; no individual potency rank is assigned. Evidence access: Primary abstract OCT2 and MATE1 provide bidirectional agmatine transport. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21128598/ · DOI 10.1021/mp100180a

evidence_access

Primary abstract

experimental_model

Primary rat hepatocyte cultures and radiolabeled substrate.

limitations

Different selectivity from other polyamine uptake systems is a context difference, not a universal contradiction.

nutrient_topic

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

plain_language

Competition depends on which cell and transport route is being studied.

primary_references

Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

transport_effect

raises Hepatocytes showed high-affinity agmatine uptake with a Km of 0.03 mM.

transport_pool

the hepatocyte interior Hepatocytes showed high-affinity agmatine uptake with a Km of 0.03 mM.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 76–82

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary rat hepatocyte cultures and radiolabeled substrate. · source_derived_draft · unverified_draft

## agmatine-sulfate-rat-liver-uptake Competition depends on which cell and transport route is being studied. Rat hepatocytes exhibited high-affinity agmatine uptake with Km 0.03 mM; the system also transported putrescine but not arginine, spermidine or spermine. Model: Primary rat hepatocyte cultures and radiolabeled substrate. Limitations: Different selectivity from other polyamine uptake systems is a context difference, not a universal contradiction. Evidence access: Primary abstract Transport and metabolism of agmatine in rat hepatocyte cultures. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11179960/ · DOI 10.1046/j.1432-1327.2001.01955.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293T knockout and re-expression experiments.

limitations

Loss of one sensor does not make methionine dispensable for proteins or methylation.

nutrient_topic

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

plain_language

Different amino acids enter the growth-control network through different sensors.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 244–250

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T knockout and re-expression experiments. · source_derived_draft · unverified_draft

## methionine-samtor-specificity Different amino acids enter the growth-control network through different sensors. SAMTOR loss made mTORC1 resistant to methionine starvation while leaving leucine- and arginine-starvation sensitivity intact. Model: Human HEK293T knockout and re-expression experiments. Limitations: Loss of one sensor does not make methionine dispensable for proteins or methylation. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

evidence_span

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experimental_model

Human AGAT crystal structures and inactive-mutant substrate complex

exposure

Native, ornithine-bound and inactive mutant structures

limitations

Structures support an amidino-transfer mechanism; substrate availability in a person and effects of amino-acid supplementation were not measured.

nutrient_topic

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

organism

Recombinant human enzyme

plain_language

The first synthesis step joins material from arginine and glycine to make the precursor of creatine.

primary_references

[creatine-p9218780] Crystal structure and mechanism of human L-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. (1997). https://pubmed.ncbi.nlm.nih.gov/9218780/ DOI: 10.1093/emboj/16.12.3373

tissue_or_cell_type

Purified protein

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 177–188

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human AGAT crystal structures and inactive-mutant substrate complex · source_derived_draft · unverified_draft

### creatine-agat-reaction AGAT catalyzes transfer of an amidino group from arginine to glycine, forming guanidinoacetate and ornithine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The first synthesis step joins material from arginine and glycine to make the precursor of creatine. organism: Recombinant human enzyme tissue_or_cell_type: Purified protein experimental_model: Human AGAT crystal structures and inactive-mutant substrate complex limitations: Structures support an amidino-transfer mechanism; substrate availability in a person and effects of amino-acid supplementation were not measured. exposure: Native, ornithine-bound and inactive mutant structures evidence_span: {"source_cache": "artifacts/creatine-research/9218780.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "407baedc2f982a5abb9d14a01e8ac9dc331d60115acc716604c1e6003aa12c1b", "start_char": 0, "end_char": 1112, "text_sha256": "407baedc2f982a5abb9d14a01e8ac9dc331d60115acc716604c1e6003aa12c1b"} [creatine-p9218780] Crystal structure and mechanism of human L-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. (1997). https://pubmed.ncbi.nlm.nih.gov/9218780/ DOI: 10.1093/emboj/16.12.3373

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/creatine-research/29506905.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e443eeda80f65e6e7cd3b0b07a4a86b5f11b6b4feef6201ce97a99bc27af0b66", "start_char": 0, "end_char": 1609, "text_sha256": "e443eeda80f65e6e7cd3b0b07a4a86b5f11b6b4feef6201ce97a99bc27af0b66"}

experimental_model

International retrospective registry

exposure

All received creatine; 18 ornithine and 15 arginine/protein restriction

limitations

Nonrandomized combination treatment and variable diagnosis timing prevent attribution of improvements to a single component.

nutrient_topic

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

organism

22 people with GAMT deficiency

plain_language

The registry supports the importance of treating this disorder, but cannot tell us which component caused each improvement.

primary_references

[creatine-p29506905] Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study. (2018). https://pubmed.ncbi.nlm.nih.gov/29506905/ DOI: 10.1016/j.ejpn.2018.02.007

tissue_or_cell_type

Clinical outcomes

trigger_kind

machinery_impairment Imported condition classification; unverified.

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 893–904

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · International retrospective registry · source_derived_draft · unverified_draft

### creatine-gamt-combination-outcomes In the GAMT registry, clinical severity improved in 13 patients, 11 became seizure-free and movement disorder resolved in four during treatment combinations. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The registry supports the importance of treating this disorder, but cannot tell us which component caused each improvement. organism: 22 people with GAMT deficiency tissue_or_cell_type: Clinical outcomes experimental_model: International retrospective registry limitations: Nonrandomized combination treatment and variable diagnosis timing prevent attribution of improvements to a single component. exposure: All received creatine; 18 ornithine and 15 arginine/protein restriction evidence_span: {"source_cache": "artifacts/creatine-research/29506905.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e443eeda80f65e6e7cd3b0b07a4a86b5f11b6b4feef6201ce97a99bc27af0b66", "start_char": 0, "end_char": 1609, "text_sha256": "e443eeda80f65e6e7cd3b0b07a4a86b5f11b6b4feef6201ce97a99bc27af0b66"} [creatine-p29506905] Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study. (2018). https://pubmed.ncbi.nlm.nih.gov/29506905/ DOI: 10.1016/j.ejpn.2018.02.007

evidence_span

{"source_cache": "artifacts/theanine-research/36596553.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d932aa2f599868e52419cee62048a12b929d575cbb78c95645195083668ea245", "start_char": 0, "end_char": 1550, "text_sha256": "d932aa2f599868e52419cee62048a12b929d575cbb78c95645195083668ea245"}

experimental_model

Randomized three-arm placebo-controlled stress trial

exposure

200 mg theanine; 200 mg theanine plus 50 mg arginine; placebo

limitations

Short stress challenge. Both active arms differed from placebo, but combination versus theanine alone did not (p=0.74); no established synergy.

nutrient_topic

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

organism

120 healthy young adults

plain_language

This is a measured stress marker, not proof of treatment for an anxiety disorder.

primary_references

[theanine-p36596553] Effect of Combined Ingestion of L-Theanine and L-Arginine for Short-Term Psychological Stress in Young Adults: A Randomized Placebo-Controlled Study. (2022). https://pubmed.ncbi.nlm.nih.gov/36596553/ DOI: 10.3177/jnsv.68.540

tissue_or_cell_type

Salivary alpha-amylase after mental stress

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 913–924

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized three-arm placebo-controlled stress trial · source_derived_draft · unverified_draft

### theanine-stress-arginine The active arm had a smaller salivary alpha-amylase change 15 minutes after stress than placebo. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is a measured stress marker, not proof of treatment for an anxiety disorder. organism: 120 healthy young adults tissue_or_cell_type: Salivary alpha-amylase after mental stress experimental_model: Randomized three-arm placebo-controlled stress trial limitations: Short stress challenge. Both active arms differed from placebo, but combination versus theanine alone did not (p=0.74); no established synergy. exposure: 200 mg theanine; 200 mg theanine plus 50 mg arginine; placebo evidence_span: {"source_cache": "artifacts/theanine-research/36596553.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d932aa2f599868e52419cee62048a12b929d575cbb78c95645195083668ea245", "start_char": 0, "end_char": 1550, "text_sha256": "d932aa2f599868e52419cee62048a12b929d575cbb78c95645195083668ea245"} [theanine-p36596553] Effect of Combined Ingestion of L-Theanine and L-Arginine for Short-Term Psychological Stress in Young Adults: A Randomized Placebo-Controlled Study. (2022). https://pubmed.ncbi.nlm.nih.gov/36596553/ DOI: 10.3177/jnsv.68.540

evidence_access

Primary full text

experimental_model

Human transporter cryo-EM and functional study; structural ligand was arginine.

limitations

Do not describe the arginine-bound structure as a captured cystine-bound state or infer dietary competition from binding alone.

nutrient_topic

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

plain_language

The kidney and intestine use a two-protein exchange system to handle cystine.

primary_references

Cryo-EM structure of the human heteromeric amino acid transporter b0,+AT-rBAT. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32494597/ · DOI 10.1126/sciadv.aay6379

L-Cysteine: sulfur allocation, redox supply and cross-nutrient mechanisms (2026-09-19) · lines 20–26

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter cryo-EM and functional study; structural ligand was arginine. · source_derived_draft · unverified_draft

## l-cysteine-renal-cystine-exchange The kidney and intestine use a two-protein exchange system to handle cystine. Human SLC7A9 and SLC3A1 form the b0,+AT–rBAT obligatory exchanger for cystine/cationic amino-acid influx coupled to neutral amino-acid efflux. Model: Human transporter cryo-EM and functional study; structural ligand was arginine. Limitations: Do not describe the arginine-bound structure as a captured cystine-bound state or infer dietary competition from binding alone. Evidence access: Primary full text Cryo-EM structure of the human heteromeric amino acid transporter b0,+AT-rBAT. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32494597/ · DOI 10.1126/sciadv.aay6379

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

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

organism

Human, 20 healthy volunteers

plain_language

The substrate-to-inhibitor ratio changed; this does not mean ADMA itself was removed.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 879–890

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-adma-ratio At 3 g twice daily, the arginine/ADMA ratio rose from 186 to 278. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The substrate-to-inhibitor ratio changed; this does not mean ADMA itself was removed. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/citrulline-research/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"}

experimental_model

Patient vascular testing, hypomorphic mice and molecular experiments

exposure

ASL loss; extracellular arginine; nitrite or NO donor interventions

limitations

Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine.

nutrient_topic

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

organism

Human ASL deficiency and Asl-deficient mice, model specified

plain_language

Providing arginine did not bypass every function of ASL.

primary_references

[citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544

tissue_or_cell_type

Arginine synthesis, NOS-associated protein complex and vasculature

trigger_kind

machinery_impairment Imported condition classification; unverified.

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 632–643

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient vascular testing, hypomorphic mice and molecular experiments · source_derived_draft · unverified_draft

### citrulline-asl-external-arginine ASL loss impaired use of extracellular arginine for NO production as well as reducing endogenous arginine synthesis. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Providing arginine did not bypass every function of ASL. organism: Human ASL deficiency and Asl-deficient mice, model specified tissue_or_cell_type: Arginine synthesis, NOS-associated protein complex and vasculature experimental_model: Patient vascular testing, hypomorphic mice and molecular experiments limitations: Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine. exposure: ASL loss; extracellular arginine; nitrite or NO donor interventions evidence_span: {"source_cache": "artifacts/citrulline-research/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"} [citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544

evidence_span

{"source_cache": "artifacts/citrulline-research/11747433.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1", "start_char": 0, "end_char": 1617, "text_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1"}

experimental_model

Recombinant human enzyme complementation and stability experiments

exposure

Wild type and Q286R, D87G, M360T or A398D variants

limitations

Reaction identity and complementation are established in enzyme systems; these variants do not describe all ASL deficiencies.

nutrient_topic

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

organism

Human ASL expressed experimentally

plain_language

This reaction connects amino-acid nitrogen handling with a carbon-metabolism intermediate.

primary_references

[citrulline-p11747433] Mechanisms for intragenic complementation at the human argininosuccinate lyase locus. (2001). https://pubmed.ncbi.nlm.nih.gov/11747433/ DOI: 10.1021/bi011526e

tissue_or_cell_type

Argininosuccinate cleavage

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 190–201

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

### citrulline-asl-fumarate Fumarate is the other product of the ASL-catalyzed argininosuccinate cleavage reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This reaction connects amino-acid nitrogen handling with a carbon-metabolism intermediate. organism: Human ASL expressed experimentally tissue_or_cell_type: Argininosuccinate cleavage experimental_model: Recombinant human enzyme complementation and stability experiments limitations: Reaction identity and complementation are established in enzyme systems; these variants do not describe all ASL deficiencies. exposure: Wild type and Q286R, D87G, M360T or A398D variants evidence_span: {"source_cache": "artifacts/citrulline-research/11747433.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1", "start_char": 0, "end_char": 1617, "text_sha256": "1d57b633c558211169c38f4dc40cceeeb373c63d291c80d2523c8e48b54427b1"} [citrulline-p11747433] Mechanisms for intragenic complementation at the human argininosuccinate lyase locus. (2001). https://pubmed.ncbi.nlm.nih.gov/11747433/ DOI: 10.1021/bi011526e

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/citrulline-research/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"}

experimental_model

Patient vascular testing, hypomorphic mice and molecular experiments

exposure

ASL loss; extracellular arginine; nitrite or NO donor interventions

limitations

Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine.

nutrient_topic

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

organism

Human ASL deficiency and Asl-deficient mice, model specified

plain_language

An intact downstream enzyme matters to the NO pathway.

primary_references

[citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544

tissue_or_cell_type

Arginine synthesis, NOS-associated protein complex and vasculature

trigger_kind

machinery_impairment Imported condition classification; unverified.

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 619–630

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient vascular testing, hypomorphic mice and molecular experiments · source_derived_draft · unverified_draft

### citrulline-asl-no-low ASL deficiency reduced nitric-oxide synthesis in the studied humans and mice. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intact downstream enzyme matters to the NO pathway. organism: Human ASL deficiency and Asl-deficient mice, model specified tissue_or_cell_type: Arginine synthesis, NOS-associated protein complex and vasculature experimental_model: Patient vascular testing, hypomorphic mice and molecular experiments limitations: Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine. exposure: ASL loss; extracellular arginine; nitrite or NO donor interventions evidence_span: {"source_cache": "artifacts/citrulline-research/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"} [citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/citrulline-research/14970240.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d7acfd232edfd5d968d7afcbaf80ea27807a4313b5a385c90fd11b437403056", "start_char": 0, "end_char": 1589, "text_sha256": "7d7acfd232edfd5d968d7afcbaf80ea27807a4313b5a385c90fd11b437403056"}

experimental_model

RNA-interference and NO-donor rescue experiments

exposure

ASS1 knockdown despite saturating extracellular arginine

limitations

Bovine cell model; no claim that every human tissue exclusively uses regenerated arginine.

nutrient_topic

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

organism

Bovine aortic endothelial cells

plain_language

Bulk substrate abundance did not compensate for impaired local recycling.

primary_references

[citrulline-p14970240] Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/14970240/ DOI: 10.1074/jbc.m308160200

tissue_or_cell_type

Citrulline recycling, NO synthesis and viability

trigger_kind

machinery_impairment Imported condition classification; unverified.

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 658–669

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RNA-interference and NO-donor rescue experiments · source_derived_draft · unverified_draft

### citrulline-ass1-local-no ASS1 knockdown reduced basal and stimulated NO despite saturating arginine in the culture medium. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bulk substrate abundance did not compensate for impaired local recycling. organism: Bovine aortic endothelial cells tissue_or_cell_type: Citrulline recycling, NO synthesis and viability experimental_model: RNA-interference and NO-donor rescue experiments limitations: Bovine cell model; no claim that every human tissue exclusively uses regenerated arginine. exposure: ASS1 knockdown despite saturating extracellular arginine evidence_span: {"source_cache": "artifacts/citrulline-research/14970240.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7d7acfd232edfd5d968d7afcbaf80ea27807a4313b5a385c90fd11b437403056", "start_char": 0, "end_char": 1589, "text_sha256": "7d7acfd232edfd5d968d7afcbaf80ea27807a4313b5a385c90fd11b437403056"} [citrulline-p14970240] Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/14970240/ DOI: 10.1074/jbc.m308160200

evidence_span

{"source_cache": "artifacts/citrulline-research/25332337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0", "start_char": 0, "end_char": 1788, "text_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0"}

experimental_model

Stable-isotope whole-body and renal balance study

exposure

Perioperative intravenous alanyl-glutamine 0.5 g/kg/day

limitations

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

nutrient_topic

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

organism

Human, seven surgical patients

plain_language

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

primary_references

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

tissue_or_cell_type

Intestinal-renal amino-acid axis

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

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

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

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

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

organism

Human, 20 healthy volunteers

plain_language

Better precursor exposure did not produce a detectable improvement in this vascular endpoint.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 918–929

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-healthy-fmd-null No treatment improved FMD over baseline in the healthy-volunteer study. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Better precursor exposure did not produce a detectable improvement in this vascular endpoint. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/citrulline-research/6776014.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d", "start_char": 0, "end_char": 1189, "text_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d"}

experimental_model

Oral amino-acid loading comparison

exposure

Separate diamino-acid and citrulline loads

limitations

Inherited transport disorder, not ordinary competition from mixed dietary protein; the study predates gene identification.

nutrient_topic

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

organism

Human LPI patients, heterozygotes and controls

plain_language

A different entry route can bypass this particular transport problem.

primary_references

[citrulline-p6776014] Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline. (1980). https://pubmed.ncbi.nlm.nih.gov/6776014/ DOI: 10.1136/gut.21.6.519

tissue_or_cell_type

Intestinal amino-acid absorption inferred from plasma and urine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 840–851

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral amino-acid loading comparison · source_derived_draft · unverified_draft

### citrulline-lpi-citrulline-absorption Citrulline plasma increments after oral loads were similar in LPI homozygotes and controls, unlike diamino-acid increments. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A different entry route can bypass this particular transport problem. organism: Human LPI patients, heterozygotes and controls tissue_or_cell_type: Intestinal amino-acid absorption inferred from plasma and urine experimental_model: Oral amino-acid loading comparison limitations: Inherited transport disorder, not ordinary competition from mixed dietary protein; the study predates gene identification. exposure: Separate diamino-acid and citrulline loads evidence_span: {"source_cache": "artifacts/citrulline-research/6776014.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d", "start_char": 0, "end_char": 1189, "text_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d"} [citrulline-p6776014] Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline. (1980). https://pubmed.ncbi.nlm.nih.gov/6776014/ DOI: 10.1136/gut.21.6.519

evidence_span

{"source_cache": "artifacts/citrulline-research/6401349.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e98ad3132221fd0deae9dd89d6c14a4f6b010655656a6e0ea44a7c47f2ca1545", "start_char": 0, "end_char": 349, "text_sha256": "e98ad3132221fd0deae9dd89d6c14a4f6b010655656a6e0ea44a7c47f2ca1545"}

experimental_model

Clinical oral-intermediate comparison

exposure

Oral citrulline, arginine or ornithine

limitations

Brief indexed abstract; no trial size or dosing is inferred; not evidence that citrulline replaces lysine.

nutrient_topic

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

organism

Human lysinuric protein intolerance

plain_language

The alternative precursor improved downstream amino-acid availability in this disorder.

primary_references

[citrulline-p6401349] Oral administration of urea cycle intermediates in lysinuric protein intolerance: effect on plasma and urinary arginine and ornithine. (1983). https://pubmed.ncbi.nlm.nih.gov/6401349/ DOI: 10.1016/0026-0495(83)90154-3

tissue_or_cell_type

Plasma urea-cycle intermediates

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 853–864

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical oral-intermediate comparison · source_derived_draft · unverified_draft

### citrulline-lpi-precursor-response Oral citrulline raised plasma urea-cycle intermediates more than oral arginine or ornithine in the LPI report. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The alternative precursor improved downstream amino-acid availability in this disorder. organism: Human lysinuric protein intolerance tissue_or_cell_type: Plasma urea-cycle intermediates experimental_model: Clinical oral-intermediate comparison limitations: Brief indexed abstract; no trial size or dosing is inferred; not evidence that citrulline replaces lysine. exposure: Oral citrulline, arginine or ornithine evidence_span: {"source_cache": "artifacts/citrulline-research/6401349.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e98ad3132221fd0deae9dd89d6c14a4f6b010655656a6e0ea44a7c47f2ca1545", "start_char": 0, "end_char": 349, "text_sha256": "e98ad3132221fd0deae9dd89d6c14a4f6b010655656a6e0ea44a7c47f2ca1545"} [citrulline-p6401349] Oral administration of urea cycle intermediates in lysinuric protein intolerance: effect on plasma and urinary arginine and ornithine. (1983). https://pubmed.ncbi.nlm.nih.gov/6401349/ DOI: 10.1016/0026-0495(83)90154-3

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

Supplying substrate does not replace the required pterin cofactor.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 515–526

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-bh4 Purified human eNOS showed an absolute BH4 requirement for the measured catalytic reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying substrate does not replace the required pterin cofactor. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

Citrulline is also produced when the nitric-oxide pathway uses arginine.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 502–513

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-citrulline Purified human eNOS converted arginine in an assay measuring citrulline formation, with an arginine Km of 3.9 micromolar. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline is also produced when the nitric-oxide pathway uses arginine. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

Cofactor and substrate helped stabilize the paired enzyme structure.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 580–591

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-dimer BH4 plus arginine shifted human eNOS toward dimers during low-temperature electrophoresis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cofactor and substrate helped stabilize the paired enzyme structure. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

One vitamin-B2-derived flavin is part of the enzyme.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 528–539

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-fad The purified human eNOS preparation contained approximately 0.56 FAD equivalents per subunit. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: One vitamin-B2-derived flavin is part of the enzyme. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

A second B2-derived flavin participates in the enzyme system.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 541–552

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-fmn The human eNOS preparation contained approximately 0.79 FMN equivalents per subunit. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second B2-derived flavin participates in the enzyme system. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

The nitric-oxide machinery includes an iron-containing heme group.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 554–565

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-heme Heme and protein-bound iron were detected in purified human eNOS by independent analytical methods. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The nitric-oxide machinery includes an iron-containing heme group. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/1378832.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206", "start_char": 0, "end_char": 1652, "text_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206"}

experimental_model

Functional expression and reporter-cell coculture

exposure

NOS3 transfection and calcium ionophore A23187

limitations

Heterologous expression; reporter activation supports bioactive NO production, not a clinical calcium supplementation effect.

nutrient_topic

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

organism

Human NOS3 expressed in NIH3T3 cells; rat reporter fibroblasts

plain_language

Arginine feeds an enzyme that makes the signal NO while also producing citrulline.

primary_references

[citrulline-p1378832] Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. (1992). https://pubmed.ncbi.nlm.nih.gov/1378832/ DOI: 10.1016/s0021-9258(18)42066-2

tissue_or_cell_type

Arginine conversion and NO-dependent reporter guanylate cyclase activity

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 463–474

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Functional expression and reporter-cell coculture · source_derived_draft · unverified_draft

### citrulline-nos-no Cells expressing human endothelial NOS produced bioactive NO that increased guanylate cyclase activity in cocultured reporter cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine feeds an enzyme that makes the signal NO while also producing citrulline. organism: Human NOS3 expressed in NIH3T3 cells; rat reporter fibroblasts tissue_or_cell_type: Arginine conversion and NO-dependent reporter guanylate cyclase activity experimental_model: Functional expression and reporter-cell coculture limitations: Heterologous expression; reporter activation supports bioactive NO production, not a clinical calcium supplementation effect. exposure: NOS3 transfection and calcium ionophore A23187 evidence_span: {"source_cache": "artifacts/citrulline-research/1378832.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206", "start_char": 0, "end_char": 1652, "text_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206"} [citrulline-p1378832] Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. (1992). https://pubmed.ncbi.nlm.nih.gov/1378832/ DOI: 10.1016/s0021-9258(18)42066-2

evidence_span

{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}

experimental_model

Purified recombinant enzyme activity and cofactor analysis

exposure

Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements

limitations

Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.

nutrient_topic

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

organism

Human NOS3 expressed in yeast

plain_language

Zinc is a structural component measured in the enzyme, not an automatic reason for high-dose zinc.

primary_references

[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

tissue_or_cell_type

Endothelial NOS enzyme preparation

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 567–578

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft

### citrulline-nos-zinc Metal analysis detected approximately 0.43 zinc equivalents per human eNOS subunit. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc is a structural component measured in the enzyme, not an automatic reason for high-dose zinc. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

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

organism

Human, 20 healthy volunteers

plain_language

Taking the precursor can raise circulating arginine efficiently.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 866–877

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-oral-arginine Oral citrulline increased plasma arginine AUC and peak concentration dose-dependently, more effectively than the tested oral arginine regimens. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Taking the precursor can raise circulating arginine efficiently. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}

experimental_model

Patient genetics and recombinant variant expression

exposure

ALDH18A1 R84Q compared with wild-type isoforms

limitations

Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.

nutrient_topic

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

organism

Human, two siblings and mammalian expression systems

plain_language

Low citrulline can arise from a defective upstream enzyme.

primary_references

[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

tissue_or_cell_type

Mitochondrial P5CS and circulating amino acids

trigger_kind

machinery_impairment Imported condition classification; unverified.

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 320–331

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft

### citrulline-p5cs-low-citrulline The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low citrulline can arise from a defective upstream enzyme. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853

evidence_span

{"source_cache": "artifacts/citrulline-research/25332337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0", "start_char": 0, "end_char": 1788, "text_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0"}

experimental_model

Stable-isotope whole-body and renal balance study

exposure

Perioperative intravenous alanyl-glutamine 0.5 g/kg/day

limitations

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

nutrient_topic

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

organism

Human, seven surgical patients

plain_language

The kidney is a major conversion site, but it is not the only possible site.

primary_references

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

tissue_or_cell_type

Intestinal-renal amino-acid axis

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 450–461

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

### citrulline-renal-conversion The kidneys accounted for 75% of whole-body arginine production from citrulline in the isotope study. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidney is a major conversion site, but it is not the only possible site. organism: Human, seven surgical patients tissue_or_cell_type: Intestinal-renal amino-acid axis experimental_model: Stable-isotope whole-body and renal balance study limitations: Small perioperative study; the reported doubling versus previous studies was not a concurrent randomized control comparison. exposure: Perioperative intravenous alanyl-glutamine 0.5 g/kg/day evidence_span: {"source_cache": "artifacts/citrulline-research/25332337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0", "start_char": 0, "end_char": 1788, "text_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0"} [citrulline-p25332337] Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. (2014). https://pubmed.ncbi.nlm.nih.gov/25332337/ DOI: 10.3945/ajcn.113.081547

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

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

organism

Human, 20 healthy volunteers

plain_language

A downstream signaling marker increased.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 892–903

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-urine-cgmp The highest citrulline regimen increased urinary cGMP from 38 to 50 nmol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A downstream signaling marker increased. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

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

organism

Human, 20 healthy volunteers

plain_language

Another NO-related marker changed.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 905–916

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-urine-nitrate The highest regimen increased urinary nitrate from 92 to 125 micromol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Another NO-related marker changed. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/cold-research/28844881.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1341345f147cd7e59119d062b0523a4bf6087a6936b3434bb76a305033a724eb", "start_char": 0, "end_char": 1069, "text_sha256": "1341345f147cd7e59119d062b0523a4bf6087a6936b3434bb76a305033a724eb"}

experimental_model

Adipocyte-selective knockout of glycine amidinotransferase in mice

exposure

High-calorie feeding, beta-3 adrenergic activation, and dietary creatine supplementation

limitations

A genetic test of the same cycle with a dietary rescue. It concerns diet-induced thermogenesis rather than cold thermogenesis directly.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Mouse

plain_language

Blocking the cell from making creatine caused obesity, and feeding creatine fixed it.

primary_references

[cold-p28844881] Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. (2017). https://pubmed.ncbi.nlm.nih.gov/28844881/ DOI: 10.1016/j.cmet.2017.08.009

tissue_or_cell_type

Adipose tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 468–479

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adipocyte-selective knockout of glycine amidinotransferase in mice · source_derived_draft · unverified_draft

### cold-gatm-knockout-obesity Mice lacking the first and rate-limiting enzyme of creatine biosynthesis selectively in fat were prone to diet-induced obesity through suppression of the elevated energy expenditure normally seen with high-calorie feeding, with a blunted capacity for beta-3 adrenergic activation of metabolic rate that was rescued by dietary creatine supplementation. Condition category: machinery_impairment nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Blocking the cell from making creatine caused obesity, and feeding creatine fixed it. organism: Mouse tissue_or_cell_type: Adipose tissue experimental_model: Adipocyte-selective knockout of glycine amidinotransferase in mice limitations: A genetic test of the same cycle with a dietary rescue. It concerns diet-induced thermogenesis rather than cold thermogenesis directly. exposure: High-calorie feeding, beta-3 adrenergic activation, and dietary creatine supplementation evidence_span: {"source_cache": "artifacts/cold-research/28844881.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1341345f147cd7e59119d062b0523a4bf6087a6936b3434bb76a305033a724eb", "start_char": 0, "end_char": 1069, "text_sha256": "1341345f147cd7e59119d062b0523a4bf6087a6936b3434bb76a305033a724eb"} [cold-p28844881] Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. (2017). https://pubmed.ncbi.nlm.nih.gov/28844881/ DOI: 10.1016/j.cmet.2017.08.009

experimental_model

X-ray structures of human ARG1 with boronic-acid transition-state analogues

exposure

ABH and BEC inhibitor complexes

limitations

Transition-state analogue crystallography and author mechanistic inference; not direct nutritional manganese restriction.

nutrient_topic

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

organism

Homo sapiens protein

plain_language

ARG1 holds two manganese ions at the site where arginine is hydrolyzed.

primary_references

[mn-enz-16141327] Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response. (2005). https://pubmed.ncbi.nlm.nih.gov/16141327/ DOI: 10.1073/pnas.0504027102

tissue_or_cell_type

Purified ARG1

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 534–544

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures of human ARG1 with boronic-acid transition-state analogues · source_derived_draft · unverified_draft

### mn-enz-arg1-binuclear-transition-state Human ARG1 structures show a binuclear manganese site binding a boronate transition-state analogue, supporting metal stabilization of the arginine-hydrolysis transition state. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: ARG1 holds two manganese ions at the site where arginine is hydrolyzed. organism: Homo sapiens protein tissue_or_cell_type: Purified ARG1 experimental_model: X-ray structures of human ARG1 with boronic-acid transition-state analogues limitations: Transition-state analogue crystallography and author mechanistic inference; not direct nutritional manganese restriction. exposure: ABH and BEC inhibitor complexes [mn-enz-16141327] Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response. (2005). https://pubmed.ncbi.nlm.nih.gov/16141327/ DOI: 10.1073/pnas.0504027102

experimental_model

Crystal structure of active truncated human ARG2 with transition-state analogue

exposure

Boronic-acid inhibitor complex; 2.7-A structure

limitations

Structural consistency with the proposed mechanism; truncated active recombinant human ARG2 with inhibitor, not direct dietary manganese perturbation.

nutrient_topic

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

organism

Homo sapiens protein

plain_language

Two manganese ions help ARG2 activate the water-derived attacking group.

primary_references

[mn-enz-12859189] Human arginase II: crystal structure and physiological role in male and female sexual arousal. (2003). https://pubmed.ncbi.nlm.nih.gov/12859189/ DOI: 10.1021/bi034340j

tissue_or_cell_type

Purified ARG2

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 584–594

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of active truncated human ARG2 with transition-state analogue · source_derived_draft · unverified_draft

### mn-enz-arg2-metal-hydroxide The active truncated human ARG2 structure with a transition-state analogue supports a binuclear-manganese, metal-activated hydroxide mechanism for arginine hydrolysis. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two manganese ions help ARG2 activate the water-derived attacking group. organism: Homo sapiens protein tissue_or_cell_type: Purified ARG2 experimental_model: Crystal structure of active truncated human ARG2 with transition-state analogue limitations: Structural consistency with the proposed mechanism; truncated active recombinant human ARG2 with inhibitor, not direct dietary manganese perturbation. exposure: Boronic-acid inhibitor complex; 2.7-A structure [mn-enz-12859189] Human arginase II: crystal structure and physiological role in male and female sexual arousal. (2003). https://pubmed.ncbi.nlm.nih.gov/12859189/ DOI: 10.1021/bi034340j

experimental_model

Six-day randomized crossover feeding study in 14 women

limitations

Combined amino acids; small sample; specifically low-protein background diet; no long-term skeletal endpoint.

organism

Homo sapiens

plain_language

The trial did not establish a statistically significant absorption benefit.

primary_references

[bihuniak2014] Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3927545/ DOI: 10.3945/jn.113.185009

tissue_or_cell_type

Intestine

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 769–777

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-day randomized crossover feeding study in 14 women · source_derived_draft · unverified_draft

### dibasic-calcium-absorption-trend Adding lysine plus arginine to a low-protein diet produced only a nonsignificant calcium-absorption trend: 25.2% versus 22.3% with control, P=0.094. Plain language: The trial did not establish a statistically significant absorption benefit. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Intestine experimental_model: Six-day randomized crossover feeding study in 14 women limitations: Combined amino acids; small sample; specifically low-protein background diet; no long-term skeletal endpoint. [bihuniak2014] Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3927545/ DOI: 10.3945/jn.113.185009

experimental_model

Randomized crossover feeding trial in 14 women

limitations

No lysine-only arm or demonstrated long-term calcium-balance effect.

organism

Homo sapiens

plain_language

More urinary calcium accompanied the mixture; it cannot by itself be read as either bone loss or better bone health.

primary_references

[bihuniak2014] Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3927545/ DOI: 10.3945/jn.113.185009

tissue_or_cell_type

Kidney and urine

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 779–787

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover feeding trial in 14 women · source_derived_draft · unverified_draft

### dibasic-urinary-calcium-increase In the same crossover study, lysine plus arginine significantly increased urinary calcium compared with the low-protein control diet. Plain language: More urinary calcium accompanied the mixture; it cannot by itself be read as either bone loss or better bone health. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Kidney and urine experimental_model: Randomized crossover feeding trial in 14 women limitations: No lysine-only arm or demonstrated long-term calcium-balance effect. [bihuniak2014] Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3927545/ DOI: 10.3945/jn.113.185009

experimental_model

Randomized double-blind placebo-controlled trial; 2.64 g/day of each amino acid

limitations

Short duration; no lysine-only arm; no established treatment effect for diagnosed anxiety disorders.

organism

Homo sapiens

plain_language

The tested mixture improved anxiety scores; the contribution of lysine alone is unknown.

primary_references

[smriga2007] Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans (2007). https://pubmed.ncbi.nlm.nih.gov/17510493/ DOI: 10.2220/biomedres.28.85

tissue_or_cell_type

Behavioral questionnaires

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 729–737

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind placebo-controlled trial; 2.64 g/day of each amino acid · source_derived_draft · unverified_draft

### lysine-arginine-anxiety One week of combined lysine and arginine reduced trait and stress-induced state anxiety in a randomized trial of 108 healthy Japanese adults. Plain language: The tested mixture improved anxiety scores; the contribution of lysine alone is unknown. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Behavioral questionnaires experimental_model: Randomized double-blind placebo-controlled trial; 2.64 g/day of each amino acid limitations: Short duration; no lysine-only arm; no established treatment effect for diagnosed anxiety disorders. [smriga2007] Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans (2007). https://pubmed.ncbi.nlm.nih.gov/17510493/ DOI: 10.2220/biomedres.28.85

experimental_model

Ten-day randomized trial; 3 g/day of each amino acid, followed by public-speaking stress

limitations

Small combination trial; authors' proposed normalization is an interpretation, not a proven lysine-specific mechanism.

organism

Homo sapiens

plain_language

The mixture did not simply suppress all stress hormones.

primary_references

[jezova2005] Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety (2005). https://pubmed.ncbi.nlm.nih.gov/16117182/ DOI: 10.1080/10284150500162937

tissue_or_cell_type

Blood stress hormones and cardiovascular measurements

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 739–747

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten-day randomized trial; 3 g/day of each amino acid, followed by public-speaking stress · source_derived_draft · unverified_draft

### lysine-arginine-stress-hormones In 29 high-trait-anxiety participants, lysine plus arginine increased stress-evoked ACTH, cortisol, adrenaline, and noradrenaline responses without changing heart-rate or blood-pressure responses. Plain language: The mixture did not simply suppress all stress hormones. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Blood stress hormones and cardiovascular measurements experimental_model: Ten-day randomized trial; 3 g/day of each amino acid, followed by public-speaking stress limitations: Small combination trial; authors' proposed normalization is an interpretation, not a proven lysine-specific mechanism. [jezova2005] Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety (2005). https://pubmed.ncbi.nlm.nih.gov/16117182/ DOI: 10.1080/10284150500162937

affected_machinery

SLC7A7-containing transporter

availability_state

machinery_impairment Imported condition classification; unverified.

deficiency_not_equivalent

Dietary lysine deficiency

experimental_model

Human inherited disease genetics and transport characterization

limitations

A multiamino-acid transport disorder; systemic manifestations are not attributable solely to dietary lysine shortage.

organism

Homo sapiens

plain_language

A transport defect can limit lysine delivery despite its presence in food.

primary_references

[torrents1999] Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene (1999). https://www.nature.com/articles/ng0399_293 DOI: 10.1038/6809

tissue_or_cell_type

Intestinal and renal epithelial basolateral membranes

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 218–228

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human inherited disease genetics and transport characterization · source_derived_draft · unverified_draft

### slc7a7-lpi Pathogenic SLC7A7 variants impair epithelial dibasic-amino-acid transport in lysinuric protein intolerance. Plain language: A transport defect can limit lysine delivery despite its presence in food. Condition category: machinery_impairment organism: Homo sapiens tissue_or_cell_type: Intestinal and renal epithelial basolateral membranes experimental_model: Human inherited disease genetics and transport characterization limitations: A multiamino-acid transport disorder; systemic manifestations are not attributable solely to dietary lysine shortage. affected_machinery: SLC7A7-containing transporter deficiency_not_equivalent: Dietary lysine deficiency [torrents1999] Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene (1999). https://www.nature.com/articles/ng0399_293 DOI: 10.1038/6809

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

evidence_access

Primary abstract

experimental_model

Experimental NO assays and human renal-failure observations.

limitations

The abstract does not isolate a single NOS isoform.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

An internal inhibitor can limit the pathway even when arginine is present.

primary_references

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1347093/ · DOI 10.1016/0140-6736(92)90865-z

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 94–100

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Experimental NO assays and human renal-failure observations. · source_derived_draft · unverified_draft

## arg-adma-nos An internal inhibitor can limit the pathway even when arginine is present. In-vitro and in-vivo experiments identified ADMA as an endogenous inhibitor of NO synthesis. Model: Experimental NO assays and human renal-failure observations. Limitations: The abstract does not isolate a single NOS isoform. Evidence access: Primary abstract Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. · 1992 · https://pubmed.ncbi.nlm.nih.gov/1347093/ · DOI 10.1016/0140-6736(92)90865-z

evidence_access

Full-text methods/results/discussion, Europe PMC PMC9217908.

experimental_model

HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake.

limitations

Transport competition is distinct from direct NOS inhibition.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

An endogenous arginine derivative can compete at the entry step.

primary_references

Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 30–36

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. · source_derived_draft · unverified_draft

## arg-adma-transport An endogenous arginine derivative can compete at the entry step. ADMA produced a competitive inhibition pattern for CAT1-mediated arginine uptake. Model: HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. Limitations: Transport competition is distinct from direct NOS inhibition. Evidence access: Full-text methods/results/discussion, Europe PMC PMC9217908. Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mammalian-cell signaling experiments and biochemical CASTOR1 binding.

limitations

Experimental starvation response; no universal dietary cutoff.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Low arginine is sensed through specific machinery.

primary_references

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 190–196

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian-cell signaling experiments and biochemical CASTOR1 binding. · source_derived_draft · unverified_draft

## arg-castor-starvation Low arginine is sensed through specific machinery. CASTOR1 was required for arginine deprivation to inhibit mTORC1. Model: Mammalian-cell signaling experiments and biochemical CASTOR1 binding. Limitations: Experimental starvation response; no universal dietary cutoff. Evidence access: Primary abstract The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

evidence_access

Primary abstract

experimental_model

35 adults aged at least 70; 14 g arginine, 3 g HMB and 14 g glutamine daily versus isonitrogenous/isocaloric control.

limitations

Cannot isolate arginine, prove the proline route caused the effect, or establish faster healing of clinical wounds.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The study measured a tissue-building outcome, with several ingredients acting together.

primary_references

Effect of a specialized amino acid mixture on human collagen deposition. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12192323/ · DOI 10.1097/00000658-200209000-00013

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 422–428

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 35 adults aged at least 70; 14 g arginine, 3 g HMB and 14 g glutamine daily versus isonitrogenous/isocaloric control. · source_derived_draft · unverified_draft

## arg-collagen-mixture The study measured a tissue-building outcome, with several ingredients acting together. The mixture increased implant hydroxyproline, a collagen-accumulation measure, without increasing total protein deposition. Model: 35 adults aged at least 70; 14 g arginine, 3 g HMB and 14 g glutamine daily versus isonitrogenous/isocaloric control. Limitations: Cannot isolate arginine, prove the proline route caused the effect, or establish faster healing of clinical wounds. Evidence access: Primary abstract Effect of a specialized amino acid mixture on human collagen deposition. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12192323/ · DOI 10.1097/00000658-200209000-00013

evidence_access

Full-text methods/results/discussion, Europe PMC PMC9217908.

experimental_model

HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake.

limitations

No clinical benefit or harm follows from the assay alone.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A related amino acid shares transport machinery.

primary_references

Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 38–44

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. · source_derived_draft · unverified_draft

## arg-homoarg-transport A related amino acid shares transport machinery. Homoarginine produced a competitive inhibition pattern for CAT1-mediated arginine uptake. Model: HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. Limitations: No clinical benefit or harm follows from the assay alone. Evidence access: Full-text methods/results/discussion, Europe PMC PMC9217908. Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Jurkat T cells in arginine-free culture medium.

limitations

Not a clinical dietary-deficiency threshold.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The receptor’s signaling machinery could recover when arginine returned.

primary_references

Regulation of T cell receptor CD3zeta chain expression by L-arginine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11950832/ · DOI 10.1074/jbc.m110675200

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 278–284

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Jurkat T cells in arginine-free culture medium. · source_derived_draft · unverified_draft

## arg-jurkat-protein The receptor’s signaling machinery could recover when arginine returned. Arginine removal lowered CD3-zeta and proliferation; replacing arginine reversed the changes. Model: Jurkat T cells in arginine-free culture medium. Limitations: Not a clinical dietary-deficiency threshold. Evidence access: Primary abstract Regulation of T cell receptor CD3zeta chain expression by L-arginine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11950832/ · DOI 10.1074/jbc.m110675200

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Jurkat T cells in arginine-free culture medium.

limitations

Cell-line result; primary T cells showed a different regulatory level in the later study.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Low availability changed how long an immune-signaling message survived.

primary_references

Regulation of T cell receptor CD3zeta chain expression by L-arginine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11950832/ · DOI 10.1074/jbc.m110675200

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 270–276

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Jurkat T cells in arginine-free culture medium. · source_derived_draft · unverified_draft

## arg-jurkat-rna Low availability changed how long an immune-signaling message survived. Arginine removal shortened CD247 mRNA half-life without reducing its transcription rate. Model: Jurkat T cells in arginine-free culture medium. Limitations: Cell-line result; primary T cells showed a different regulatory level in the later study. Evidence access: Primary abstract Regulation of T cell receptor CD3zeta chain expression by L-arginine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11950832/ · DOI 10.1074/jbc.m110675200

evidence_access

Primary abstract

experimental_model

Cellular proteolysis and mTORC1 experiments.

limitations

Not evidence that a high blood arginine level guarantees lysosomal amino-acid release.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Stored or ingested protein must be released from the lysosome before its amino acids can signal.

primary_references

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 214–220

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cellular proteolysis and mTORC1 experiments. · source_derived_draft · unverified_draft

## arg-lysosome-growth Stored or ingested protein must be released from the lysosome before its amino acids can signal. Leucine generated by lysosomal proteolysis required SLC38A9 for export and subsequent mTORC1 activation. Model: Cellular proteolysis and mTORC1 experiments. Limitations: Not evidence that a high blood arginine level guarantees lysosomal amino-acid release. Evidence access: Primary abstract mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046

evidence_access

Primary abstract

experimental_model

Lysosomal transport and mammalian-cell experiments.

limitations

This is a compartment-specific mechanism, not a demonstrated arginine–leucine supplement synergy.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Arginine sensing helps make another amino acid available to the cell.

primary_references

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 206–212

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Lysosomal transport and mammalian-cell experiments. · source_derived_draft · unverified_draft

## arg-lysosome-leucine Arginine sensing helps make another amino acid available to the cell. SLC38A9 mediated arginine-regulated export of essential amino acids, including leucine, from lysosomes. Model: Lysosomal transport and mammalian-cell experiments. Limitations: This is a compartment-specific mechanism, not a demonstrated arginine–leucine supplement synergy. Evidence access: Primary abstract mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046

evidence_access

Primary abstract

experimental_model

Rat cerebellar NOS preparation; separated partial reactions.

limitations

Assay-specific stimulation, not a dietary BH4 or arginine treatment rule.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Substrate availability and cofactor availability are separate requirements.

primary_references

Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 86–92

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat cerebellar NOS preparation; separated partial reactions. · source_derived_draft · unverified_draft

## arg-nos-bh4 Substrate availability and cofactor availability are separate requirements. BH4 stimulated both partial reactions; the first increased approximately threefold. Model: Rat cerebellar NOS preparation; separated partial reactions. Limitations: Assay-specific stimulation, not a dietary BH4 or arginine treatment rule. Evidence access: Primary abstract Characteristics of the nitric oxide synthase-catalyzed conversion of arginine to N-hydroxyarginine, the first oxygenation step in the enzymic synthesis of nitric oxide. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7530247/ · DOI 10.1074/jbc.270.4.1721

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Activated human T-lymphocyte culture.

limitations

Unlike Jurkat findings, lower mRNA, greater degradation and apoptosis did not explain this result. Model difference is retained.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Availability affected rebuilding the receptor after stimulation.

primary_references

L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15922712/ · DOI 10.1016/j.cellimm.2005.01.004

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 286–292

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Activated human T-lymphocyte culture. · source_derived_draft · unverified_draft

## arg-primary-cd3 Availability affected rebuilding the receptor after stimulation. Activated human T cells failed to restore CD3-zeta in arginine-free medium; replenishment restored expression. Model: Activated human T-lymphocyte culture. Limitations: Unlike Jurkat findings, lower mRNA, greater degradation and apoptosis did not explain this result. Model difference is retained. Evidence access: Primary abstract L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15922712/ · DOI 10.1016/j.cellimm.2005.01.004

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Activated human T-lymphocyte culture.

limitations

Not evidence that all cytokines or all immune functions decline together.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The immune response changed selectively.

primary_references

L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15922712/ · DOI 10.1016/j.cellimm.2005.01.004

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 294–300

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Activated human T-lymphocyte culture. · source_derived_draft · unverified_draft

## arg-primary-cytokines The immune response changed selectively. IFN-gamma, IL-5 and IL-10 output decreased, whereas IL-2 did not show the same decrease. Model: Activated human T-lymphocyte culture. Limitations: Not evidence that all cytokines or all immune functions decline together. Evidence access: Primary abstract L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15922712/ · DOI 10.1016/j.cellimm.2005.01.004

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Human T-cell clones; CRISPR perturbation.

limitations

Does not establish a sole sensor or benefit against human cancer.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

This regulator contributed to the survival response.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 246–252

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell clones; CRISPR perturbation. · source_derived_draft · unverified_draft

## arg-tcell-baz1b This regulator contributed to the survival response. Knockout reduced the arginine-associated survival benefit. Model: Human T-cell clones; CRISPR perturbation. Limitations: Does not establish a sole sensor or benefit against human cancer. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Human T-cell clones; CRISPR perturbation.

limitations

Does not establish a sole sensor or benefit against human cancer.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

This regulator contributed to the survival response.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 254–260

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell clones; CRISPR perturbation. · source_derived_draft · unverified_draft

## arg-tcell-psip1 This regulator contributed to the survival response. Knockout reduced the arginine-associated survival benefit. Model: Human T-cell clones; CRISPR perturbation. Limitations: Does not establish a sole sensor or benefit against human cancer. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract.

experimental_model

Human T-cell clones; CRISPR perturbation.

limitations

Does not establish a sole sensor or benefit against human cancer.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

This regulator contributed to the survival response.

primary_references

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 262–268

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell clones; CRISPR perturbation. · source_derived_draft · unverified_draft

## arg-tcell-tsn This regulator contributed to the survival response. Knockout reduced the arginine-associated survival benefit. Model: Human T-cell clones; CRISPR perturbation. Limitations: Does not establish a sole sensor or benefit against human cancer. Evidence access: Full-text results, Figures 2 and 6, Europe PMC PMC5075284; primary abstract. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27745970/ · DOI 10.1016/j.cell.2016.09.031

evidence_access

Primary abstract

experimental_model

Same chemotherapy-combination trial.

limitations

Do not attribute the combination outcome to ordinary dietary arginine intake.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The clinical benefit record retains the treatment tradeoff.

primary_references

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38358753/ · DOI 10.1001/jamaoncol.2023.6789

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 414–420

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same chemotherapy-combination trial. · source_derived_draft · unverified_draft

## arg-tumor-adverse The clinical benefit record retains the treatment tradeoff. Grade 3–4 adverse events were reported in 28.8% with pegargiminase versus 16.9% with placebo. Model: Same chemotherapy-combination trial. Limitations: Do not attribute the combination outcome to ordinary dietary arginine intake. Evidence access: Primary abstract Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38358753/ · DOI 10.1001/jamaoncol.2023.6789

evidence_access

Primary abstract

experimental_model

ATOMIC-Meso: 249 patients, nonepithelioid pleural mesothelioma; weekly 36.8 mg/m² plus pemetrexed/platinum.

limitations

Drug combination trial, not dietary restriction or a general cancer treatment.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Arginine depletion can have a therapeutic role in a specific tumor context.

primary_references

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38358753/ · DOI 10.1001/jamaoncol.2023.6789

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 406–412

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · ATOMIC-Meso: 249 patients, nonepithelioid pleural mesothelioma; weekly 36.8 mg/m² plus pemetrexed/platinum. · source_derived_draft · unverified_draft

## arg-tumor-survival Arginine depletion can have a therapeutic role in a specific tumor context. Adding pegargiminase to chemotherapy increased median survival from 7.7 to 9.3 months; death hazard ratio 0.71. Model: ATOMIC-Meso: 249 patients, nonepithelioid pleural mesothelioma; weekly 36.8 mg/m² plus pemetrexed/platinum. Limitations: Drug combination trial, not dietary restriction or a general cancer treatment. Evidence access: Primary abstract Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38358753/ · DOI 10.1001/jamaoncol.2023.6789

evidence_access

Full-text methods/results/discussion, Europe PMC PMC9217908.

experimental_model

HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake.

limitations

Far above free therapeutic plasma exposure; the authors considered a significant clinical transport interaction unlikely.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

A laboratory drug effect acts at the transport step.

primary_references

Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 46–52

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. · source_derived_draft · unverified_draft

## arg-verapamil A laboratory drug effect acts at the transport step. Verapamil inhibited CAT1 arginine uptake with IC50 85.3 micromolar and an uncompetitive pattern. Model: HEK cells expressing human CAT1, compared with vector controls; radiolabeled substrate uptake. Limitations: Far above free therapeutic plasma exposure; the authors considered a significant clinical transport interaction unlikely. Evidence access: Full-text methods/results/discussion, Europe PMC PMC9217908. Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35377022/ · DOI 10.1007/s00726-022-03156-2