Nutrient chapter

L-Arginine

Independent small molecule record; interpretation is limited by each linked claim and its study context.

104 recorded mechanisms · 4 availability situations · 7 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

CAT1 expression supported measurable uptake of arginine in the transporter assay.
CAT1 / SLC7A1 → L-Arginine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
ADMA produced a competitive inhibition pattern for CAT1-mediated arginine uptake.
Asymmetric dimethylarginine / ADMA → Human CAT1-mediated arginine uptake source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Homoarginine produced a competitive inhibition pattern for CAT1-mediated arginine uptake.
Homoarginine → Human CAT1-mediated arginine uptake source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Verapamil inhibited CAT1 arginine uptake with IC50 85.3 micromolar and an uncompetitive pattern.
Verapamil → Human CAT1-mediated arginine uptake source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Amino-acid loading experiments indicated inhibition of renal citrulline transport by arginine, lysine and ornithine.
L-Arginine → Renal citrulline transport in loading experiments source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 54–60
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
Complete structured claim and evidence
Rat neuronal uptake showed a sodium-independent component consistent with CAT1, with Km 47 ± 8 micromolar.
Rat cationic amino acid transporter 1 / Slc7a1 → L-Arginine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
NOS converted arginine to N-hydroxyarginine in an oxygen- and calcium/calmodulin-dependent partial reaction.
L-Arginine → Nω-Hydroxy-L-arginine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The second oxygenation yielded NO and citrulline and required added NADPH and calcium/calmodulin.
Nω-Hydroxy-L-arginine → NO source_derived_draftungraded
Experimental context and source evidence
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
The next reaction produces the signal and recycles the carbon skeleton.
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 78–84
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-second The next reaction produces the signal and recycles the carbon skeleton. The second oxygenation yielded NO and citrulline and required added NADPH and calcium/calmodulin. 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
Complete structured claim and evidence
BH4 stimulated both partial reactions; the first increased approximately threefold.
Tetrahydrobiopterin / BH4 → Rat neuronal nitric oxide synthase / Nos1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In-vitro and in-vivo experiments identified ADMA as an endogenous inhibitor of NO synthesis.
Asymmetric dimethylarginine / ADMA → NOS-dependent nitric oxide production, model specified source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Biochemical binding and structural experiments identify PLP as the human ODC coenzyme.
PLP → Human ornithine decarboxylase / ODC1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human and Leishmania ODC comparison; human inhibitor-bound structure.
limitations
Cofactor dependence does not establish that extra B6 raises polyamines in a replete person.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
The polyamine branch connects to vitamin B6.
primary_references
A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 102–108
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human and Leishmania ODC comparison; human inhibitor-bound structure. · source_derived_draft · unverified_draft
## arg-odc-cofactor The polyamine branch connects to vitamin B6. Biochemical binding and structural experiments identify PLP as the human ODC coenzyme. Model: Human and Leishmania ODC comparison; human inhibitor-bound structure. Limitations: Cofactor dependence does not establish that extra B6 raises polyamines in a replete person. Evidence access: Primary abstract A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
Complete structured claim and evidence
ODC catalyzes conversion of ornithine into putrescine.
L-Ornithine → Putrescine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and indexed primary full-text introduction, PMC1904517
experimental_model
Human ODC study; reaction identified in the primary paper introduction.
limitations
Reaction identity does not establish net pathway flux after supplementation.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
This reaction opens the polyamine branch.
primary_references
A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 110–116
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human ODC study; reaction identified in the primary paper introduction. · source_derived_draft · unverified_draft
## arg-odc-reaction This reaction opens the polyamine branch. ODC catalyzes conversion of ornithine into putrescine. Model: Human ODC study; reaction identified in the primary paper introduction. Limitations: Reaction identity does not establish net pathway flux after supplementation. Evidence access: Primary abstract and indexed primary full-text introduction, PMC1904517 A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17407445/ · DOI 10.1042/bj20070188
Complete structured claim and evidence
OAT transfers the ornithine delta-amino group to 2-oxoglutarate, producing glutamate-5-semialdehyde and glutamate.
L-Ornithine → L-Glutamate-5-semialdehyde source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human OAT structure and described catalytic reaction.
limitations
Reversible pathway; net flux depends on tissue and substrate conditions.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
Ornithine also feeds a pathway connected to proline metabolism.
primary_references
Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 118–124
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human OAT structure and described catalytic reaction. · source_derived_draft · unverified_draft
## arg-oat-reaction Ornithine also feeds a pathway connected to proline metabolism. OAT transfers the ornithine delta-amino group to 2-oxoglutarate, producing glutamate-5-semialdehyde and glutamate. Model: Recombinant human OAT structure and described catalytic reaction. Limitations: Reversible pathway; net flux depends on tissue and substrate conditions. Evidence access: Primary abstract Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Glutamate-5-semialdehyde spontaneously cyclizes to P5C.
L-Glutamate-5-semialdehyde → Delta-1-pyrroline-5-carboxylate / P5C source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Reaction chemistry described in the human OAT study.
limitations
This step alone does not demonstrate arginine supplementation improves collagen deposition.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
A separate chemical step links the reaction products.
primary_references
Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 126–132
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Reaction chemistry described in the human OAT study. · source_derived_draft · unverified_draft
## arg-p5c A separate chemical step links the reaction products. Glutamate-5-semialdehyde spontaneously cyclizes to P5C. Model: Reaction chemistry described in the human OAT study. Limitations: This step alone does not demonstrate arginine supplementation improves collagen deposition. Evidence access: Primary abstract Crystal structure of human recombinant ornithine aminotransferase. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9514741/ · DOI 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM.
Putrescine → Spermidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human enzyme structural, biochemical and mutagenesis experiments.
limitations
This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch.
primary_references
Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 134–140
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structural, biochemical and mutagenesis experiments. · source_derived_draft · unverified_draft
## arg-srm Polyamine synthesis combines an ornithine-derived branch with a SAM-derived branch. Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM. Model: Human enzyme structural, biochemical and mutagenesis experiments. Limitations: This consumes an aminopropyl donor, not a direct methyl transfer from ordinary SAM. Evidence access: Primary abstract Structure and mechanism of spermidine synthases. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17585781/ · DOI 10.1021/bi602498k
Complete structured claim and evidence
Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site.
Putrescine → Human S-adenosylmethionine decarboxylase / AMD1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human AMD1 structures, binding measurements and targeted mutants.
limitations
Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
A pathway product helps activate production of the next branch’s donor.
primary_references
Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 142–148
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human AMD1 structures, binding measurements and targeted mutants. · source_derived_draft · unverified_draft
## arg-amd-feedback A pathway product helps activate production of the next branch’s donor. Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site. Model: Human AMD1 structures, binding measurements and targeted mutants. Limitations: Feedback demonstrated at enzyme level; not a measured systemic methyl-donor drain. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
Complete structured claim and evidence
AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis.
S-Adenosyl-L-methionine → Decarboxylated S-adenosylmethionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human S-adenosylmethionine decarboxylase biochemical study.
limitations
Do not confuse aminopropyl donation with GAMT methyl transfer.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
SAM must be chemically changed before this branch uses it.
primary_references
Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 150–156
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human S-adenosylmethionine decarboxylase biochemical study. · source_derived_draft · unverified_draft
## arg-amd-reaction SAM must be chemically changed before this branch uses it. AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis. Model: Human S-adenosylmethionine decarboxylase biochemical study. Limitations: Do not confuse aminopropyl donation with GAMT methyl transfer. Evidence access: Primary abstract Structural basis for putrescine activation of human S-adenosylmethionine decarboxylase. · 2008 · https://pubmed.ncbi.nlm.nih.gov/19053272/ · DOI 10.1021/bi801732m
Complete structured claim and evidence
Human spermine-synthase substrate/product structures and mutagenesis support aminopropyl transfer to spermidine.
Spermidine → Spermine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human SMS structures and catalytic assays.
limitations
A pathway connection does not mean arginine is always rate limiting.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
The polyamine pathway extends beyond spermidine.
primary_references
Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 158–164
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human SMS structures and catalytic assays. · source_derived_draft · unverified_draft
## arg-sms The polyamine pathway extends beyond spermidine. Human spermine-synthase substrate/product structures and mutagenesis support aminopropyl transfer to spermidine. Model: Human SMS structures and catalytic assays. Limitations: A pathway connection does not mean arginine is always rate limiting. Evidence access: Primary abstract Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200
Complete structured claim and evidence
The product-bound SMS structure supplied a mechanistic explanation for inhibition by methylthioadenosine.
5′-Methylthioadenosine → Human spermine synthase / SMS source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human SMS structural and biochemical study.
limitations
Product inhibition is not a measured dietary-arginine effect.
nutrient_topic
L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine
plain_language
A reaction product can slow its own production pathway.
primary_references
Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 166–172
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human SMS structural and biochemical study. · source_derived_draft · unverified_draft
## arg-sms-inhibition A reaction product can slow its own production pathway. The product-bound SMS structure supplied a mechanistic explanation for inhibition by methylthioadenosine. Model: Human SMS structural and biochemical study. Limitations: Product inhibition is not a measured dietary-arginine effect. Evidence access: Primary abstract Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18367445/ · DOI 10.1074/jbc.m710323200
Complete structured claim and evidence
Arginine bound CASTOR1 with an approximate dissociation constant of 30 micromolar.
L-Arginine → Human cellular arginine sensor CASTOR1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine binding disrupted the CASTOR1–GATOR2 complex; arginine-binding capacity was needed for pathway activation.
L-Arginine → Human CASTOR1–GATOR2 complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
CASTOR1 was required for arginine deprivation to inhibit mTORC1.
Human cellular arginine sensor CASTOR1 → Mechanistic target of rapamycin complex 1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine binds between two ACT domains, controlling the neighboring GATOR2-binding site.
L-Arginine → Human cellular arginine sensor CASTOR1 source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 198–204
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
Complete structured claim and evidence
SLC38A9 mediated arginine-regulated export of essential amino acids, including leucine, from lysosomes.
Human lysosomal amino acid transporter SLC38A9 → Leucine export from lysosomes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Leucine generated by lysosomal proteolysis required SLC38A9 for export and subsequent mTORC1 activation.
Human lysosomal amino acid transporter SLC38A9 → mTORC1 activation from lysosomally degraded protein source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Tracer carbon appeared in putrescine and proline; arginase inhibition reduced these labeled products.
L-Arginine → Putrescine source_derived_draftungraded
Experimental context and source evidence
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
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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
Complete structured claim and evidence
Arginine-derived tracer also appeared in agmatine, without suppression by the arginase inhibitor.
L-Arginine → Agmatine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Higher arginine shifted activated T cells toward oxidative phosphorylation.
L-Arginine → Oxidative metabolic program in activated T cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Knockout reduced the arginine-associated survival benefit.
Human BAZ1B transcriptional regulator → Activated T-cell survival after IL-2 withdrawal source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Knockout reduced the arginine-associated survival benefit.
Human PSIP1 transcriptional coactivator → Activated T-cell survival after IL-2 withdrawal source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Knockout reduced the arginine-associated survival benefit.
Human translin / TSN → Activated T-cell survival after IL-2 withdrawal source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine removal shortened CD247 mRNA half-life without reducing its transcription rate.
Experimental arginine-depleted culture medium → Human CD247 messenger RNA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine removal lowered CD3-zeta and proliferation; replacing arginine reversed the changes.
Experimental arginine-depleted culture medium → Human T-cell receptor CD3-zeta chain / CD247 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Activated human T cells failed to restore CD3-zeta in arginine-free medium; replenishment restored expression.
Experimental arginine-depleted culture medium → Human T-cell receptor CD3-zeta chain / CD247 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
IFN-gamma, IL-5 and IL-10 output decreased, whereas IL-2 did not show the same decrease.
Experimental arginine-depleted culture medium → Activated T-cell cytokine output source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine generated an inward current carried by the amino acid; CAT2A-mediated electrogenic uptake was the proposed route.
L-Arginine → Arginine-carried inward current in mouse beta cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The calcium response required depolarization and extracellular calcium.
L-Arginine → Mouse beta-cell intracellular calcium response source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Results supported insulin stimulation through electrogenic transport; arginine did not directly enhance the measured exocytotic machinery.
L-Arginine → Insulin secretion from mouse beta cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Arginine infusion increased GH, and its combination with GHRH produced a larger response than either stimulus alone.
L-Arginine → Human growth hormone source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The authors inferred suppression of endogenous somatostatin from human stimulation tests and absent direct effects in rat pituitary cultures.
L-Arginine → Somatostatin source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 334–340
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
Complete structured claim and evidence
Estimated oral bioavailability was 68 ± 9% after 6 g in eight healthy men.
L-Arginine → Absolute oral arginine bioavailability source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
A 10 g oral dose had approximately 20% absolute bioavailability in the crossover study.
L-Arginine → Absolute oral arginine bioavailability source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 350–356
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
Complete structured claim and evidence
Rapid early disappearance after intravenous dosing included concentration-dependent renal clearance; renal elimination was not observed after the 10 g oral dose.
L-Arginine → Renal clearance of arginine source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 358–364
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
Complete structured claim and evidence
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.
L-Arginine → Systemic vascular resistance source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
VINTAGE MI found no significant improvement in ejection fraction or vascular stiffness over six months.
L-Arginine → Left-ventricular ejection fraction after myocardial infarction source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Six arginine-group participants died versus none receiving placebo; enrollment stopped for safety concerns.
L-Arginine → Mortality in the post-MI arginine trial source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Plasma arginine rose, but NO-related measurements were reduced or unimproved versus placebo.
L-Arginine → NO availability markers in peripheral arterial disease source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Walking distance improved less with arginine than placebo in the six-month PAD trial.
L-Arginine → Treadmill claudication distance in peripheral arterial disease source_derived_draftungraded
Experimental context and source evidence
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
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 398–404
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
Complete structured claim and evidence
Adding pegargiminase to chemotherapy increased median survival from 7.7 to 9.3 months; death hazard ratio 0.71.
Pegargiminase / ADI-PEG20 → Overall survival in nonepithelioid pleural mesothelioma source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Grade 3–4 adverse events were reported in 28.8% with pegargiminase versus 16.9% with placebo.
Pegargiminase / ADI-PEG20 → Grade 3–4 adverse events in the ATOMIC-Meso trial source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The mixture increased implant hydroxyproline, a collagen-accumulation measure, without increasing total protein deposition.
Arginine–HMB–glutamine trial mixture → Collagen deposition in subcutaneous PTFE implants source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
One week of combined lysine and arginine reduced trait and stress-induced state anxiety in a randomized trial of 108 healthy Japanese adults.
L-Lysine → Trait and stress-induced state anxiety source_derived_draftungraded
Experimental context and source evidence
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
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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
Complete structured claim and evidence
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.
L-Lysine → Neuroendocrine stress response source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
L-Lysine → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In the same crossover study, lysine plus arginine significantly increased urinary calcium compared with the low-protein control diet.
L-Lysine → Urinary calcium excretion source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human ARG1 structures show a binuclear manganese site binding a boronate transition-state analogue, supporting metal stabilization of the arginine-hydrolysis transition state.
Mn2+ → Human arginase 1 / ARG1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified recombinant human ARG2 catalyzes arginine hydrolysis to ornithine and urea.
Human arginase 2 / ARG2 → L-Arginine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The active truncated human ARG2 structure with a transition-state analogue supports a binuclear-manganese, metal-activated hydroxide mechanism for arginine hydrolysis.
Mn2+ → Human arginase 2 / ARG2 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Boron-deprived rats with marginal methionine had lower bone magnesium; interactions with magnesium deprivation were strongest under severe restriction and abundant arginine.
Boron → Bone magnesium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/boron-research/2484371.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13", "start_char": 0, "end_char": 2179, "text_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13"}
experimental_model
Nine factorial dietary experiments in rats
exposure
Six to ten weeks; boron supplement 0 or 3 µg/g; magnesium 100/200 versus 400 µg/g; methionine and arginine contexts varied
limitations
Dependence on severe magnesium restriction and amino-acid background is central. Rat growth/bone findings do not establish an essential human role, a methylation mechanism or a human rescue regimen.
nutrient_topic
Boron research collection; topical membership is not evidence of a direct dietary effect. · Boron
organism
Sprague-Dawley rats and one spontaneously hypertensive rat experiment
plain_language
The effect of low boron depended strongly on the rest of the diet.
primary_references
[boron-p2484371] Magnesium and methionine deprivation affect the response of rats to boron deprivation. (1988). https://pubmed.ncbi.nlm.nih.gov/2484371/ DOI: 10.1007/bf02795449
tissue_or_cell_type
Whole-animal growth and bone mineral endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17) · lines 794–805
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine factorial dietary experiments in rats · source_derived_draft · unverified_draft
### boron-rat-mg-amino-acid-context Boron-deprived rats with marginal methionine had lower bone magnesium; interactions with magnesium deprivation were strongest under severe restriction and abundant arginine. Condition category: nutrient_deficiency nutrient_topic: Boron research collection; topical membership is not evidence of a direct dietary effect. plain_language: The effect of low boron depended strongly on the rest of the diet. organism: Sprague-Dawley rats and one spontaneously hypertensive rat experiment tissue_or_cell_type: Whole-animal growth and bone mineral endpoints experimental_model: Nine factorial dietary experiments in rats limitations: Dependence on severe magnesium restriction and amino-acid background is central. Rat growth/bone findings do not establish an essential human role, a methylation mechanism or a human rescue regimen. exposure: Six to ten weeks; boron supplement 0 or 3 µg/g; magnesium 100/200 versus 400 µg/g; methionine and arginine contexts varied evidence_span: {"source_cache": "artifacts/boron-research/2484371.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13", "start_char": 0, "end_char": 2179, "text_sha256": "324fa75871a385d9890c32c6d4ddd62af6fff561174e439afb94f3bd4662ed13"} [boron-p2484371] Magnesium and methionine deprivation affect the response of rats to boron deprivation. (1988). https://pubmed.ncbi.nlm.nih.gov/2484371/ DOI: 10.1007/bf02795449
Complete structured claim and evidence
AGAT catalyzes transfer of an amidino group from arginine to glycine, forming guanidinoacetate and ornithine.
Human glycine amidinotransferase AGAT / GATM → Guanidinoacetate source_derived_draftungraded
Experimental context and source evidence
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"}
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
Complete structured claim and evidence
Isolated rat hepatocytes synthesized creatine from guanidinoacetate but could not carry out the entire pathway from methionine, arginine and glycine under the tested conditions.
Guanidinoacetate → Hepatic synthesis of creatine from guanidinoacetate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"}
experimental_model
Rat feeding, isolated hepatocytes and in-vivo hepatic balance
exposure
Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments
limitations
Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Rats
plain_language
In this preparation, the liver needed the precursor supplied by the earlier synthesis step.
primary_references
[creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008
tissue_or_cell_type
Kidney, liver, plasma and isolated hepatocytes
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 269–280
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat feeding, isolated hepatocytes and in-vivo hepatic balance · source_derived_draft · unverified_draft
### creatine-hepatocyte-gaa-conversion Isolated rat hepatocytes synthesized creatine from guanidinoacetate but could not carry out the entire pathway from methionine, arginine and glycine under the tested conditions. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this preparation, the liver needed the precursor supplied by the earlier synthesis step. organism: Rats tissue_or_cell_type: Kidney, liver, plasma and isolated hepatocytes experimental_model: Rat feeding, isolated hepatocytes and in-vivo hepatic balance limitations: Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally. exposure: Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments evidence_span: {"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"} [creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008
Complete structured claim and evidence
AGAT expression increased homoarginine in cells, and homoarginine was absent in AGAT-deficient mice.
Human glycine amidinotransferase AGAT / GATM → Homoarginine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/creatine-research/24004504.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a", "start_char": 0, "end_char": 1911, "text_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a"}
experimental_model
Human genetic/observational analyses, cell expression and mouse gene deletion
exposure
GATM variation, AGAT expression, AGAT or GAMT deletion and homoarginine rescue
limitations
Human stroke associations are not supplementation causation. AGAT deletion disrupts more than creatine synthesis.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Humans, cultured cells and mice
plain_language
The first creatine-synthesis enzyme also helps make another metabolite, homoarginine.
primary_references
[creatine-p24004504] Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. (2013). https://pubmed.ncbi.nlm.nih.gov/24004504/ DOI: 10.1161/circulationaha.112.000580
tissue_or_cell_type
Plasma, expressing cells and experimental stroke models
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 815–826
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human genetic/observational analyses, cell expression and mouse gene deletion · source_derived_draft · unverified_draft
### creatine-agat-homoarginine AGAT expression increased homoarginine in cells, and homoarginine was absent in AGAT-deficient mice. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The first creatine-synthesis enzyme also helps make another metabolite, homoarginine. organism: Humans, cultured cells and mice tissue_or_cell_type: Plasma, expressing cells and experimental stroke models experimental_model: Human genetic/observational analyses, cell expression and mouse gene deletion limitations: Human stroke associations are not supplementation causation. AGAT deletion disrupts more than creatine synthesis. exposure: GATM variation, AGAT expression, AGAT or GAMT deletion and homoarginine rescue evidence_span: {"source_cache": "artifacts/creatine-research/24004504.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a", "start_char": 0, "end_char": 1911, "text_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a"} [creatine-p24004504] Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. (2013). https://pubmed.ncbi.nlm.nih.gov/24004504/ DOI: 10.1161/circulationaha.112.000580
Complete structured claim and evidence
Homoarginine supplementation rescued the aggravated stroke phenotype in AGAT-deficient mice in this study.
Homoarginine → Cerebral damage and neurological deficits after experimental ischemic stroke in mice source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/creatine-research/24004504.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a", "start_char": 0, "end_char": 1911, "text_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a"}
experimental_model
Human genetic/observational analyses, cell expression and mouse gene deletion
exposure
GATM variation, AGAT expression, AGAT or GAMT deletion and homoarginine rescue
limitations
Mouse stroke experiment; homoarginine rescue shows that AGAT deletion has a non-creatine consequence, not that homoarginine treats human stroke.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Humans, cultured cells and mice
plain_language
An AGAT-knockout effect cannot automatically be blamed entirely on creatine loss.
primary_references
[creatine-p24004504] Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. (2013). https://pubmed.ncbi.nlm.nih.gov/24004504/ DOI: 10.1161/circulationaha.112.000580
tissue_or_cell_type
Plasma, expressing cells and experimental stroke models
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 828–839
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human genetic/observational analyses, cell expression and mouse gene deletion · source_derived_draft · unverified_draft
### creatine-agat-knockout-confounding Homoarginine supplementation rescued the aggravated stroke phenotype in AGAT-deficient mice in this study. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An AGAT-knockout effect cannot automatically be blamed entirely on creatine loss. organism: Humans, cultured cells and mice tissue_or_cell_type: Plasma, expressing cells and experimental stroke models experimental_model: Human genetic/observational analyses, cell expression and mouse gene deletion limitations: Mouse stroke experiment; homoarginine rescue shows that AGAT deletion has a non-creatine consequence, not that homoarginine treats human stroke. exposure: GATM variation, AGAT expression, AGAT or GAMT deletion and homoarginine rescue evidence_span: {"source_cache": "artifacts/creatine-research/24004504.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a", "start_char": 0, "end_char": 1911, "text_sha256": "301113d570a67df12332ca3574aa0714c6dc3c62297e72c2dd7863b146187d6a"} [creatine-p24004504] Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. (2013). https://pubmed.ncbi.nlm.nih.gov/24004504/ DOI: 10.1161/circulationaha.112.000580
Complete structured claim and evidence
The AGAT-deficient sisters had low urinary guanidinoacetate, absent AGAT activity and brain creatine depletion.
Human glycine amidinotransferase AGAT / GATM → Brain total creatine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/creatine-research/11555793.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "89ef028281e917c6af5ac6975c05f6ff421852645e695550b737ca4eff6d78f3", "start_char": 0, "end_char": 1044, "text_sha256": "89ef028281e917c6af5ac6975c05f6ff421852645e695550b737ca4eff6d78f3"}
experimental_model
Biochemical and genetic investigation with oral replacement observations
exposure
Inherited AGAT deficiency and oral creatine substitution
limitations
Rare synthesis disorder; treatment response is not equivalent to a diagnosis of dietary creatine deficiency.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Two human sisters
plain_language
A broken first synthesis step can leave both precursor and brain creatine low.
primary_references
[creatine-p11555793] Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11555793/ DOI: 10.1086/323765
tissue_or_cell_type
Urine, brain magnetic-resonance spectroscopy and AGAT assays
trigger_kind
machinery_impairment Imported condition classification; unverified.
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 841–852
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical and genetic investigation with oral replacement observations · source_derived_draft · unverified_draft
### creatine-agat-brain-deficiency The AGAT-deficient sisters had low urinary guanidinoacetate, absent AGAT activity and brain creatine depletion. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A broken first synthesis step can leave both precursor and brain creatine low. organism: Two human sisters tissue_or_cell_type: Urine, brain magnetic-resonance spectroscopy and AGAT assays experimental_model: Biochemical and genetic investigation with oral replacement observations limitations: Rare synthesis disorder; treatment response is not equivalent to a diagnosis of dietary creatine deficiency. exposure: Inherited AGAT deficiency and oral creatine substitution evidence_span: {"source_cache": "artifacts/creatine-research/11555793.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "89ef028281e917c6af5ac6975c05f6ff421852645e695550b737ca4eff6d78f3", "start_char": 0, "end_char": 1044, "text_sha256": "89ef028281e917c6af5ac6975c05f6ff421852645e695550b737ca4eff6d78f3"} [creatine-p11555793] Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. (2001). https://pubmed.ncbi.nlm.nih.gov/11555793/ DOI: 10.1086/323765
Complete structured claim and evidence
Adding 50 mg arginine did not significantly improve the stress marker compared with 200 mg theanine alone.
L-Theanine plus L-arginine, study-specific combination → Salivary alpha-amylase stress response source_derived_draftungraded
Experimental context and source evidence
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
A numerical difference between active groups did not establish an added benefit.
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 926–937
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-arginine-no-added-benefit Adding 50 mg arginine did not significantly improve the stress marker compared with 200 mg theanine alone. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A numerical difference between active groups did not establish an added benefit. 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
Complete structured claim and evidence
Human ASS1 combines citrulline and aspartate to form argininosuccinate in an ATP-dependent reaction.
Human argininosuccinate synthetase 1 / ASS1 → L-Argininosuccinate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"}
experimental_model
Crystal structure and biochemical reaction characterization
exposure
Citrulline and aspartate bound to recombinant enzyme
limitations
Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human ASS1
plain_language
Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine.
primary_references
[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
tissue_or_cell_type
Cytosolic arginine-regeneration reaction
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 125–136
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft
### citrulline-ass1-reaction Human ASS1 combines citrulline and aspartate to form argininosuccinate in an ATP-dependent reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline needs a second amino acid and an enzyme-controlled step before it becomes arginine. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
Complete structured claim and evidence
Mg-ATP almost completely protected human ASS1 against alpha-dicarbonyl inactivation, implicating arginine residues in its binding site.
Magnesium-ATP complex → Human ASS1 magnesium-ATP binding source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/2788888.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676", "start_char": 0, "end_char": 1043, "text_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676"}
experimental_model
Chemical modification and substrate protection of enzyme
exposure
Alpha-dicarbonyl modification with Mg-ATP protection
limitations
Protection assay identifies binding requirements; it is not a magnesium supplementation or depletion study.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human ASS1
plain_language
The active energy substrate is linked to magnesium, but more magnesium is not automatically rate-limiting.
primary_references
[citrulline-p2788888] Identification of essential arginine residue(s) for Mg-ATP binding of human argininosuccinate synthetase. (1989). https://pubmed.ncbi.nlm.nih.gov/2788888/
tissue_or_cell_type
ATP-binding region
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 164–175
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chemical modification and substrate protection of enzyme · source_derived_draft · unverified_draft
### citrulline-ass1-mg-atp Mg-ATP almost completely protected human ASS1 against alpha-dicarbonyl inactivation, implicating arginine residues in its binding site. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The active energy substrate is linked to magnesium, but more magnesium is not automatically rate-limiting. organism: Human ASS1 tissue_or_cell_type: ATP-binding region experimental_model: Chemical modification and substrate protection of enzyme limitations: Protection assay identifies binding requirements; it is not a magnesium supplementation or depletion study. exposure: Alpha-dicarbonyl modification with Mg-ATP protection evidence_span: {"source_cache": "artifacts/citrulline-research/2788888.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676", "start_char": 0, "end_char": 1043, "text_sha256": "29b1553359d37a53c529b8a2b53ba646cca6b4b401ba7a9722e0e1f15510e676"} [citrulline-p2788888] Identification of essential arginine residue(s) for Mg-ATP binding of human argininosuccinate synthetase. (1989). https://pubmed.ncbi.nlm.nih.gov/2788888/
Complete structured claim and evidence
Human ASL catalyzes reversible cleavage of argininosuccinate to arginine and fumarate.
Human argininosuccinate lyase / ASL → L-Arginine source_derived_draftungraded
Experimental context and source evidence
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
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
Complete structured claim and evidence
Fumarate is the other product of the ASL-catalyzed argininosuccinate cleavage reaction.
Human argininosuccinate lyase / ASL → Fumarate source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Recombinant human NAGS catalyzed N-acetylglutamate formation from glutamate and acetyl-CoA.
Human N-acetylglutamate synthase / NAGS → N-Acetyl-L-glutamate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"}
experimental_model
Purified recombinant NAGS kinetics
exposure
Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs
limitations
Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human and mouse enzymes; human findings specified
plain_language
The activator for CPS1 has its own synthesis step.
primary_references
[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003
tissue_or_cell_type
N-acetylglutamate formation
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 255–266
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft
### citrulline-nags-product Recombinant human NAGS catalyzed N-acetylglutamate formation from glutamate and acetyl-CoA. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The activator for CPS1 has its own synthesis step. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003
Complete structured claim and evidence
Arginine approximately doubled the activity of both tested human NAGS constructs.
L-Arginine → Human NAGS catalytic activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"}
experimental_model
Purified recombinant NAGS kinetics
exposure
Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs
limitations
Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human and mouse enzymes; human findings specified
plain_language
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
Complete structured claim and evidence
The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.
Human ALDH18A1 / P5CS R84Q variant → Circulating citrulline concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The kidneys accounted for 75% of whole-body arginine production from citrulline in the isotope study.
L-Citrulline → Renal arginine synthesis from citrulline source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The calcium ionophore A23187 increased arginine-to-citrulline conversion in cells expressing human endothelial NOS.
Calcium ion → Human eNOS catalytic activity source_derived_draftungraded
Experimental context and source evidence
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
Calcium signaling can activate this enzyme; this experiment did not test taking calcium tablets.
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 476–487
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-calcium-nos The calcium ionophore A23187 increased arginine-to-citrulline conversion in cells expressing human endothelial NOS. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium signaling can activate this enzyme; this experiment did not test taking calcium tablets. 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
Complete structured claim and evidence
Purified human eNOS converted arginine in an assay measuring citrulline formation, with an arginine Km of 3.9 micromolar.
Human endothelial nitric oxide synthase / eNOS / NOS3 → L-Citrulline source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
BH4 plus arginine shifted human eNOS toward dimers during low-temperature electrophoresis.
Tetrahydrobiopterin / BH4 → Human eNOS dimer stability source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
ASL loss impaired use of extracellular arginine for NO production as well as reducing endogenous arginine synthesis.
ASL-deficient state, human or mouse model specified → Utilization of extracellular arginine for nitric oxide production source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Mechanistic experiments identified a structural ASL role in assembly of a multiprotein complex required for NO production.
Human argininosuccinate lyase / ASL → ASL-supported nitric-oxide synthesis complex assembly source_derived_draftungraded
Experimental context and source evidence
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
This enzyme helps organize the machinery as well as catalyze a reaction.
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
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 645–656
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-scaffold Mechanistic experiments identified a structural ASL role in assembly of a multiprotein complex required for NO production. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme helps organize the machinery as well as catalyze a reaction. 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
Complete structured claim and evidence
ASS1 knockdown reduced basal and stimulated NO despite saturating arginine in the culture medium.
Bovine endothelial ASS1 knockdown → NOS-dependent nitric oxide production, model specified source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Ascorbate increased arginine-to-citrulline conversion and NO-related output in porcine endothelial cells.
L-Ascorbate → NOS-dependent nitric oxide production, model specified source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/10749876.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed", "start_char": 0, "end_char": 1519, "text_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed"}
experimental_model
Cell exposure and recombinant-enzyme assays
exposure
Ascorbate loading; BH4 or sepiapterin comparisons
limitations
Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Porcine aortic endothelial cells and bovine eNOS
plain_language
Protecting the machinery can matter as well as supplying arginine.
primary_references
[citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200
tissue_or_cell_type
BH4 availability and NO bioactivity
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 710–721
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell exposure and recombinant-enzyme assays · source_derived_draft · unverified_draft
### citrulline-vitaminc-no Ascorbate increased arginine-to-citrulline conversion and NO-related output in porcine endothelial cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protecting the machinery can matter as well as supplying arginine. organism: Porcine aortic endothelial cells and bovine eNOS tissue_or_cell_type: BH4 availability and NO bioactivity experimental_model: Cell exposure and recombinant-enzyme assays limitations: Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline. exposure: Ascorbate loading; BH4 or sepiapterin comparisons evidence_span: {"source_cache": "artifacts/citrulline-research/10749876.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed", "start_char": 0, "end_char": 1519, "text_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed"} [citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200
Complete structured claim and evidence
Oral citrulline raised plasma urea-cycle intermediates more than oral arginine or ornithine in the LPI report.
L-Citrulline → Circulating ornithine concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Oral citrulline increased plasma arginine AUC and peak concentration dose-dependently, more effectively than the tested oral arginine regimens.
L-Citrulline → Circulating arginine concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
At 3 g twice daily, the arginine/ADMA ratio rose from 186 to 278.
L-Citrulline → Plasma arginine-to-ADMA ratio source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
At the largest doses, plasma citrulline accumulated while arginine rose less than expected.
L-Citrulline → Circulating citrulline concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/17953788.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b57ecb5b3484e857904f38ae7c5d5eea51177e2e0a9a9c15ba5f81c2200a11bd", "start_char": 0, "end_char": 1603, "text_sha256": "b57ecb5b3484e857904f38ae7c5d5eea51177e2e0a9a9c15ba5f81c2200a11bd"}
experimental_model
Randomized-order oral dose-loading study
exposure
Separate 2, 5, 10 and 15 g citrulline loads
limitations
Small acute tolerance study; saturation was an interpretation, not directly localized or measured renal enzyme saturation.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, eight healthy fasting men
plain_language
More precursor did not yield a proportional arginine increase.
primary_references
[citrulline-p17953788] Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. (2008). https://pubmed.ncbi.nlm.nih.gov/17953788/ DOI: 10.1017/s0007114507841110
tissue_or_cell_type
Plasma amino acids and 24-hour urine
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 931–942
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized-order oral dose-loading study · source_derived_draft · unverified_draft
### citrulline-dose-disproportion At the largest doses, plasma citrulline accumulated while arginine rose less than expected. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: More precursor did not yield a proportional arginine increase. organism: Human, eight healthy fasting men tissue_or_cell_type: Plasma amino acids and 24-hour urine experimental_model: Randomized-order oral dose-loading study limitations: Small acute tolerance study; saturation was an interpretation, not directly localized or measured renal enzyme saturation. exposure: Separate 2, 5, 10 and 15 g citrulline loads evidence_span: {"source_cache": "artifacts/citrulline-research/17953788.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b57ecb5b3484e857904f38ae7c5d5eea51177e2e0a9a9c15ba5f81c2200a11bd", "start_char": 0, "end_char": 1603, "text_sha256": "b57ecb5b3484e857904f38ae7c5d5eea51177e2e0a9a9c15ba5f81c2200a11bd"} [citrulline-p17953788] Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. (2008). https://pubmed.ncbi.nlm.nih.gov/17953788/ DOI: 10.1017/s0007114507841110
Complete structured claim and evidence
Despite reduced renal function, whole-body de novo arginine synthesis appeared preserved in the ESRD patients.
L-Citrulline → Whole-body de novo arginine synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/10791996.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "80c58ac3892fcee1c04da2c05c0005b4b40e6c3479127a3da3528e46162c7f49", "start_char": 0, "end_char": 1285, "text_sha256": "80c58ac3892fcee1c04da2c05c0005b4b40e6c3479127a3da3528e46162c7f49"}
experimental_model
Stable-isotope kinetic study around hemodialysis
exposure
Two pre- and two postdialysis tracer studies
limitations
Whole-body flux does not locate the compensating tissues; elevated plasma concentration is not evidence of adequate function in every compartment.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, six end-stage renal disease patients
plain_language
Loss of kidney function did not abolish all arginine synthesis in this small study.
primary_references
[citrulline-p10791996] Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. (2000). https://pubmed.ncbi.nlm.nih.gov/10791996/ DOI: 10.1172/jci7199
tissue_or_cell_type
Whole-body arginine and NO metabolism
trigger_kind
biomarker_context Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1009–1020
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope kinetic study around hemodialysis · source_derived_draft · unverified_draft
### citrulline-renal-arginine-preserved Despite reduced renal function, whole-body de novo arginine synthesis appeared preserved in the ESRD patients. Condition category: biomarker_context nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of kidney function did not abolish all arginine synthesis in this small study. organism: Human, six end-stage renal disease patients tissue_or_cell_type: Whole-body arginine and NO metabolism experimental_model: Stable-isotope kinetic study around hemodialysis limitations: Whole-body flux does not locate the compensating tissues; elevated plasma concentration is not evidence of adequate function in every compartment. exposure: Two pre- and two postdialysis tracer studies evidence_span: {"source_cache": "artifacts/citrulline-research/10791996.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "80c58ac3892fcee1c04da2c05c0005b4b40e6c3479127a3da3528e46162c7f49", "start_char": 0, "end_char": 1285, "text_sha256": "80c58ac3892fcee1c04da2c05c0005b4b40e6c3479127a3da3528e46162c7f49"} [citrulline-p10791996] Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. (2000). https://pubmed.ncbi.nlm.nih.gov/10791996/ DOI: 10.1172/jci7199
Complete structured claim and evidence
Despite higher arginine, blood flow and muscle microvascular perfusion did not differ between treatments.
L-Citrulline → Skeletal-muscle microvascular perfusion source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/24824653.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3c9cb88e6978c602b77415910ae94823f258788387d0623bfe89af339fed5ebb", "start_char": 0, "end_char": 1815, "text_sha256": "3c9cb88e6978c602b77415910ae94823f258788387d0623bfe89af339fed5ebb"}
experimental_model
Postexercise feeding and tracer study
exposure
15 g whey plus 10 g citrulline or nonessential amino acids; comparator 45 g whey
limitations
Different population, protein background and protein fraction from the low-protein pilot; no automatic claim of contradiction.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 21 men aged 65-80
plain_language
Higher blood arginine was not enough to improve measured muscle perfusion.
primary_references
[citrulline-p24824653] Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise. (2014). https://pubmed.ncbi.nlm.nih.gov/24824653/ DOI: 10.1152/ajpendo.00096.2014
tissue_or_cell_type
Rested and exercised skeletal muscle
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1074–1085
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Postexercise feeding and tracer study · source_derived_draft · unverified_draft
### citrulline-older-perfusion-null Despite higher arginine, blood flow and muscle microvascular perfusion did not differ between treatments. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Higher blood arginine was not enough to improve measured muscle perfusion. organism: Human, 21 men aged 65-80 tissue_or_cell_type: Rested and exercised skeletal muscle experimental_model: Postexercise feeding and tracer study limitations: Different population, protein background and protein fraction from the low-protein pilot; no automatic claim of contradiction. exposure: 15 g whey plus 10 g citrulline or nonessential amino acids; comparator 45 g whey evidence_span: {"source_cache": "artifacts/citrulline-research/24824653.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3c9cb88e6978c602b77415910ae94823f258788387d0623bfe89af339fed5ebb", "start_char": 0, "end_char": 1815, "text_sha256": "3c9cb88e6978c602b77415910ae94823f258788387d0623bfe89af339fed5ebb"} [citrulline-p24824653] Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise. (2014). https://pubmed.ncbi.nlm.nih.gov/24824653/ DOI: 10.1152/ajpendo.00096.2014
Complete structured claim and evidence
Citrulline supplementation increased plasma citrulline seventeenfold and arginine threefold in the SBS trial.
L-Citrulline → Circulating arginine concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/30642738.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0d8869660890cdf77bcc2056b8871bc7be2b4828791a4681c87657a8efe42737", "start_char": 0, "end_char": 2343, "text_sha256": "0d8869660890cdf77bcc2056b8871bc7be2b4828791a4681c87657a8efe42737"}
experimental_model
Double-blind crossover isotope study
exposure
0.18 g/kg/day citrulline for seven days versus isonitrogenous placebo
limitations
Near-normal nutritional status long after surgery; exploratory low-baseline subgroups were too small for a treatment rule.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, nine adults with stable nonmalignant short-bowel syndrome
plain_language
The oral precursor reached blood and increased downstream arginine.
primary_references
[citrulline-p30642738] Effect of oral citrulline supplementation on whole body protein metabolism in adult patients with short bowel syndrome: A pilot, randomized, double-blind, cross-over study. (2019). https://pubmed.ncbi.nlm.nih.gov/30642738/ DOI: 10.1016/j.clnu.2018.12.030
tissue_or_cell_type
Whole-body protein metabolism
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1087–1098
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind crossover isotope study · source_derived_draft · unverified_draft
### citrulline-sbs-exposure Citrulline supplementation increased plasma citrulline seventeenfold and arginine threefold in the SBS trial. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The oral precursor reached blood and increased downstream arginine. organism: Human, nine adults with stable nonmalignant short-bowel syndrome tissue_or_cell_type: Whole-body protein metabolism experimental_model: Double-blind crossover isotope study limitations: Near-normal nutritional status long after surgery; exploratory low-baseline subgroups were too small for a treatment rule. exposure: 0.18 g/kg/day citrulline for seven days versus isonitrogenous placebo evidence_span: {"source_cache": "artifacts/citrulline-research/30642738.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0d8869660890cdf77bcc2056b8871bc7be2b4828791a4681c87657a8efe42737", "start_char": 0, "end_char": 2343, "text_sha256": "0d8869660890cdf77bcc2056b8871bc7be2b4828791a4681c87657a8efe42737"} [citrulline-p30642738] Effect of oral citrulline supplementation on whole body protein metabolism in adult patients with short bowel syndrome: A pilot, randomized, double-blind, cross-over study. (2019). https://pubmed.ncbi.nlm.nih.gov/30642738/ DOI: 10.1016/j.clnu.2018.12.030
Complete structured claim and evidence
Human CAT1 transports L-lysine across the plasma membrane.
CAT1 / SLC7A1 → L-Lysine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human CAT1 expressed in Xenopus oocytes
limitations
Transporter expression assay; the relative contribution varies by tissue.
organism
Homo sapiens
plain_language
CAT1 moves free lysine across cell membranes.
primary_references
[furesz2002] Lysine uptake by cloned hCAT-2B: comparison with hCAT-1 and with trophoblast surface membranes. (2002). https://pubmed.ncbi.nlm.nih.gov/12202949/ DOI: 10.1007/s00232-002-1001-0
tissue_or_cell_type
Plasma membrane; compared with placental trophoblast membranes
transport_effect
depends The record names the membrane lysine crosses and not which way it crosses it.
transport_pool
the cytosol across the plasma membrane The record names the membrane lysine crosses and not which way it crosses it.
L-Lysine: mechanism-first literature curation (2026-09-17) · lines 14–22
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CAT1 expressed in Xenopus oocytes · source_derived_draft · unverified_draft
### cat1-lysine-transport Human CAT1 transports L-lysine across the plasma membrane. Plain language: CAT1 moves free lysine across cell membranes. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Plasma membrane; compared with placental trophoblast membranes experimental_model: Human CAT1 expressed in Xenopus oocytes limitations: Transporter expression assay; the relative contribution varies by tissue. [furesz2002] Lysine uptake by cloned hCAT-2B: comparison with hCAT-1 and with trophoblast surface membranes. (2002). https://pubmed.ncbi.nlm.nih.gov/12202949/ DOI: 10.1007/s00232-002-1001-0
Complete structured claim and evidence
Pathogenic SLC7A7 variants impair epithelial dibasic-amino-acid transport in lysinuric protein intolerance.
y+LAT1 / SLC7A7 → Basolateral lysine export source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine.
DHPS → eIF5A1 with unmodified Lys50 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human DHPS structural biochemistry.
limitations
NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.
organism
Human
plain_language
A particular protein lysine becomes a specialized translation-factor residue.
primary_references
[dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/
tissue_or_cell_type
Not specified as a whole tissue; see experimental model.
L-Lysine: mechanism-first literature curation (2026-09-17) · lines 578–586
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DHPS structural biochemistry. · source_derived_draft · unverified_draft
### dhps-eif5a-deoxyhypusine DHPS transfers spermidine-derived aminobutyl onto eIF5A Lys50 to form deoxyhypusine. Plain language: A particular protein lysine becomes a specialized translation-factor residue. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human DHPS structural biochemistry. limitations: NAD cycles during catalysis; it is not represented as a net consumed substrate here. This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [dhps-2020] Half Way to Hypusine-Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase (2020). https://pubmed.ncbi.nlm.nih.gov/32235505/
Complete structured claim and evidence
GAMT transfers a methyl group from S-adenosylmethionine to guanidinoacetate, producing creatine and S-adenosylhomocysteine.
Rat guanidinoacetate methyltransferase / Gamt → Guanidinoacetate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/creatine-research/12079381.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6", "start_char": 0, "end_char": 1161, "text_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6"}
experimental_model
SAH-bound crystal structure and mutagenesis
exposure
SAH-bound structure at 2.5 angstrom resolution
limitations
The crystallized construct lacks 36 N-terminal residues; its dimer arrangement is not assigned universally to native human GAMT.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Rat GAMT
plain_language
The second synthesis step spends one SAM methyl group to finish each creatine molecule.
primary_references
[creatine-p12079381] Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12079381/ DOI: 10.1016/s0022-2836(02)00448-5 [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095
tissue_or_cell_type
Purified, N-terminally truncated enzyme
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 203–215
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SAH-bound crystal structure and mutagenesis · source_derived_draft · unverified_draft
### creatine-gamt-methyl-transfer GAMT transfers a methyl group from S-adenosylmethionine to guanidinoacetate, producing creatine and S-adenosylhomocysteine. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The second synthesis step spends one SAM methyl group to finish each creatine molecule. organism: Rat GAMT tissue_or_cell_type: Purified, N-terminally truncated enzyme experimental_model: SAH-bound crystal structure and mutagenesis limitations: The crystallized construct lacks 36 N-terminal residues; its dimer arrangement is not assigned universally to native human GAMT. exposure: SAH-bound structure at 2.5 angstrom resolution evidence_span: {"source_cache": "artifacts/creatine-research/12079381.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6", "start_char": 0, "end_char": 1161, "text_sha256": "4f63981cbaa4b7614a24f0a637893d05f9eff2c2143991404b0a7af1ea6667c6"} [creatine-p12079381] Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12079381/ DOI: 10.1016/s0022-2836(02)00448-5 [creatine-p11595668] Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. (2001). https://pubmed.ncbi.nlm.nih.gov/11595668/ DOI: 10.1152/ajpendo.2001.281.5.e1095
Complete structured claim and evidence
Creatine feeding reduced renal AGAT and circulating guanidinoacetate without reducing hepatic GAMT activity or capacity to synthesize creatine from guanidinoacetate.
Creatine → Rat guanidinoacetate methyltransferase / Gamt source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"}
experimental_model
Rat feeding, isolated hepatocytes and in-vivo hepatic balance
exposure
Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments
limitations
Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Rats
plain_language
Feedback mainly limited precursor supply in this rat experiment; it did not switch off every synthesis step.
primary_references
[creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008
tissue_or_cell_type
Kidney, liver, plasma and isolated hepatocytes
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 295–306
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat feeding, isolated hepatocytes and in-vivo hepatic balance · source_derived_draft · unverified_draft
### creatine-feedback-spares-gamt-capacity Creatine feeding reduced renal AGAT and circulating guanidinoacetate without reducing hepatic GAMT activity or capacity to synthesize creatine from guanidinoacetate. Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Feedback mainly limited precursor supply in this rat experiment; it did not switch off every synthesis step. organism: Rats tissue_or_cell_type: Kidney, liver, plasma and isolated hepatocytes experimental_model: Rat feeding, isolated hepatocytes and in-vivo hepatic balance limitations: Interorgan division of synthesis is established here in rats; this is not proof that human tissues never synthesize both steps locally. exposure: Creatine-fed versus creatine-free conditions; guanidinoacetate and methionine substrate experiments evidence_span: {"source_cache": "artifacts/creatine-research/19017728.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee", "start_char": 0, "end_char": 1599, "text_sha256": "8394bd0e01991356b47a2e57593a5054e565b4020d50226b1331dbb290fc0cee"} [creatine-p19017728] Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. (2009). https://pubmed.ncbi.nlm.nih.gov/19017728/ DOI: 10.1152/ajpendo.90547.2008
Complete structured claim and evidence
The GAMT-deficient children had high brain guanidinoacetate, low blood creatine and severely deficient liver GAMT activity.
Human guanidinoacetate methyltransferase / GAMT → Brain guanidinoacetate accumulation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/creatine-research/8651275.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d6999ce02dd6012eefd5981a91374d6c933af0924d5e82b1447fd322e8f211de", "start_char": 0, "end_char": 706, "text_sha256": "d6999ce02dd6012eefd5981a91374d6c933af0924d5e82b1447fd322e8f211de"}
experimental_model
Biochemical diagnosis and treatment observations
exposure
GAMT deficiency with oral creatine substitution
limitations
Small case series; biochemical and neurological responses are not a universal prognosis.
nutrient_topic
Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine
organism
Two human children
plain_language
The blocked final step left precursor behind while reducing the finished product.
primary_references
[creatine-p8651275] Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. (1996). https://pubmed.ncbi.nlm.nih.gov/8651275/
tissue_or_cell_type
Brain spectroscopy, blood and liver enzyme assay
trigger_kind
machinery_impairment Imported condition classification; unverified.
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 867–878
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical diagnosis and treatment observations · source_derived_draft · unverified_draft
### creatine-gamt-gaa-accumulation The GAMT-deficient children had high brain guanidinoacetate, low blood creatine and severely deficient liver GAMT activity. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The blocked final step left precursor behind while reducing the finished product. organism: Two human children tissue_or_cell_type: Brain spectroscopy, blood and liver enzyme assay experimental_model: Biochemical diagnosis and treatment observations limitations: Small case series; biochemical and neurological responses are not a universal prognosis. exposure: GAMT deficiency with oral creatine substitution evidence_span: {"source_cache": "artifacts/creatine-research/8651275.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d6999ce02dd6012eefd5981a91374d6c933af0924d5e82b1447fd322e8f211de", "start_char": 0, "end_char": 706, "text_sha256": "d6999ce02dd6012eefd5981a91374d6c933af0924d5e82b1447fd322e8f211de"} [creatine-p8651275] Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. (1996). https://pubmed.ncbi.nlm.nih.gov/8651275/
Complete structured claim and evidence
Human OTC converts ornithine and carbamoyl phosphate into citrulline, releasing inorganic phosphate.
Human ornithine transcarbamylase / OTC → L-Citrulline source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/38940639.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5eca9d57812cf3d8efe7c0beb62b9b364cc25e1aeca647c95e4abf0fd9eb8365", "start_char": 194, "end_char": 364, "text_sha256": "c5ddbcd5c91cfcdc72d6e556c77228f8ecd6c25ebaa3c25fd9617f6baa145692"}
experimental_model
Recombinant enzyme site-directed mutagenesis and kinetic assays
exposure
Ornithine and carbamoyl phosphate; active-site and remote variants
limitations
Recombinant mutation experiments; do not equate altered enzyme function with a dietary shortage.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human OTC
plain_language
Citrulline is built from ornithine and a nitrogen-containing carbamoyl group.
primary_references
[citrulline-p38940639] Revisiting the Roles of Catalytic Residues in Human Ornithine Transcarbamylase. (2024). https://pubmed.ncbi.nlm.nih.gov/38940639/ DOI: 10.1021/acs.biochem.4c00206
tissue_or_cell_type
Mitochondrial urea-cycle enzyme
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 203–214
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme site-directed mutagenesis and kinetic assays · source_derived_draft · unverified_draft
### citrulline-otc-citrulline Human OTC converts ornithine and carbamoyl phosphate into citrulline, releasing inorganic phosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline is built from ornithine and a nitrogen-containing carbamoyl group. organism: Human OTC tissue_or_cell_type: Mitochondrial urea-cycle enzyme experimental_model: Recombinant enzyme site-directed mutagenesis and kinetic assays limitations: Recombinant mutation experiments; do not equate altered enzyme function with a dietary shortage. exposure: Ornithine and carbamoyl phosphate; active-site and remote variants evidence_span: {"source_cache": "artifacts/citrulline-research/38940639.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5eca9d57812cf3d8efe7c0beb62b9b364cc25e1aeca647c95e4abf0fd9eb8365", "start_char": 194, "end_char": 364, "text_sha256": "c5ddbcd5c91cfcdc72d6e556c77228f8ecd6c25ebaa3c25fd9617f6baa145692"} [citrulline-p38940639] Revisiting the Roles of Catalytic Residues in Human Ornithine Transcarbamylase. (2024). https://pubmed.ncbi.nlm.nih.gov/38940639/ DOI: 10.1021/acs.biochem.4c00206
Complete structured claim and evidence
Mutation of human OTC D263 substantially reduced catalysis without reducing protein stability.
Human OTC D263A variant → Human OTC catalytic activity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/38940639.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "82d823cdd140b9a12d55151b3b343206f37fa7f042b5cbdc7dc0c3a8f98fd9b9", "start_char": 0, "end_char": 1695, "text_sha256": "82d823cdd140b9a12d55151b3b343206f37fa7f042b5cbdc7dc0c3a8f98fd9b9"}
experimental_model
Recombinant enzyme site-directed mutagenesis and kinetic assays
exposure
Ornithine and carbamoyl phosphate; active-site and remote variants
limitations
Recombinant mutation experiments; do not equate altered enzyme function with a dietary shortage.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human OTC
plain_language
An enzyme can be present yet work poorly.
primary_references
[citrulline-p38940639] Revisiting the Roles of Catalytic Residues in Human Ornithine Transcarbamylase. (2024). https://pubmed.ncbi.nlm.nih.gov/38940639/ DOI: 10.1021/acs.biochem.4c00206
tissue_or_cell_type
Mitochondrial urea-cycle enzyme
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 216–227
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme site-directed mutagenesis and kinetic assays · source_derived_draft · unverified_draft
### citrulline-otc-d263 Mutation of human OTC D263 substantially reduced catalysis without reducing protein stability. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme can be present yet work poorly. organism: Human OTC tissue_or_cell_type: Mitochondrial urea-cycle enzyme experimental_model: Recombinant enzyme site-directed mutagenesis and kinetic assays limitations: Recombinant mutation experiments; do not equate altered enzyme function with a dietary shortage. exposure: Ornithine and carbamoyl phosphate; active-site and remote variants evidence_span: {"source_cache": "artifacts/citrulline-research/38940639.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "82d823cdd140b9a12d55151b3b343206f37fa7f042b5cbdc7dc0c3a8f98fd9b9", "start_char": 0, "end_char": 1695, "text_sha256": "82d823cdd140b9a12d55151b3b343206f37fa7f042b5cbdc7dc0c3a8f98fd9b9"} [citrulline-p38940639] Revisiting the Roles of Catalytic Residues in Human Ornithine Transcarbamylase. (2024). https://pubmed.ncbi.nlm.nih.gov/38940639/ DOI: 10.1021/acs.biochem.4c00206
Complete structured claim and evidence
N-acetylglutamate binding reshaped human CPS1 and established the channel linking its two phosphorylation sites.
N-Acetyl-L-glutamate → Human carbamoyl-phosphate synthetase 1 / CPS1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/26592762.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "55b398f0f6c85b023e3eee96e6841df398d328bc8201dfb5207147aa871be581", "start_char": 0, "end_char": 1079, "text_sha256": "55b398f0f6c85b023e3eee96e6841df398d328bc8201dfb5207147aa871be581"}
experimental_model
Human recombinant enzyme crystallography and mutation analysis
exposure
Structures without NAG and with NAG plus nucleotides
limitations
Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human CPS1
plain_language
An activator switches the upstream nitrogen-handling enzyme into a functional shape.
primary_references
[citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950
tissue_or_cell_type
Mitochondrial carbamoyl-phosphate synthesis
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 229–240
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant enzyme crystallography and mutation analysis · source_derived_draft · unverified_draft
### citrulline-cps1-nag N-acetylglutamate binding reshaped human CPS1 and established the channel linking its two phosphorylation sites. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: An activator switches the upstream nitrogen-handling enzyme into a functional shape. organism: Human CPS1 tissue_or_cell_type: Mitochondrial carbamoyl-phosphate synthesis experimental_model: Human recombinant enzyme crystallography and mutation analysis limitations: Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested. exposure: Structures without NAG and with NAG plus nucleotides evidence_span: {"source_cache": "artifacts/citrulline-research/26592762.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "55b398f0f6c85b023e3eee96e6841df398d328bc8201dfb5207147aa871be581", "start_char": 0, "end_char": 1079, "text_sha256": "55b398f0f6c85b023e3eee96e6841df398d328bc8201dfb5207147aa871be581"} [citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950
Complete structured claim and evidence
CPS1 uses two ATP-dependent phosphorylation steps to convert bicarbonate and ammonia into carbamoyl phosphate.
Human carbamoyl-phosphate synthetase 1 / CPS1 → Carbamoyl phosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/26592762.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9807338d87ba1b5602512aa3765c7cc48d391595cc1f35e6a43bcbe1250d3c7d", "start_char": 1169, "end_char": 1477, "text_sha256": "c5e2a8e1d3e3a09064b7b233635f7d573f8761b3f6ae18a68bc9b102a2d5874c"}
experimental_model
Human recombinant enzyme crystallography and mutation analysis
exposure
Structures without NAG and with NAG plus nucleotides
limitations
Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human CPS1
plain_language
The upstream part of citrulline synthesis consumes energy to handle ammonia.
primary_references
[citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950
tissue_or_cell_type
Mitochondrial carbamoyl-phosphate synthesis
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 242–253
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant enzyme crystallography and mutation analysis · source_derived_draft · unverified_draft
### citrulline-cps1-product CPS1 uses two ATP-dependent phosphorylation steps to convert bicarbonate and ammonia into carbamoyl phosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The upstream part of citrulline synthesis consumes energy to handle ammonia. organism: Human CPS1 tissue_or_cell_type: Mitochondrial carbamoyl-phosphate synthesis experimental_model: Human recombinant enzyme crystallography and mutation analysis limitations: Mechanism of enzyme activation; clinical effects of adding nutritional cofactors were not tested. exposure: Structures without NAG and with NAG plus nucleotides evidence_span: {"source_cache": "artifacts/citrulline-research/26592762.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9807338d87ba1b5602512aa3765c7cc48d391595cc1f35e6a43bcbe1250d3c7d", "start_char": 1169, "end_char": 1477, "text_sha256": "c5e2a8e1d3e3a09064b7b233635f7d573f8761b3f6ae18a68bc9b102a2d5874c"} [citrulline-p26592762] Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. (2015). https://pubmed.ncbi.nlm.nih.gov/26592762/ DOI: 10.1038/srep16950
Complete structured claim and evidence
Human OAT bound pyridoxal phosphate through a Schiff base to Lys292.
PLP → Human ornithine aminotransferase / OAT source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"}
experimental_model
Recombinant enzyme crystal structure
exposure
PLP-bound enzyme structure
limitations
The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human OAT
plain_language
Vitamin B6 has a defined role in the machinery handling ornithine.
primary_references
[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
tissue_or_cell_type
Mitochondrial ornithine transamination
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 333–344
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft
### citrulline-oat-plp Human OAT bound pyridoxal phosphate through a Schiff base to Lys292. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin B6 has a defined role in the machinery handling ornithine. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Purified human eNOS showed an absolute BH4 requirement for the measured catalytic reaction.
Tetrahydrobiopterin / BH4 → Human eNOS catalytic activity source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The purified human eNOS preparation contained approximately 0.56 FAD equivalents per subunit.
FAD → Human endothelial nitric oxide synthase / eNOS / NOS3 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human eNOS preparation contained approximately 0.79 FMN equivalents per subunit.
Flavin mononucleotide → Human endothelial nitric oxide synthase / eNOS / NOS3 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Heme and protein-bound iron were detected in purified human eNOS by independent analytical methods.
Heme → Human endothelial nitric oxide synthase / eNOS / NOS3 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Metal analysis detected approximately 0.43 zinc equivalents per human eNOS subunit.
Zinc(II) ion → Human endothelial nitric oxide synthase / eNOS / NOS3 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Cells expressing human endothelial NOS produced bioactive NO that increased guanylate cyclase activity in cocultured reporter cells.
Human endothelial nitric oxide synthase / eNOS / NOS3 → NO source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Low arginine signals through CASTOR1

Condition: nutrient_deficiency · Experimental arginine deprivation.

Normal role: Available arginine and intact sensing/regulatory machinery support the measured cellular response.

Recorded consequence: CASTOR1 was required for arginine deprivation to inhibit mTORC1.

Scope: Experimental cellular availability or machinery perturbation.

Arginine depletion reduces Jurkat CD3-zeta

Condition: nutrient_deficiency · Arginine removed from Jurkat culture medium.

Normal role: Available arginine and intact sensing/regulatory machinery support the measured cellular response.

Recorded consequence: Arginine removal shortened CD247 mRNA half-life without reducing its transcription rate.; Arginine removal lowered CD3-zeta and proliferation; replacing arginine reversed the changes.

Scope: Experimental cellular availability or machinery perturbation.

Low availability disrupts activated primary T-cell responses

Condition: nutrient_deficiency · Arginine-free activated T-cell culture.

Normal role: Available arginine and intact sensing/regulatory machinery support the measured cellular response.

Recorded consequence: Activated human T cells failed to restore CD3-zeta in arginine-free medium; replenishment restored expression.; IFN-gamma, IL-5 and IL-10 output decreased, whereas IL-2 did not show the same decrease.

Scope: Experimental cellular availability or machinery perturbation.

Regulator loss attenuates an arginine survival response

Condition: machinery_impairment · Individual CRISPR knockouts of BAZ1B, PSIP1 or TSN.

Normal role: Available arginine and intact sensing/regulatory machinery support the measured cellular response.

Recorded consequence: Knockout reduced the arginine-associated survival benefit.; Knockout reduced the arginine-associated survival benefit.; Knockout reduced the arginine-associated survival benefit.

Scope: Experimental cellular availability or machinery perturbation.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Boron: chemistry, nutrient interactions, low-intake studies and mechanistic uncertainties (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18)AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
L-Lysine: mechanism-first literature curation (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Lysine-related interventions do not uniformly lower stress-hormone responsesThe trials differ in sex, diet, stressor, baseline anxiety, and arginine cointervention. Increased and decreased evoked hormones are not directly contradictory observations; neither supports a universal cortisol-lowering claim.Read the recorded disagreement
Urinary calcium changes differ across intervention contextsAn acute calcium load with lysine differs from several days of lysine-plus-arginine on a low-protein diet. Urinary calcium alone does not settle net calcium balance or bone health.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

L-Arginine

The mechanisms

CAT1 expression supported measurable uptake of arginine in the transporter assay.

ADMA produced a competitive inhibition pattern for CAT1-mediated arginine uptake.

Homoarginine produced a competitive inhibition pattern for CAT1-mediated arginine uptake.

Verapamil inhibited CAT1 arginine uptake with IC50 85.3 micromolar and an uncompetitive pattern.

Amino-acid loading experiments indicated inhibition of renal citrulline transport by arginine, lysine and ornithine.

Rat neuronal uptake showed a sodium-independent component consistent with CAT1, with Km 47 ± 8 micromolar.

NOS converted arginine to N-hydroxyarginine in an oxygen- and calcium/calmodulin-dependent partial reaction.

The second oxygenation yielded NO and citrulline and required added NADPH and calcium/calmodulin.

BH4 stimulated both partial reactions; the first increased approximately threefold.

In-vitro and in-vivo experiments identified ADMA as an endogenous inhibitor of NO synthesis.

Biochemical binding and structural experiments identify PLP as the human ODC coenzyme.

ODC catalyzes conversion of ornithine into putrescine.

OAT transfers the ornithine delta-amino group to 2-oxoglutarate, producing glutamate-5-semialdehyde and glutamate.

Glutamate-5-semialdehyde spontaneously cyclizes to P5C.

Human SRM uses putrescine as the amine acceptor for aminopropyl transfer from decarboxylated SAM.

Putrescine stimulated human AMD1 autoprocessing and decarboxylation through a binding pocket separate from the active site.

AMD1 decarboxylation generates the aminopropyl donor used in polyamine synthesis.

Human spermine-synthase substrate/product structures and mutagenesis support aminopropyl transfer to spermidine.

The product-bound SMS structure supplied a mechanistic explanation for inhibition by methylthioadenosine.

Arginine bound CASTOR1 with an approximate dissociation constant of 30 micromolar.

Arginine binding disrupted the CASTOR1–GATOR2 complex; arginine-binding capacity was needed for pathway activation.

CASTOR1 was required for arginine deprivation to inhibit mTORC1.

Arginine binds between two ACT domains, controlling the neighboring GATOR2-binding site.

SLC38A9 mediated arginine-regulated export of essential amino acids, including leucine, from lysosomes.

Leucine generated by lysosomal proteolysis required SLC38A9 for export and subsequent mTORC1 activation.

Tracer carbon appeared in putrescine and proline; arginase inhibition reduced these labeled products.

Arginine-derived tracer also appeared in agmatine, without suppression by the arginase inhibitor.

Higher arginine shifted activated T cells toward oxidative phosphorylation.

Knockout reduced the arginine-associated survival benefit.

Knockout reduced the arginine-associated survival benefit.

Knockout reduced the arginine-associated survival benefit.

Arginine removal shortened CD247 mRNA half-life without reducing its transcription rate.

Arginine removal lowered CD3-zeta and proliferation; replacing arginine reversed the changes.

Activated human T cells failed to restore CD3-zeta in arginine-free medium; replenishment restored expression.

IFN-gamma, IL-5 and IL-10 output decreased, whereas IL-2 did not show the same decrease.

Arginine generated an inward current carried by the amino acid; CAT2A-mediated electrogenic uptake was the proposed route.

The calcium response required depolarization and extracellular calcium.

Results supported insulin stimulation through electrogenic transport; arginine did not directly enhance the measured exocytotic machinery.

Arginine infusion increased GH, and its combination with GHRH produced a larger response than either stimulus alone.

The authors inferred suppression of endogenous somatostatin from human stimulation tests and absent direct effects in rat pituitary cultures.

Estimated oral bioavailability was 68 ± 9% after 6 g in eight healthy men.

A 10 g oral dose had approximately 20% absolute bioavailability in the crossover study.

Rapid early disappearance after intravenous dosing included concentration-dependent renal clearance; renal elimination was not observed after the 10 g oral dose.

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.

VINTAGE MI found no significant improvement in ejection fraction or vascular stiffness over six months.

Six arginine-group participants died versus none receiving placebo; enrollment stopped for safety concerns.

Plasma arginine rose, but NO-related measurements were reduced or unimproved versus placebo.

Walking distance improved less with arginine than placebo in the six-month PAD trial.

Adding pegargiminase to chemotherapy increased median survival from 7.7 to 9.3 months; death hazard ratio 0.71.

Grade 3–4 adverse events were reported in 28.8% with pegargiminase versus 16.9% with placebo.

The mixture increased implant hydroxyproline, a collagen-accumulation measure, without increasing total protein deposition.

One week of combined lysine and arginine reduced trait and stress-induced state anxiety in a randomized trial of 108 healthy Japanese adults.

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.

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.

In the same crossover study, lysine plus arginine significantly increased urinary calcium compared with the low-protein control diet.

Human ARG1 structures show a binuclear manganese site binding a boronate transition-state analogue, supporting metal stabilization of the arginine-hydrolysis transition state.

Purified recombinant human ARG2 catalyzes arginine hydrolysis to ornithine and urea.

The active truncated human ARG2 structure with a transition-state analogue supports a binuclear-manganese, metal-activated hydroxide mechanism for arginine hydrolysis.

Boron-deprived rats with marginal methionine had lower bone magnesium; interactions with magnesium deprivation were strongest under severe restriction and abundant arginine.

AGAT catalyzes transfer of an amidino group from arginine to glycine, forming guanidinoacetate and ornithine.

Isolated rat hepatocytes synthesized creatine from guanidinoacetate but could not carry out the entire pathway from methionine, arginine and glycine under the tested conditions.

AGAT expression increased homoarginine in cells, and homoarginine was absent in AGAT-deficient mice.

Homoarginine supplementation rescued the aggravated stroke phenotype in AGAT-deficient mice in this study.

The AGAT-deficient sisters had low urinary guanidinoacetate, absent AGAT activity and brain creatine depletion.

Adding 50 mg arginine did not significantly improve the stress marker compared with 200 mg theanine alone.

Human ASS1 combines citrulline and aspartate to form argininosuccinate in an ATP-dependent reaction.

Mg-ATP almost completely protected human ASS1 against alpha-dicarbonyl inactivation, implicating arginine residues in its binding site.

Human ASL catalyzes reversible cleavage of argininosuccinate to arginine and fumarate.

Fumarate is the other product of the ASL-catalyzed argininosuccinate cleavage reaction.

Recombinant human NAGS catalyzed N-acetylglutamate formation from glutamate and acetyl-CoA.

Arginine approximately doubled the activity of both tested human NAGS constructs.

The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.

The kidneys accounted for 75% of whole-body arginine production from citrulline in the isotope study.

The calcium ionophore A23187 increased arginine-to-citrulline conversion in cells expressing human endothelial NOS.

Purified human eNOS converted arginine in an assay measuring citrulline formation, with an arginine Km of 3.9 micromolar.

BH4 plus arginine shifted human eNOS toward dimers during low-temperature electrophoresis.

ASL loss impaired use of extracellular arginine for NO production as well as reducing endogenous arginine synthesis.

Mechanistic experiments identified a structural ASL role in assembly of a multiprotein complex required for NO production.