Nutrient chapter

L-Citrulline

L-Citrulline is a non-proteinogenic amino acid made in the body. It participates in nitrogen disposal and supplies arginine through ASS1 and ASL. Low blood citrulline, impaired conversion and dietary intake are distinct; each mechanism retains its experimental scope.

97 recorded mechanisms · 8 availability situations · 8 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.

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
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
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
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
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
Recombinant human soluble guanylate cyclase converted GTP to cGMP and pyrophosphate; both products inhibited enzyme activity in the kinetic assays.
Human soluble guanylate cyclase alpha1-beta1 heterodimer → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/10995472.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244", "start_char": 0, "end_char": 1300, "text_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244"}
experimental_model
Recombinant heterodimer purification and enzyme kinetics
exposure
NO donor and YC-1 activation; GTP, cGMP and pyrophosphate kinetics
limitations
Purified-enzyme study; not a citrulline supplementation trial.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human alpha1-beta1 sGC expressed in insect cells
plain_language
The NO receptor makes a second messenger, cGMP, linking the initial signal to downstream responses.
primary_references
[citrulline-p10995472] Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. (2000). https://pubmed.ncbi.nlm.nih.gov/10995472/ DOI: 10.1073/pnas.190333697
tissue_or_cell_type
GTP conversion, heme and product inhibition
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 489–500
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant heterodimer purification and enzyme kinetics · source_derived_draft · unverified_draft
### citrulline-sgc-cgmp Recombinant human soluble guanylate cyclase converted GTP to cGMP and pyrophosphate; both products inhibited enzyme activity in the kinetic assays. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The NO receptor makes a second messenger, cGMP, linking the initial signal to downstream responses. organism: Human alpha1-beta1 sGC expressed in insect cells tissue_or_cell_type: GTP conversion, heme and product inhibition experimental_model: Recombinant heterodimer purification and enzyme kinetics limitations: Purified-enzyme study; not a citrulline supplementation trial. exposure: NO donor and YC-1 activation; GTP, cGMP and pyrophosphate kinetics evidence_span: {"source_cache": "artifacts/citrulline-research/10995472.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244", "start_char": 0, "end_char": 1300, "text_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244"} [citrulline-p10995472] Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. (2000). https://pubmed.ncbi.nlm.nih.gov/10995472/ DOI: 10.1073/pnas.190333697
Complete structured claim and evidence
Acetyl-CoA is a substrate for human NAGS-mediated N-acetylglutamate synthesis.
Acetyl-CoA → Human N-acetylglutamate synthase / NAGS 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
This creates a connection to the B5-derived coenzyme-A system.
primary_references
[citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003
tissue_or_cell_type
N-acetylglutamate formation
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 268–279
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant NAGS kinetics · source_derived_draft · unverified_draft
### citrulline-nags-acetyl-coa Acetyl-CoA is a substrate for human NAGS-mediated N-acetylglutamate synthesis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This creates a connection to the B5-derived coenzyme-A system. organism: Human and mouse enzymes; human findings specified tissue_or_cell_type: N-acetylglutamate formation experimental_model: Purified recombinant NAGS kinetics limitations: Construct-specific kinetics; no human B5-deficiency or arginine-repletion trial. exposure: Glutamate, acetyl-CoA and arginine; mature and conserved-domain constructs evidence_span: {"source_cache": "artifacts/citrulline-research/16321554.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5", "start_char": 0, "end_char": 1498, "text_sha256": "5ce9d57aba8d7973c01de32ab7d5d0287858119fa75f0a372e3ed99523a861a5"} [citrulline-p16321554] Biochemical properties of recombinant human and mouse N-acetylglutamate synthase. (2006). https://pubmed.ncbi.nlm.nih.gov/16321554/ DOI: 10.1016/j.ymgme.2005.10.003
Complete structured claim and evidence
5-MTHF improved eNOS coupling and increased its dimer-to-monomer ratio and activity in the human vessel study.
5-Methyltetrahydrofolate → Endothelial nitric oxide synthase uncoupling, model specified source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"}
experimental_model
Ex-vivo vessel exposure and randomized pre-harvest infusion
exposure
5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset
limitations
Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, vessels from 117 CABG patients
plain_language
The enzyme used its electron supply more productively under the tested conditions.
primary_references
[citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
tissue_or_cell_type
Saphenous veins and internal mammary arteries
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 749–760
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ex-vivo vessel exposure and randomized pre-harvest infusion · source_derived_draft · unverified_draft
### citrulline-folate-coupling 5-MTHF improved eNOS coupling and increased its dimer-to-monomer ratio and activity in the human vessel study. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme used its electron supply more productively under the tested conditions. organism: Human, vessels from 117 CABG patients tissue_or_cell_type: Saphenous veins and internal mammary arteries experimental_model: Ex-vivo vessel exposure and randomized pre-harvest infusion limitations: Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements. exposure: 5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset evidence_span: {"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"} [citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
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
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
No treatment improved FMD over baseline in the healthy-volunteer study.
L-Citrulline → Brachial flow-mediated dilation 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
Better precursor exposure did not produce a detectable improvement in this vascular endpoint.
primary_references
[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
tissue_or_cell_type
Plasma amino acids, urine NO markers and brachial FMD
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 918–929
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft
### citrulline-healthy-fmd-null No treatment improved FMD over baseline in the healthy-volunteer study. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Better precursor exposure did not produce a detectable improvement in this vascular endpoint. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
Complete structured claim and evidence
Aspartate is a substrate of human ASS1 and was resolved with citrulline in the enzyme structure.
L-Aspartate → Human argininosuccinate synthetase 1 / ASS1 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
Aspartate supplies part of the molecule built at this step.
primary_references
[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
tissue_or_cell_type
Cytosolic arginine-regeneration reaction
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 138–149
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft
### citrulline-ass1-aspartate Aspartate is a substrate of human ASS1 and was resolved with citrulline in the enzyme structure. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Aspartate supplies part of the molecule built at this step. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
Complete structured claim and evidence
The ASS1 reaction uses ATP cleavage to AMP and pyrophosphate.
ATP → Human argininosuccinate synthetase 1 / ASS1 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
Arginine regeneration has an energy cost.
primary_references
[citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
tissue_or_cell_type
Cytosolic arginine-regeneration reaction
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 151–162
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure and biochemical reaction characterization · source_derived_draft · unverified_draft
### citrulline-ass1-energy The ASS1 reaction uses ATP cleavage to AMP and pyrophosphate. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Arginine regeneration has an energy cost. organism: Human ASS1 tissue_or_cell_type: Cytosolic arginine-regeneration reaction experimental_model: Crystal structure and biochemical reaction characterization limitations: Structure and established reaction; no clinical magnesium, aspartate or ATP deficiency threshold is established. exposure: Citrulline and aspartate bound to recombinant enzyme evidence_span: {"source_cache": "artifacts/citrulline-research/18323623.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f", "start_char": 0, "end_char": 840, "text_sha256": "079be80a0ea1a47308efb069d3c9522c96c0aa5923ad1d7ce79ac620b2d9502f"} [citrulline-p18323623] Structure of human argininosuccinate synthetase. (2008). https://pubmed.ncbi.nlm.nih.gov/18323623/ DOI: 10.1107/s0907444907067455
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
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
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
Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry.
Human pyrroline-5-carboxylate synthase / ALDH18A1 → Delta-1-pyrroline-5-carboxylate / P5C source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}
experimental_model
Patient genetics and recombinant variant expression
exposure
ALDH18A1 R84Q compared with wild-type isoforms
limitations
Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, two siblings and mammalian expression systems
plain_language
This supplies a precursor route connected to ornithine and arginine production.
primary_references
[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
tissue_or_cell_type
Mitochondrial P5CS and circulating amino acids
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 294–305
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft
### citrulline-p5cs-reaction Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This supplies a precursor route connected to ornithine and arginine production. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
Complete structured claim and evidence
P5CS requires NADPH for its reductive step in glutamate-to-P5C synthesis.
NADPH → Human pyrroline-5-carboxylate synthase / ALDH18A1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"}
experimental_model
Patient genetics and recombinant variant expression
exposure
ALDH18A1 R84Q compared with wild-type isoforms
limitations
Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, two siblings and mammalian expression systems
plain_language
A niacin-derived electron donor participates upstream of citrulline.
primary_references
[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
tissue_or_cell_type
Mitochondrial P5CS and circulating amino acids
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 307–318
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant variant expression · source_derived_draft · unverified_draft
### citrulline-p5cs-nadph P5CS requires NADPH for its reductive step in glutamate-to-P5C synthesis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A niacin-derived electron donor participates upstream of citrulline. organism: Human, two siblings and mammalian expression systems tissue_or_cell_type: Mitochondrial P5CS and circulating amino acids experimental_model: Patient genetics and recombinant variant expression limitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype. exposure: ALDH18A1 R84Q compared with wild-type isoforms evidence_span: {"source_cache": "artifacts/citrulline-research/11092761.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2", "start_char": 0, "end_char": 1688, "text_sha256": "09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2"} [citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853
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
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
OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C.
Human ornithine aminotransferase / OAT → L-Glutamate-5-semialdehyde 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
This is an ornithine-processing reaction; its direction depends on the biological setting.
primary_references
[citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
tissue_or_cell_type
Mitochondrial ornithine transamination
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 346–357
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme crystal structure · source_derived_draft · unverified_draft
### citrulline-oat-reaction OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is an ornithine-processing reaction; its direction depends on the biological setting. organism: Human OAT tissue_or_cell_type: Mitochondrial ornithine transamination experimental_model: Recombinant enzyme crystal structure limitations: The described reaction direction is ornithine transamination; this structure alone does not quantify reverse flux in human intestine. exposure: PLP-bound enzyme structure evidence_span: {"source_cache": "artifacts/citrulline-research/9514741.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0", "start_char": 0, "end_char": 2979, "text_sha256": "cca17abd35f0211a043dd3cc8883369e230209206ff62b62242197f90201cea0"} [citrulline-p9514741] Crystal structure of human recombinant ornithine aminotransferase. (1998). https://pubmed.ncbi.nlm.nih.gov/9514741/ DOI: 10.1006/jmbi.1997.1583
Complete structured claim and evidence
Reconstituted citrin exchanged aspartate for glutamate plus a proton.
Human citrin / SLC25A13 → Mitochondrial aspartate/glutamate exchange source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}
experimental_model
Reconstituted transporter and transfected-cell assays
exposure
Aspartate exchange for glutamate plus proton; external calcium stimulation
limitations
Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human citrin and aralar proteins
plain_language
Moving aspartate between compartments helps connect nitrogen handling and redox metabolism.
primary_references
[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
tissue_or_cell_type
Inner mitochondrial membrane transport; malate-aspartate shuttle
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 359–370
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft
### citrulline-citrin-aspartate Reconstituted citrin exchanged aspartate for glutamate plus a proton. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Moving aspartate between compartments helps connect nitrogen handling and redox metabolism. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
Complete structured claim and evidence
Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange.
Calcium ion → Human citrin / SLC25A13 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}
experimental_model
Reconstituted transporter and transfected-cell assays
exposure
Aspartate exchange for glutamate plus proton; external calcium stimulation
limitations
Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human citrin and aralar proteins
plain_language
Calcium is a regulatory signal for the transporter.
primary_references
[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
tissue_or_cell_type
Inner mitochondrial membrane transport; malate-aspartate shuttle
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 372–383
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft
### citrulline-citrin-calcium Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium is a regulatory signal for the transporter. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
Complete structured claim and evidence
Citrin overexpression increased malate-aspartate shuttle activity in transfected human cells.
Human citrin / SLC25A13 → Malate-aspartate shuttle activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}
experimental_model
Reconstituted transporter and transfected-cell assays
exposure
Aspartate exchange for glutamate plus proton; external calcium stimulation
limitations
Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human citrin and aralar proteins
plain_language
The same transporter participates in moving reducing equivalents between compartments.
primary_references
[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
tissue_or_cell_type
Inner mitochondrial membrane transport; malate-aspartate shuttle
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 385–396
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft
### citrulline-citrin-shuttle Citrin overexpression increased malate-aspartate shuttle activity in transfected human cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same transporter participates in moving reducing equivalents between compartments. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060
Complete structured claim and evidence
Silencing SLC6A19 reduced citrulline uptake in human HK-2 renal cells.
Human neutral amino acid transporter B0AT1 / SLC6A19 → Apical citrulline uptake in renal proximal tubular cells source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"}
experimental_model
Apical transport kinetics and transporter knockdown
exposure
Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing
limitations
Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human HK-2 cells; rat cultures studied separately
plain_language
A neutral-amino-acid transporter contributes to kidney uptake.
primary_references
[citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
tissue_or_cell_type
Renal proximal tubular epithelium
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 398–409
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Apical transport kinetics and transporter knockdown · source_derived_draft · unverified_draft
### citrulline-renal-b0at1 Silencing SLC6A19 reduced citrulline uptake in human HK-2 renal cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A neutral-amino-acid transporter contributes to kidney uptake. organism: Human HK-2 cells; rat cultures studied separately tissue_or_cell_type: Renal proximal tubular epithelium experimental_model: Apical transport kinetics and transporter knockdown limitations: Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism. exposure: Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing evidence_span: {"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"} [citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
Complete structured claim and evidence
Silencing SLC7A9 also reduced citrulline uptake in HK-2 cells.
b0,+AT / SLC7A9 → Apical citrulline uptake in renal proximal tubular cells source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"}
experimental_model
Apical transport kinetics and transporter knockdown
exposure
Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing
limitations
Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human HK-2 cells; rat cultures studied separately
plain_language
A separate transporter contributes to the measured uptake.
primary_references
[citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
tissue_or_cell_type
Renal proximal tubular epithelium
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 411–422
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Apical transport kinetics and transporter knockdown · source_derived_draft · unverified_draft
### citrulline-renal-b0plus Silencing SLC7A9 also reduced citrulline uptake in HK-2 cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate transporter contributes to the measured uptake. organism: Human HK-2 cells; rat cultures studied separately tissue_or_cell_type: Renal proximal tubular epithelium experimental_model: Apical transport kinetics and transporter knockdown limitations: Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism. exposure: Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing evidence_span: {"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"} [citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
Complete structured claim and evidence
HK-2 citrulline uptake included two sodium-dependent saturable components and one sodium-independent component.
Sodium ion → Apical citrulline uptake in renal proximal tubular cells source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"}
experimental_model
Apical transport kinetics and transporter knockdown
exposure
Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing
limitations
Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human HK-2 cells; rat cultures studied separately
plain_language
Sodium dependence applies to part of the transport system, not every citrulline transporter.
primary_references
[citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
tissue_or_cell_type
Renal proximal tubular epithelium
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 424–435
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Apical transport kinetics and transporter knockdown · source_derived_draft · unverified_draft
### citrulline-renal-sodium HK-2 citrulline uptake included two sodium-dependent saturable components and one sodium-independent component. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Sodium dependence applies to part of the transport system, not every citrulline transporter. organism: Human HK-2 cells; rat cultures studied separately tissue_or_cell_type: Renal proximal tubular epithelium experimental_model: Apical transport kinetics and transporter knockdown limitations: Renal evidence must not be relabeled as a demonstrated human intestinal transport mechanism. exposure: Citrulline uptake on permeable supports; SLC6A19 or SLC7A9 silencing evidence_span: {"source_cache": "artifacts/citrulline-research/19322909.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece", "start_char": 0, "end_char": 1531, "text_sha256": "f466fcced77ee9fe7a97f010112a035332d513382d13e6187d10bc02be152ece"} [citrulline-p19322909] Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. (2009). https://pubmed.ncbi.nlm.nih.gov/19322909/ DOI: 10.1002/bdd.653
Complete structured claim and evidence
In glutamine-supplemented surgical patients, 91% of total citrulline turnover was attributed to glutamine.
L-Glutamine → L-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
Glutamine supplied much of the precursor carbon in this experimental setting.
primary_references
[citrulline-p25332337] Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. (2014). https://pubmed.ncbi.nlm.nih.gov/25332337/ DOI: 10.3945/ajcn.113.081547
tissue_or_cell_type
Intestinal-renal amino-acid axis
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 437–448
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope whole-body and renal balance study · source_derived_draft · unverified_draft
### citrulline-glutamine-source In glutamine-supplemented surgical patients, 91% of total citrulline turnover was attributed to glutamine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutamine supplied much of the precursor carbon in this experimental setting. organism: Human, seven surgical patients tissue_or_cell_type: Intestinal-renal amino-acid axis experimental_model: Stable-isotope whole-body and renal balance study limitations: Small perioperative study; the reported doubling versus previous studies was not a concurrent randomized control comparison. exposure: Perioperative intravenous alanyl-glutamine 0.5 g/kg/day evidence_span: {"source_cache": "artifacts/citrulline-research/25332337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0", "start_char": 0, "end_char": 1788, "text_sha256": "d517656dd9033a9df73e29b10d07fdccbc7c369155450ba662fe006d045cf4d0"} [citrulline-p25332337] Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study. (2014). https://pubmed.ncbi.nlm.nih.gov/25332337/ DOI: 10.3945/ajcn.113.081547
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
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
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
Coexpressing human calmodulin stabilized eNOS and raised its specific activity; later calmodulin addition did not reproduce the gain.
Calmodulin → Human eNOS catalytic activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/8951046.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f5c5176d8e2b671f5311c529c09abe80b8661050e73c156ee2916959aa5030cb", "start_char": 0, "end_char": 1362, "text_sha256": "f5c5176d8e2b671f5311c529c09abe80b8661050e73c156ee2916959aa5030cb"}
experimental_model
Recombinant coexpression and enzyme activity comparison
exposure
Calmodulin coexpression versus adding calmodulin after expression
limitations
Expression-system result; not a test of dietary calcium or calmodulin supplementation.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human NOS3 and human calmodulin expressed in E. coli
plain_language
How the enzyme assembles with its regulatory protein mattered.
primary_references
[citrulline-p8951046] Human endothelial nitric oxide synthase: expression in Escherichia coli, coexpression with calmodulin, and characterization. (1996). https://pubmed.ncbi.nlm.nih.gov/8951046/ DOI: 10.1006/abbi.1996.0543
tissue_or_cell_type
NOS expression and catalytic function
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 593–604
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant coexpression and enzyme activity comparison · source_derived_draft · unverified_draft
### citrulline-calmodulin-nos Coexpressing human calmodulin stabilized eNOS and raised its specific activity; later calmodulin addition did not reproduce the gain. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: How the enzyme assembles with its regulatory protein mattered. organism: Human NOS3 and human calmodulin expressed in E. coli tissue_or_cell_type: NOS expression and catalytic function experimental_model: Recombinant coexpression and enzyme activity comparison limitations: Expression-system result; not a test of dietary calcium or calmodulin supplementation. exposure: Calmodulin coexpression versus adding calmodulin after expression evidence_span: {"source_cache": "artifacts/citrulline-research/8951046.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f5c5176d8e2b671f5311c529c09abe80b8661050e73c156ee2916959aa5030cb", "start_char": 0, "end_char": 1362, "text_sha256": "f5c5176d8e2b671f5311c529c09abe80b8661050e73c156ee2916959aa5030cb"} [citrulline-p8951046] Human endothelial nitric oxide synthase: expression in Escherichia coli, coexpression with calmodulin, and characterization. (1996). https://pubmed.ncbi.nlm.nih.gov/8951046/ DOI: 10.1006/abbi.1996.0543
Complete structured claim and evidence
The NOS2 zinc-tetrathiolate center supported intersubunit contacts and integrity of the BH4-binding site.
Zinc(II) ion → Human iNOS dimer stability source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/10409685.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b", "start_char": 0, "end_char": 942, "text_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b"}
experimental_model
Crystal structures of zinc-free and zinc-bound heme domains
exposure
Zinc-free versus zinc-tetrathiolate-containing structures
limitations
Direct structure is NOS2; similarity to NOS3 does not justify silently treating the proteins as identical.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human NOS2
plain_language
The structural metal and the pterin-binding region are connected.
primary_references
[citrulline-p10409685] Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase. (1999). https://pubmed.ncbi.nlm.nih.gov/10409685/ DOI: 10.1074/jbc.274.30.21276
tissue_or_cell_type
NOS dimer interface and pterin-binding region
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 606–617
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structures of zinc-free and zinc-bound heme domains · source_derived_draft · unverified_draft
### citrulline-inos-zinc-interface The NOS2 zinc-tetrathiolate center supported intersubunit contacts and integrity of the BH4-binding site. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The structural metal and the pterin-binding region are connected. organism: Human NOS2 tissue_or_cell_type: NOS dimer interface and pterin-binding region experimental_model: Crystal structures of zinc-free and zinc-bound heme domains limitations: Direct structure is NOS2; similarity to NOS3 does not justify silently treating the proteins as identical. exposure: Zinc-free versus zinc-tetrathiolate-containing structures evidence_span: {"source_cache": "artifacts/citrulline-research/10409685.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b", "start_char": 0, "end_char": 942, "text_sha256": "c320fb6f3fd659a2e7df4a8ddd3467a902a07b84380075d429040eaf244ccf6b"} [citrulline-p10409685] Crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. Implications for dimer stability and comparison with endothelial nitric-oxide synthase. (1999). https://pubmed.ncbi.nlm.nih.gov/10409685/ DOI: 10.1074/jbc.274.30.21276
Complete structured claim and evidence
ASL deficiency reduced nitric-oxide synthesis in the studied humans and mice.
ASL-deficient state, human or mouse model specified → 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/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"}
experimental_model
Patient vascular testing, hypomorphic mice and molecular experiments
exposure
ASL loss; extracellular arginine; nitrite or NO donor interventions
limitations
Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human ASL deficiency and Asl-deficient mice, model specified
plain_language
An intact downstream enzyme matters to the NO pathway.
primary_references
[citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544
tissue_or_cell_type
Arginine synthesis, NOS-associated protein complex and vasculature
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 619–630
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient vascular testing, hypomorphic mice and molecular experiments · source_derived_draft · unverified_draft
### citrulline-asl-no-low ASL deficiency reduced nitric-oxide synthesis in the studied humans and mice. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intact downstream enzyme matters to the NO pathway. organism: Human ASL deficiency and Asl-deficient mice, model specified tissue_or_cell_type: Arginine synthesis, NOS-associated protein complex and vasculature experimental_model: Patient vascular testing, hypomorphic mice and molecular experiments limitations: Rare genetic deficiency; molecular scaffolding is distinct from supplying enough circulating arginine. exposure: ASL loss; extracellular arginine; nitrite or NO donor interventions evidence_span: {"source_cache": "artifacts/citrulline-research/22081021.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b", "start_char": 0, "end_char": 1137, "text_sha256": "2f9f02564dadd246299fe5eded3ddb08e3c68f08d27cae8b16f2506fe9eaf68b"} [citrulline-p22081021] Requirement of argininosuccinate lyase for systemic nitric oxide production. (2011). https://pubmed.ncbi.nlm.nih.gov/22081021/ DOI: 10.1038/nm.2544
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
ASS1 knockdown increased apoptotic indicators; an NO donor prevented the associated apoptosis.
Bovine endothelial ASS1 knockdown → Bovine aortic endothelial cell viability source_derived_draftungraded
Experimental context and source evidence
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
The impaired signaling was linked to survival in this cell model.
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
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 671–682
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-cell-viability ASS1 knockdown increased apoptotic indicators; an NO donor prevented the associated apoptosis. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The impaired signaling was linked to survival in this cell model. 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
NO binding to the beta1 H-NOX region drove structural changes that increased human soluble guanylate cyclase activity.
NO → Human soluble guanylate cyclase alpha1-beta1 heterodimer source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/31514202.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3001c79d449d8a5545278fdaa6dd7a2dd9e1a67b6e4553d78bbc5848a35362d", "start_char": 0, "end_char": 991, "text_sha256": "e3001c79d449d8a5545278fdaa6dd7a2dd9e1a67b6e4553d78bbc5848a35362d"}
experimental_model
Cryo-EM structures in multiple functional states
exposure
NO-bound and other functional enzyme states
limitations
Structural signal transduction, not a clinical citrulline efficacy experiment.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human soluble guanylate cyclase alpha1-beta1
plain_language
NO is a signal received by another enzyme, rather than the final vascular response.
primary_references
[citrulline-p31514202] Structural insights into the mechanism of human soluble guanylate cyclase. (2019). https://pubmed.ncbi.nlm.nih.gov/31514202/ DOI: 10.1038/s41586-019-1584-6
tissue_or_cell_type
NO sensor, transducer and catalytic modules
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 684–695
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cryo-EM structures in multiple functional states · source_derived_draft · unverified_draft
### citrulline-no-sgc NO binding to the beta1 H-NOX region drove structural changes that increased human soluble guanylate cyclase activity. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: NO is a signal received by another enzyme, rather than the final vascular response. organism: Human soluble guanylate cyclase alpha1-beta1 tissue_or_cell_type: NO sensor, transducer and catalytic modules experimental_model: Cryo-EM structures in multiple functional states limitations: Structural signal transduction, not a clinical citrulline efficacy experiment. exposure: NO-bound and other functional enzyme states evidence_span: {"source_cache": "artifacts/citrulline-research/31514202.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3001c79d449d8a5545278fdaa6dd7a2dd9e1a67b6e4553d78bbc5848a35362d", "start_char": 0, "end_char": 991, "text_sha256": "e3001c79d449d8a5545278fdaa6dd7a2dd9e1a67b6e4553d78bbc5848a35362d"} [citrulline-p31514202] Structural insights into the mechanism of human soluble guanylate cyclase. (2019). https://pubmed.ncbi.nlm.nih.gov/31514202/ DOI: 10.1038/s41586-019-1584-6
Complete structured claim and evidence
Ascorbate increased intracellular BH4 in porcine aortic endothelial cells.
L-Ascorbate → Endothelial tetrahydrobiopterin concentration, species 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
Vitamin C can affect cofactor availability in this cell model.
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 697–708
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-bh4 Ascorbate increased intracellular BH4 in porcine aortic endothelial cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C can affect cofactor availability in this cell model. 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
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
Ascorbate had no additional effect at high BH4 or after sepiapterin raised cellular BH4.
Tetrahydrobiopterin / BH4 → 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
The benefit depended on the starting cofactor conditions.
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 723–734
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-bh4-saturation Ascorbate had no additional effect at high BH4 or after sepiapterin raised cellular BH4. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The benefit depended on the starting cofactor conditions. 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
5-MTHF increased vascular BH4 and its proportion of total biopterin in human vessel experiments.
5-Methyltetrahydrofolate → Endothelial tetrahydrobiopterin concentration, species specified source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"}
experimental_model
Ex-vivo vessel exposure and randomized pre-harvest infusion
exposure
5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset
limitations
Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, vessels from 117 CABG patients
plain_language
A folate form affected availability of the NO-synthase cofactor.
primary_references
[citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
tissue_or_cell_type
Saphenous veins and internal mammary arteries
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 736–747
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ex-vivo vessel exposure and randomized pre-harvest infusion · source_derived_draft · unverified_draft
### citrulline-folate-bh4 5-MTHF increased vascular BH4 and its proportion of total biopterin in human vessel experiments. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A folate form affected availability of the NO-synthase cofactor. organism: Human, vessels from 117 CABG patients tissue_or_cell_type: Saphenous veins and internal mammary arteries experimental_model: Ex-vivo vessel exposure and randomized pre-harvest infusion limitations: Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements. exposure: 5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset evidence_span: {"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"} [citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
Complete structured claim and evidence
5-MTHF reduced vascular superoxide; the effect was not explained by direct superoxide scavenging or changed plasma homocysteine.
5-Methyltetrahydrofolate → Vascular superoxide production, model specified source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"}
experimental_model
Ex-vivo vessel exposure and randomized pre-harvest infusion
exposure
5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset
limitations
Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, vessels from 117 CABG patients
plain_language
The experiment distinguished this effect from simply lowering homocysteine.
primary_references
[citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
tissue_or_cell_type
Saphenous veins and internal mammary arteries
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 762–773
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ex-vivo vessel exposure and randomized pre-harvest infusion · source_derived_draft · unverified_draft
### citrulline-folate-superoxide 5-MTHF reduced vascular superoxide; the effect was not explained by direct superoxide scavenging or changed plasma homocysteine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The experiment distinguished this effect from simply lowering homocysteine. organism: Human, vessels from 117 CABG patients tissue_or_cell_type: Saphenous veins and internal mammary arteries experimental_model: Ex-vivo vessel exposure and randomized pre-harvest infusion limitations: Uses 5-MTHF and acute vessel endpoints; cannot be generalized to all folic-acid doses or combination supplements. exposure: 5-MTHF ex vivo 1-100 micromolar; intravenous 5-MTHF or placebo in a separate subset evidence_span: {"source_cache": "artifacts/citrulline-research/16940192.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b", "start_char": 0, "end_char": 1942, "text_sha256": "42c07dd0bbacfc1ff44f78d6ce69810a58946e53c76bf5d3bf8385db5278ba8b"} [citrulline-p16940192] 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. (2006). https://pubmed.ncbi.nlm.nih.gov/16940192/ DOI: 10.1161/circulationaha.106.612325
Complete structured claim and evidence
DHFR knockdown decreased intracellular BH4 and increased BH2 in the cell systems.
Mouse endothelial Dhfr knockdown → Endothelial BH4-to-BH2 ratio, 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/19666465.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af", "start_char": 0, "end_char": 1716, "text_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af"}
experimental_model
DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments
exposure
Methotrexate or RNA interference; comparison with GTPCH knockdown
limitations
Mouse models; DHFR also handles folate, but this study does not make folate and BH4 interchangeable.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Mouse endothelial and NIH-3T3-based experimental cell systems
plain_language
Recycling quality matters, not just the total amount of pterin.
primary_references
[citrulline-p19666465] Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. (2009). https://pubmed.ncbi.nlm.nih.gov/19666465/ DOI: 10.1074/jbc.m109.041483
tissue_or_cell_type
BH4/BH2 balance and NOS coupling
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 775–786
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments · source_derived_draft · unverified_draft
### citrulline-dhfr-ratio DHFR knockdown decreased intracellular BH4 and increased BH2 in the cell systems. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Recycling quality matters, not just the total amount of pterin. organism: Mouse endothelial and NIH-3T3-based experimental cell systems tissue_or_cell_type: BH4/BH2 balance and NOS coupling experimental_model: DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments limitations: Mouse models; DHFR also handles folate, but this study does not make folate and BH4 interchangeable. exposure: Methotrexate or RNA interference; comparison with GTPCH knockdown evidence_span: {"source_cache": "artifacts/citrulline-research/19666465.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af", "start_char": 0, "end_char": 1716, "text_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af"} [citrulline-p19666465] Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. (2009). https://pubmed.ncbi.nlm.nih.gov/19666465/ DOI: 10.1074/jbc.m109.041483
Complete structured claim and evidence
DHFR loss increased eNOS-dependent superoxide while reducing NO production.
Mouse endothelial Dhfr knockdown → Endothelial nitric oxide synthase uncoupling, 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/19666465.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af", "start_char": 0, "end_char": 1716, "text_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af"}
experimental_model
DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments
exposure
Methotrexate or RNA interference; comparison with GTPCH knockdown
limitations
Mouse models; DHFR also handles folate, but this study does not make folate and BH4 interchangeable.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Mouse endothelial and NIH-3T3-based experimental cell systems
plain_language
A damaged cofactor balance can change the enzyme output.
primary_references
[citrulline-p19666465] Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. (2009). https://pubmed.ncbi.nlm.nih.gov/19666465/ DOI: 10.1074/jbc.m109.041483
tissue_or_cell_type
BH4/BH2 balance and NOS coupling
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 788–799
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments · source_derived_draft · unverified_draft
### citrulline-dhfr-uncoupling DHFR loss increased eNOS-dependent superoxide while reducing NO production. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A damaged cofactor balance can change the enzyme output. organism: Mouse endothelial and NIH-3T3-based experimental cell systems tissue_or_cell_type: BH4/BH2 balance and NOS coupling experimental_model: DHFR knockdown/inhibition and controlled GTPCH-expression cell experiments limitations: Mouse models; DHFR also handles folate, but this study does not make folate and BH4 interchangeable. exposure: Methotrexate or RNA interference; comparison with GTPCH knockdown evidence_span: {"source_cache": "artifacts/citrulline-research/19666465.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af", "start_char": 0, "end_char": 1716, "text_sha256": "b1ef76ebbd312932011edd1b0f9f428026a4e4cdd53301bd66f99eaf543e77af"} [citrulline-p19666465] Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. (2009). https://pubmed.ncbi.nlm.nih.gov/19666465/ DOI: 10.1074/jbc.m109.041483
Complete structured claim and evidence
BH4 oxidation accompanied eNOS uncoupling with increased ROS and reduced NO in hypertensive mouse aortas.
7,8-Dihydrobiopterin / BH2 → Endothelial nitric oxide synthase uncoupling, model specified source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/12697739.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d56604695c8c1bda167b76198a472d814d284a3c0c1e1e1eed8943cce31d0ad0", "start_char": 0, "end_char": 1474, "text_sha256": "d56604695c8c1bda167b76198a472d814d284a3c0c1e1e1eed8943cce31d0ad0"}
experimental_model
Hypertension and knockout mouse experiments
exposure
NADPH-oxidase/NOS genetic comparisons and BH4 treatment
limitations
Disease model; the exact response cannot be assumed in people taking citrulline.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Mouse DOCA-salt hypertension model
plain_language
Adding precursor is different from fixing a damaged cofactor system.
primary_references
[citrulline-p12697739] Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12697739/ DOI: 10.1172/jci14172
tissue_or_cell_type
Aortic redox state and NO signaling
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 801–812
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Hypertension and knockout mouse experiments · source_derived_draft · unverified_draft
### citrulline-bh4-oxidation BH4 oxidation accompanied eNOS uncoupling with increased ROS and reduced NO in hypertensive mouse aortas. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding precursor is different from fixing a damaged cofactor system. organism: Mouse DOCA-salt hypertension model tissue_or_cell_type: Aortic redox state and NO signaling experimental_model: Hypertension and knockout mouse experiments limitations: Disease model; the exact response cannot be assumed in people taking citrulline. exposure: NADPH-oxidase/NOS genetic comparisons and BH4 treatment evidence_span: {"source_cache": "artifacts/citrulline-research/12697739.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d56604695c8c1bda167b76198a472d814d284a3c0c1e1e1eed8943cce31d0ad0", "start_char": 0, "end_char": 1474, "text_sha256": "d56604695c8c1bda167b76198a472d814d284a3c0c1e1e1eed8943cce31d0ad0"} [citrulline-p12697739] Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12697739/ DOI: 10.1172/jci14172
Complete structured claim and evidence
Combined citrulline and BH4 improved pulmonary vascular resistance more than either alone in hypoxic piglets.
L-Citrulline plus tetrahydrobiopterin, study-specific combination → Pulmonary vascular resistance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/32073878.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f", "start_char": 0, "end_char": 1850, "text_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f"}
experimental_model
Controlled neonatal hypoxia and combination-treatment experiment
exposure
L-citrulline, sapropterin, or both during days 3-10 of hypoxia
limitations
Animal combination evidence; does not establish neonatal clinical dosing or treatment benefit in humans.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Newborn pig
plain_language
Both substrate supply and cofactor support mattered in this animal model.
primary_references
[citrulline-p32073878] Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs. (2020). https://pubmed.ncbi.nlm.nih.gov/32073878/ DOI: 10.1152/ajplung.00280.2019
tissue_or_cell_type
Pulmonary arteries and hemodynamics
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 814–825
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled neonatal hypoxia and combination-treatment experiment · source_derived_draft · unverified_draft
### citrulline-pig-combination-pvr Combined citrulline and BH4 improved pulmonary vascular resistance more than either alone in hypoxic piglets. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both substrate supply and cofactor support mattered in this animal model. organism: Newborn pig tissue_or_cell_type: Pulmonary arteries and hemodynamics experimental_model: Controlled neonatal hypoxia and combination-treatment experiment limitations: Animal combination evidence; does not establish neonatal clinical dosing or treatment benefit in humans. exposure: L-citrulline, sapropterin, or both during days 3-10 of hypoxia evidence_span: {"source_cache": "artifacts/citrulline-research/32073878.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f", "start_char": 0, "end_char": 1850, "text_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f"} [citrulline-p32073878] Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs. (2020). https://pubmed.ncbi.nlm.nih.gov/32073878/ DOI: 10.1152/ajplung.00280.2019
Complete structured claim and evidence
Combination treatment improved eNOS dimer ratios and NO production more than either single intervention.
L-Citrulline plus tetrahydrobiopterin, study-specific combination → Pig pulmonary-artery eNOS dimer-to-monomer ratio source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/32073878.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f", "start_char": 0, "end_char": 1850, "text_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f"}
experimental_model
Controlled neonatal hypoxia and combination-treatment experiment
exposure
L-citrulline, sapropterin, or both during days 3-10 of hypoxia
limitations
Animal combination evidence; does not establish neonatal clinical dosing or treatment benefit in humans.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Newborn pig
plain_language
The measured signaling machinery responded alongside the vascular outcome.
primary_references
[citrulline-p32073878] Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs. (2020). https://pubmed.ncbi.nlm.nih.gov/32073878/ DOI: 10.1152/ajplung.00280.2019
tissue_or_cell_type
Pulmonary arteries and hemodynamics
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 827–838
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled neonatal hypoxia and combination-treatment experiment · source_derived_draft · unverified_draft
### citrulline-pig-combination-coupling Combination treatment improved eNOS dimer ratios and NO production more than either single intervention. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured signaling machinery responded alongside the vascular outcome. organism: Newborn pig tissue_or_cell_type: Pulmonary arteries and hemodynamics experimental_model: Controlled neonatal hypoxia and combination-treatment experiment limitations: Animal combination evidence; does not establish neonatal clinical dosing or treatment benefit in humans. exposure: L-citrulline, sapropterin, or both during days 3-10 of hypoxia evidence_span: {"source_cache": "artifacts/citrulline-research/32073878.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f", "start_char": 0, "end_char": 1850, "text_sha256": "3362b0aae303b9c2e54cfa8a291e4d993ab4496d26cf11a1dba96c27c4c3fb7f"} [citrulline-p32073878] Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs. (2020). https://pubmed.ncbi.nlm.nih.gov/32073878/ DOI: 10.1152/ajplung.00280.2019
Complete structured claim and evidence
Citrulline plasma increments after oral loads were similar in LPI homozygotes and controls, unlike diamino-acid increments.
L-Citrulline → Human intestinal citrulline absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/6776014.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d", "start_char": 0, "end_char": 1189, "text_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d"}
experimental_model
Oral amino-acid loading comparison
exposure
Separate diamino-acid and citrulline loads
limitations
Inherited transport disorder, not ordinary competition from mixed dietary protein; the study predates gene identification.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human LPI patients, heterozygotes and controls
plain_language
A different entry route can bypass this particular transport problem.
primary_references
[citrulline-p6776014] Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline. (1980). https://pubmed.ncbi.nlm.nih.gov/6776014/ DOI: 10.1136/gut.21.6.519
tissue_or_cell_type
Intestinal amino-acid absorption inferred from plasma and urine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 840–851
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral amino-acid loading comparison · source_derived_draft · unverified_draft
### citrulline-lpi-citrulline-absorption Citrulline plasma increments after oral loads were similar in LPI homozygotes and controls, unlike diamino-acid increments. Condition category: machinery_impairment nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A different entry route can bypass this particular transport problem. organism: Human LPI patients, heterozygotes and controls tissue_or_cell_type: Intestinal amino-acid absorption inferred from plasma and urine experimental_model: Oral amino-acid loading comparison limitations: Inherited transport disorder, not ordinary competition from mixed dietary protein; the study predates gene identification. exposure: Separate diamino-acid and citrulline loads evidence_span: {"source_cache": "artifacts/citrulline-research/6776014.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d", "start_char": 0, "end_char": 1189, "text_sha256": "6db6a42e66322b8ae26335a4f51284ede7691dcbb91e8cf7d7cd6671bd41b87d"} [citrulline-p6776014] Intestinal absorption in lysinuric protein intolerance: impaired for diamino acids, normal for citrulline. (1980). https://pubmed.ncbi.nlm.nih.gov/6776014/ DOI: 10.1136/gut.21.6.519
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
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
The highest citrulline regimen increased urinary cGMP from 38 to 50 nmol/mmol creatinine.
L-Citrulline → Urinary cyclic GMP excretion 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
A downstream signaling marker increased.
primary_references
[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
tissue_or_cell_type
Plasma amino acids, urine NO markers and brachial FMD
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 892–903
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft
### citrulline-urine-cgmp The highest citrulline regimen increased urinary cGMP from 38 to 50 nmol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A downstream signaling marker increased. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
Complete structured claim and evidence
The highest regimen increased urinary nitrate from 92 to 125 micromol/mmol creatinine.
L-Citrulline → Urinary nitrate excretion 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
Another NO-related marker changed.
primary_references
[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
tissue_or_cell_type
Plasma amino acids, urine NO markers and brachial FMD
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 905–916
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft
### citrulline-urine-nitrate The highest regimen increased urinary nitrate from 92 to 125 micromol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Another NO-related marker changed. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x
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
Less than 5% of administered citrulline was excreted in urine, even at the higher tested doses.
L-Citrulline → Urinary loss of administered citrulline 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
Most of the dose was not simply lost unchanged in urine.
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 944–955
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-urine-retention Less than 5% of administered citrulline was excreted in urine, even at the higher tested doses. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Most of the dose was not simply lost unchanged in urine. 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
Plasma insulin and growth hormone were not affected by the oral citrulline loads.
L-Citrulline → Measured plasma insulin, growth hormone or IGF-1, study specified 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
The study did not show a growth-hormone or insulin boost.
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 957–968
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-hormone-null Plasma insulin and growth hormone were not affected by the oral citrulline loads. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The study did not show a growth-hormone or insulin boost. 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
Mean plasma citrulline was 20 ± 13 micromolar in short-bowel patients versus 40 ± 10 in controls.
L-Citrulline → Circulating citrulline concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/11113071.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246", "start_char": 0, "end_char": 2196, "text_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246"}
experimental_model
Observational diagnostic study after intestinal adaptation
exposure
At least two years after final bowel reconstruction
limitations
The 20 micromolar classifier belongs to this cohort and indication, not a universal dietary deficiency cutoff.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 57 adults with short-bowel syndrome and 51 controls
plain_language
A low value can mark reduced intestinal production rather than low dietary intake.
primary_references
[citrulline-p11113071] Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. (2000). https://pubmed.ncbi.nlm.nih.gov/11113071/ DOI: 10.1053/gast.2000.20227
tissue_or_cell_type
Postabsorptive blood and intestinal absorptive function
trigger_kind
biomarker_context Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 970–981
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Observational diagnostic study after intestinal adaptation · source_derived_draft · unverified_draft
### citrulline-short-bowel-low Mean plasma citrulline was 20 ± 13 micromolar in short-bowel patients versus 40 ± 10 in controls. Condition category: biomarker_context nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A low value can mark reduced intestinal production rather than low dietary intake. organism: Human, 57 adults with short-bowel syndrome and 51 controls tissue_or_cell_type: Postabsorptive blood and intestinal absorptive function experimental_model: Observational diagnostic study after intestinal adaptation limitations: The 20 micromolar classifier belongs to this cohort and indication, not a universal dietary deficiency cutoff. exposure: At least two years after final bowel reconstruction evidence_span: {"source_cache": "artifacts/citrulline-research/11113071.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246", "start_char": 0, "end_char": 2196, "text_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246"} [citrulline-p11113071] Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. (2000). https://pubmed.ncbi.nlm.nih.gov/11113071/ DOI: 10.1053/gast.2000.20227
Complete structured claim and evidence
A 20 micromolar threshold classified permanent intestinal failure with 92% sensitivity and 90% specificity in this cohort.
Circulating citrulline concentration → Intestinal failure classification in established short-bowel syndrome source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/citrulline-research/11113071.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246", "start_char": 0, "end_char": 2196, "text_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246"}
experimental_model
Observational diagnostic study after intestinal adaptation
exposure
At least two years after final bowel reconstruction
limitations
The 20 micromolar classifier belongs to this cohort and indication, not a universal dietary deficiency cutoff.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 57 adults with short-bowel syndrome and 51 controls
plain_language
This is a study-specific diagnostic result, not a target blood level for everyone.
primary_references
[citrulline-p11113071] Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. (2000). https://pubmed.ncbi.nlm.nih.gov/11113071/ DOI: 10.1053/gast.2000.20227
tissue_or_cell_type
Postabsorptive blood and intestinal absorptive function
trigger_kind
biomarker_context Imported condition classification; unverified.
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 983–994
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Observational diagnostic study after intestinal adaptation · source_derived_draft · unverified_draft
### citrulline-short-bowel-classifier A 20 micromolar threshold classified permanent intestinal failure with 92% sensitivity and 90% specificity in this cohort. Condition category: biomarker_context nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This is a study-specific diagnostic result, not a target blood level for everyone. organism: Human, 57 adults with short-bowel syndrome and 51 controls tissue_or_cell_type: Postabsorptive blood and intestinal absorptive function experimental_model: Observational diagnostic study after intestinal adaptation limitations: The 20 micromolar classifier belongs to this cohort and indication, not a universal dietary deficiency cutoff. exposure: At least two years after final bowel reconstruction evidence_span: {"source_cache": "artifacts/citrulline-research/11113071.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246", "start_char": 0, "end_char": 2196, "text_sha256": "e2470fc206e5913038da9bb8d7a38677533224bd369ccd02563cefe760727246"} [citrulline-p11113071] Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. (2000). https://pubmed.ncbi.nlm.nih.gov/11113071/ DOI: 10.1053/gast.2000.20227
Complete structured claim and evidence
ESRD patients had elevated plasma citrulline and citrulline flux compared with healthy adults.
L-Citrulline → Circulating citrulline concentration 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
A high value can coexist with severe kidney disease.
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 996–1007
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-high-citrulline ESRD patients had elevated plasma citrulline and citrulline flux compared with healthy adults. Condition category: biomarker_context nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A high value can coexist with severe kidney disease. 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 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
Hypoxia and/or inflammation did not reduce citrulline production during the six-hour human explant experiment.
L-Citrulline → Intestinal citrulline release source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/34882863.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3971162e4b915e3dadb6408a84cf3558526ee837e3446dd61c831f076f3fd901", "start_char": 0, "end_char": 1801, "text_sha256": "3971162e4b915e3dadb6408a84cf3558526ee837e3446dd61c831f076f3fd901"}
experimental_model
Six-hour human duodenal explant experiment
exposure
Control, hypoxia, inflammation and combined exposure
limitations
Short ex-vivo exposure cannot explain all low citrulline in prolonged critical illness; increased utilization remains a proposed explanation.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human biopsies from 25 selected patients
plain_language
Low circulating citrulline during illness cannot automatically be attributed to shut-down intestinal production.
primary_references
[citrulline-p34882863] Regulation of citrulline synthesis in human enterocytes: Role of hypoxia and inflammation. (2022). https://pubmed.ncbi.nlm.nih.gov/34882863/ DOI: 10.1002/biof.1810
tissue_or_cell_type
Intestinal citrulline production
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1022–1033
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-hour human duodenal explant experiment · source_derived_draft · unverified_draft
### citrulline-explant-production-null Hypoxia and/or inflammation did not reduce citrulline production during the six-hour human explant experiment. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low circulating citrulline during illness cannot automatically be attributed to shut-down intestinal production. organism: Human biopsies from 25 selected patients tissue_or_cell_type: Intestinal citrulline production experimental_model: Six-hour human duodenal explant experiment limitations: Short ex-vivo exposure cannot explain all low citrulline in prolonged critical illness; increased utilization remains a proposed explanation. exposure: Control, hypoxia, inflammation and combined exposure evidence_span: {"source_cache": "artifacts/citrulline-research/34882863.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3971162e4b915e3dadb6408a84cf3558526ee837e3446dd61c831f076f3fd901", "start_char": 0, "end_char": 1801, "text_sha256": "3971162e4b915e3dadb6408a84cf3558526ee837e3446dd61c831f076f3fd901"} [citrulline-p34882863] Regulation of citrulline synthesis in human enterocytes: Role of hypoxia and inflammation. (2022). https://pubmed.ncbi.nlm.nih.gov/34882863/ DOI: 10.1002/biof.1810
Complete structured claim and evidence
Mixed-muscle fractional synthesis was higher with citrulline than the comparator, 0.060 versus 0.049, P=0.03.
L-Citrulline → Mixed skeletal-muscle protein fractional synthesis rate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/24972455.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995", "start_char": 0, "end_char": 1703, "text_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995"}
experimental_model
Crossover isotope muscle-protein synthesis pilot
exposure
Oral citrulline versus a nonessential-amino-acid mixture over eight hours
limitations
Acute fractional synthesis is not long-term muscle growth; participants were not representative of all malnourished or older people.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, eight healthy adults after three days of low protein intake
plain_language
One muscle protein measure improved after a short low-protein diet.
primary_references
[citrulline-p24972455] Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet - A pilot study. (2015). https://pubmed.ncbi.nlm.nih.gov/24972455/ DOI: 10.1016/j.clnu.2014.04.019
tissue_or_cell_type
Mixed and mitochondrial muscle protein fractions
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1035–1046
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crossover isotope muscle-protein synthesis pilot · source_derived_draft · unverified_draft
### citrulline-low-protein-mps Mixed-muscle fractional synthesis was higher with citrulline than the comparator, 0.060 versus 0.049, P=0.03. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: One muscle protein measure improved after a short low-protein diet. organism: Human, eight healthy adults after three days of low protein intake tissue_or_cell_type: Mixed and mitochondrial muscle protein fractions experimental_model: Crossover isotope muscle-protein synthesis pilot limitations: Acute fractional synthesis is not long-term muscle growth; participants were not representative of all malnourished or older people. exposure: Oral citrulline versus a nonessential-amino-acid mixture over eight hours evidence_span: {"source_cache": "artifacts/citrulline-research/24972455.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995", "start_char": 0, "end_char": 1703, "text_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995"} [citrulline-p24972455] Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet - A pilot study. (2015). https://pubmed.ncbi.nlm.nih.gov/24972455/ DOI: 10.1016/j.clnu.2014.04.019
Complete structured claim and evidence
Mitochondrial protein synthesis and whole-body protein turnover did not differ between treatments.
L-Citrulline → Muscle mitochondrial protein synthesis rate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/24972455.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995", "start_char": 0, "end_char": 1703, "text_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995"}
experimental_model
Crossover isotope muscle-protein synthesis pilot
exposure
Oral citrulline versus a nonessential-amino-acid mixture over eight hours
limitations
Acute fractional synthesis is not long-term muscle growth; participants were not representative of all malnourished or older people.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, eight healthy adults after three days of low protein intake
plain_language
The anabolic result did not apply to every protein compartment.
primary_references
[citrulline-p24972455] Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet - A pilot study. (2015). https://pubmed.ncbi.nlm.nih.gov/24972455/ DOI: 10.1016/j.clnu.2014.04.019
tissue_or_cell_type
Mixed and mitochondrial muscle protein fractions
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1048–1059
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crossover isotope muscle-protein synthesis pilot · source_derived_draft · unverified_draft
### citrulline-mitochondrial-mps-null Mitochondrial protein synthesis and whole-body protein turnover 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: The anabolic result did not apply to every protein compartment. organism: Human, eight healthy adults after three days of low protein intake tissue_or_cell_type: Mixed and mitochondrial muscle protein fractions experimental_model: Crossover isotope muscle-protein synthesis pilot limitations: Acute fractional synthesis is not long-term muscle growth; participants were not representative of all malnourished or older people. exposure: Oral citrulline versus a nonessential-amino-acid mixture over eight hours evidence_span: {"source_cache": "artifacts/citrulline-research/24972455.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995", "start_char": 0, "end_char": 1703, "text_sha256": "766ca1c6460f11fb78c1f94c02e42f53bf30269e7368cd62e0518e976e2b2995"} [citrulline-p24972455] Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet - A pilot study. (2015). https://pubmed.ncbi.nlm.nih.gov/24972455/ DOI: 10.1016/j.clnu.2014.04.019
Complete structured claim and evidence
Adding citrulline to 15 g whey did not augment myofibrillar protein synthesis compared with the nonessential-amino-acid addition.
L-Citrulline → Myofibrillar protein synthesis rate 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
Citrulline did not substitute for a larger protein meal in this trial.
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 1061–1072
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-mps-null Adding citrulline to 15 g whey did not augment myofibrillar protein synthesis compared with the nonessential-amino-acid addition. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Citrulline did not substitute for a larger protein meal in this trial. 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
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
Whole-body synthesis estimated by nonoxidative leucine disposal did not significantly change in the overall SBS group.
L-Citrulline → Whole-body protein synthesis estimate 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
Higher exposure did not establish an overall anabolic benefit.
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 1100–1111
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-protein-null Whole-body synthesis estimated by nonoxidative leucine disposal did not significantly change in the overall SBS group. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Higher exposure did not establish an overall anabolic benefit. 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
CM increased repetitions in later bench-press sets; the reported final-set relative gain was 52.92%.
Citrulline-malate preparation, composition specified per study → Completed repetitions in protocol-specified resistance exercise source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"}
experimental_model
Randomized double-blind crossover exercise trial
exposure
8 g citrulline malate before a high-volume pectoral session
limitations
CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 41 men
plain_language
This result belongs to a demanding repeated-set protocol.
primary_references
[citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
tissue_or_cell_type
Bench-press repetitions and self-reported soreness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1113–1124
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind crossover exercise trial · source_derived_draft · unverified_draft
### citrulline-exercise-positive CM increased repetitions in later bench-press sets; the reported final-set relative gain was 52.92%. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This result belongs to a demanding repeated-set protocol. organism: Human, 41 men tissue_or_cell_type: Bench-press repetitions and self-reported soreness experimental_model: Randomized double-blind crossover exercise trial limitations: CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective. exposure: 8 g citrulline malate before a high-volume pectoral session evidence_span: {"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"} [citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
Complete structured claim and evidence
The trial reported approximately 40% lower soreness at 24 and 48 hours with CM.
Citrulline-malate preparation, composition specified per study → Protocol-specified postexercise muscle soreness source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"}
experimental_model
Randomized double-blind crossover exercise trial
exposure
8 g citrulline malate before a high-volume pectoral session
limitations
CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 41 men
plain_language
Participants reported less soreness after this protocol.
primary_references
[citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
tissue_or_cell_type
Bench-press repetitions and self-reported soreness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1126–1137
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind crossover exercise trial · source_derived_draft · unverified_draft
### citrulline-soreness-decreased The trial reported approximately 40% lower soreness at 24 and 48 hours with CM. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Participants reported less soreness after this protocol. organism: Human, 41 men tissue_or_cell_type: Bench-press repetitions and self-reported soreness experimental_model: Randomized double-blind crossover exercise trial limitations: CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective. exposure: 8 g citrulline malate before a high-volume pectoral session evidence_span: {"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"} [citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
Complete structured claim and evidence
Stomach discomfort was reported by 14.63% of participants with CM.
Citrulline-malate preparation, composition specified per study → Gastrointestinal discomfort during supplementation trial source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"}
experimental_model
Randomized double-blind crossover exercise trial
exposure
8 g citrulline malate before a high-volume pectoral session
limitations
CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 41 men
plain_language
The study preparation was not symptom-free for everyone.
primary_references
[citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
tissue_or_cell_type
Bench-press repetitions and self-reported soreness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1139–1150
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind crossover exercise trial · source_derived_draft · unverified_draft
### citrulline-stomach-discomfort Stomach discomfort was reported by 14.63% of participants with CM. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The study preparation was not symptom-free for everyone. organism: Human, 41 men tissue_or_cell_type: Bench-press repetitions and self-reported soreness experimental_model: Randomized double-blind crossover exercise trial limitations: CM is not pure L-citrulline; last-set relative change is not a whole-workout gain; perceived soreness is subjective. exposure: 8 g citrulline malate before a high-volume pectoral session evidence_span: {"source_cache": "artifacts/citrulline-research/20386132.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847", "start_char": 0, "end_char": 1637, "text_sha256": "a095891368caeebaa857f5dcf2651e1498924f2006969255d252c1d8caa91847"} [citrulline-p20386132] Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. (2010). https://pubmed.ncbi.nlm.nih.gov/20386132/ DOI: 10.1519/jsc.0b013e3181cb28e0
Complete structured claim and evidence
Repetitions did not improve with CM: 90.9 versus 94.0 on placebo, P=0.33.
Citrulline-malate preparation, composition specified per study → Completed repetitions in protocol-specified resistance exercise source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/30097067.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2", "start_char": 0, "end_char": 1678, "text_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2"}
experimental_model
Randomized double-blind counterbalanced exercise study and product analysis
exposure
8 g CM with measured citrulline:malate ratio 1.11:1
limitations
Exercise, participant mix and product composition differed from the 2010 study; the cause of discrepant soreness is unproven.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human recreationally active men and women
plain_language
This protocol did not reproduce a performance gain.
primary_references
[citrulline-p30097067] Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females. (2018). https://pubmed.ncbi.nlm.nih.gov/30097067/ DOI: 10.1186/s12970-018-0245-8
tissue_or_cell_type
Isokinetic German Volume Training and 72-hour soreness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1152–1163
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind counterbalanced exercise study and product analysis · source_derived_draft · unverified_draft
### citrulline-exercise-null Repetitions did not improve with CM: 90.9 versus 94.0 on placebo, P=0.33. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This protocol did not reproduce a performance gain. organism: Human recreationally active men and women tissue_or_cell_type: Isokinetic German Volume Training and 72-hour soreness experimental_model: Randomized double-blind counterbalanced exercise study and product analysis limitations: Exercise, participant mix and product composition differed from the 2010 study; the cause of discrepant soreness is unproven. exposure: 8 g CM with measured citrulline:malate ratio 1.11:1 evidence_span: {"source_cache": "artifacts/citrulline-research/30097067.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2", "start_char": 0, "end_char": 1678, "text_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2"} [citrulline-p30097067] Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females. (2018). https://pubmed.ncbi.nlm.nih.gov/30097067/ DOI: 10.1186/s12970-018-0245-8
Complete structured claim and evidence
Total soreness over 72 hours was higher after CM than placebo, P=0.01, without a greater workload.
Citrulline-malate preparation, composition specified per study → Protocol-specified postexercise muscle soreness source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/30097067.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2", "start_char": 0, "end_char": 1678, "text_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2"}
experimental_model
Randomized double-blind counterbalanced exercise study and product analysis
exposure
8 g CM with measured citrulline:malate ratio 1.11:1
limitations
Exercise, participant mix and product composition differed from the 2010 study; the cause of discrepant soreness is unproven.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human recreationally active men and women
plain_language
This study reported more soreness, the opposite of the earlier soreness result.
primary_references
[citrulline-p30097067] Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females. (2018). https://pubmed.ncbi.nlm.nih.gov/30097067/ DOI: 10.1186/s12970-018-0245-8
tissue_or_cell_type
Isokinetic German Volume Training and 72-hour soreness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1165–1176
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind counterbalanced exercise study and product analysis · source_derived_draft · unverified_draft
### citrulline-soreness-increased Total soreness over 72 hours was higher after CM than placebo, P=0.01, without a greater workload. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: This study reported more soreness, the opposite of the earlier soreness result. organism: Human recreationally active men and women tissue_or_cell_type: Isokinetic German Volume Training and 72-hour soreness experimental_model: Randomized double-blind counterbalanced exercise study and product analysis limitations: Exercise, participant mix and product composition differed from the 2010 study; the cause of discrepant soreness is unproven. exposure: 8 g CM with measured citrulline:malate ratio 1.11:1 evidence_span: {"source_cache": "artifacts/citrulline-research/30097067.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2", "start_char": 0, "end_char": 1678, "text_sha256": "8f08d4e244a48b116a8a2a734514e0cf13d3953bcae33722f996121bab8efbb2"} [citrulline-p30097067] Citrulline malate supplementation does not improve German Volume Training performance or reduce muscle soreness in moderately trained males and females. (2018). https://pubmed.ncbi.nlm.nih.gov/30097067/ DOI: 10.1186/s12970-018-0245-8
Complete structured claim and evidence
Matched-dose L-citrulline did not improve maximal neuromuscular or ballistic performance versus placebo.
L-Citrulline → Protocol-specified maximal neuromuscular performance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/39662304.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092", "start_char": 0, "end_char": 1816, "text_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092"}
experimental_model
Randomized double-blind placebo-controlled crossover trial
exposure
5.3 g L-citrulline; or 5.3 g citrulline plus 2.7 g malate; or placebo 45 minutes pre-exercise
limitations
Acute low-to-moderate-volume protocol; not a universal finding for all doses, workouts or chronic use.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 43 trained adults including 21 women
plain_language
The pure amino acid did not produce a measurable advantage here.
primary_references
[citrulline-p39662304] Malate or Not? Acute Effects of L-Citrulline Versus Citrulline Malate on Neuromuscular Performance in Young, Trained Adults: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/39662304/ DOI: 10.1123/ijsnem.2024-0006
tissue_or_cell_type
Neuromuscular, ballistic and strength-endurance tests
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1178–1189
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 crossover trial · source_derived_draft · unverified_draft
### citrulline-matched-pure-null Matched-dose L-citrulline did not improve maximal neuromuscular or ballistic performance versus placebo. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The pure amino acid did not produce a measurable advantage here. organism: Human, 43 trained adults including 21 women tissue_or_cell_type: Neuromuscular, ballistic and strength-endurance tests experimental_model: Randomized double-blind placebo-controlled crossover trial limitations: Acute low-to-moderate-volume protocol; not a universal finding for all doses, workouts or chronic use. exposure: 5.3 g L-citrulline; or 5.3 g citrulline plus 2.7 g malate; or placebo 45 minutes pre-exercise evidence_span: {"source_cache": "artifacts/citrulline-research/39662304.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092", "start_char": 0, "end_char": 1816, "text_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092"} [citrulline-p39662304] Malate or Not? Acute Effects of L-Citrulline Versus Citrulline Malate on Neuromuscular Performance in Young, Trained Adults: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/39662304/ DOI: 10.1123/ijsnem.2024-0006
Complete structured claim and evidence
Neither pure citrulline nor matched-citrulline-dose CM improved repetitions or other strength-endurance measures.
Citrulline-malate preparation, composition specified per study → Completed repetitions in protocol-specified resistance exercise source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/39662304.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092", "start_char": 0, "end_char": 1816, "text_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092"}
experimental_model
Randomized double-blind placebo-controlled crossover trial
exposure
5.3 g L-citrulline; or 5.3 g citrulline plus 2.7 g malate; or placebo 45 minutes pre-exercise
limitations
Acute low-to-moderate-volume protocol; not a universal finding for all doses, workouts or chronic use.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 43 trained adults including 21 women
plain_language
Adding malate did not demonstrate an extra benefit in this trial.
primary_references
[citrulline-p39662304] Malate or Not? Acute Effects of L-Citrulline Versus Citrulline Malate on Neuromuscular Performance in Young, Trained Adults: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/39662304/ DOI: 10.1123/ijsnem.2024-0006
tissue_or_cell_type
Neuromuscular, ballistic and strength-endurance tests
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1191–1202
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 crossover trial · source_derived_draft · unverified_draft
### citrulline-matched-malate-null Neither pure citrulline nor matched-citrulline-dose CM improved repetitions or other strength-endurance measures. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding malate did not demonstrate an extra benefit in this trial. organism: Human, 43 trained adults including 21 women tissue_or_cell_type: Neuromuscular, ballistic and strength-endurance tests experimental_model: Randomized double-blind placebo-controlled crossover trial limitations: Acute low-to-moderate-volume protocol; not a universal finding for all doses, workouts or chronic use. exposure: 5.3 g L-citrulline; or 5.3 g citrulline plus 2.7 g malate; or placebo 45 minutes pre-exercise evidence_span: {"source_cache": "artifacts/citrulline-research/39662304.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092", "start_char": 0, "end_char": 1816, "text_sha256": "3f26c60b31d2021fb82143a4780ab4437e58c18d1c482a0880fdc4321f224092"} [citrulline-p39662304] Malate or Not? Acute Effects of L-Citrulline Versus Citrulline Malate on Neuromuscular Performance in Young, Trained Adults: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/39662304/ DOI: 10.1123/ijsnem.2024-0006
Complete structured claim and evidence
Walking-distance change was 20.11% with citrulline versus 5.73% with placebo, P=0.011.
L-Citrulline → Absolute claudication walking distance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/39985883.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c", "start_char": 0, "end_char": 1888, "text_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c"}
experimental_model
Phase II double-blind placebo-controlled crossover trial
exposure
3 g citrulline twice daily for 12 weeks; additional BH4 0.45 g/day for two weeks in one arm
limitations
Preliminary trial; subgroup-dependent BH4 result and study-specific ADMA cutoff require confirmation; not a general supplement prescription.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 51 peripheral-artery-disease patients
plain_language
A patient-relevant walking endpoint improved in this preliminary PAD trial.
primary_references
[citrulline-p39985883] Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). (2025). https://pubmed.ncbi.nlm.nih.gov/39985883/ DOI: 10.1016/j.jacadv.2025.101590
tissue_or_cell_type
Absolute claudication distance and plasma biomarkers
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1204–1215
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phase II double-blind placebo-controlled crossover trial · source_derived_draft · unverified_draft
### citrulline-pad-walking Walking-distance change was 20.11% with citrulline versus 5.73% with placebo, P=0.011. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A patient-relevant walking endpoint improved in this preliminary PAD trial. organism: Human, 51 peripheral-artery-disease patients tissue_or_cell_type: Absolute claudication distance and plasma biomarkers experimental_model: Phase II double-blind placebo-controlled crossover trial limitations: Preliminary trial; subgroup-dependent BH4 result and study-specific ADMA cutoff require confirmation; not a general supplement prescription. exposure: 3 g citrulline twice daily for 12 weeks; additional BH4 0.45 g/day for two weeks in one arm evidence_span: {"source_cache": "artifacts/citrulline-research/39985883.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c", "start_char": 0, "end_char": 1888, "text_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c"} [citrulline-p39985883] Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). (2025). https://pubmed.ncbi.nlm.nih.gov/39985883/ DOI: 10.1016/j.jacadv.2025.101590
Complete structured claim and evidence
Adding BH4 increased the reported walking-distance change to 28.15% only in the subgroup with baseline ADMA above 0.4 micromolar.
L-Citrulline plus tetrahydrobiopterin, study-specific combination → Absolute claudication walking distance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/39985883.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c", "start_char": 0, "end_char": 1888, "text_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c"}
experimental_model
Phase II double-blind placebo-controlled crossover trial
exposure
3 g citrulline twice daily for 12 weeks; additional BH4 0.45 g/day for two weeks in one arm
limitations
Preliminary trial; subgroup-dependent BH4 result and study-specific ADMA cutoff require confirmation; not a general supplement prescription.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 51 peripheral-artery-disease patients
plain_language
The cofactor combination result depended on the measured starting state.
primary_references
[citrulline-p39985883] Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). (2025). https://pubmed.ncbi.nlm.nih.gov/39985883/ DOI: 10.1016/j.jacadv.2025.101590
tissue_or_cell_type
Absolute claudication distance and plasma biomarkers
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1217–1228
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phase II double-blind placebo-controlled crossover trial · source_derived_draft · unverified_draft
### citrulline-pad-bh4-subgroup Adding BH4 increased the reported walking-distance change to 28.15% only in the subgroup with baseline ADMA above 0.4 micromolar. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cofactor combination result depended on the measured starting state. organism: Human, 51 peripheral-artery-disease patients tissue_or_cell_type: Absolute claudication distance and plasma biomarkers experimental_model: Phase II double-blind placebo-controlled crossover trial limitations: Preliminary trial; subgroup-dependent BH4 result and study-specific ADMA cutoff require confirmation; not a general supplement prescription. exposure: 3 g citrulline twice daily for 12 weeks; additional BH4 0.45 g/day for two weeks in one arm evidence_span: {"source_cache": "artifacts/citrulline-research/39985883.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c", "start_char": 0, "end_char": 1888, "text_sha256": "0007fe7b3fcc746e77c450f3aca50ca2834c78b84aa83977b3078ae05051ab9c"} [citrulline-p39985883] Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). (2025). https://pubmed.ncbi.nlm.nih.gov/39985883/ DOI: 10.1016/j.jacadv.2025.101590
Complete structured claim and evidence
The FMD/NMD ratio increased by 0.12 with citrulline versus 0.01 with placebo in the CAD trial.
L-Citrulline → Brachial flow-mediated to nitroglycerin-mediated dilation ratio source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/27648629.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7584e325856443da6067298d1c6ab31b95679839361f4a60adc5f7434944fb17", "start_char": 0, "end_char": 1848, "text_sha256": "7584e325856443da6067298d1c6ab31b95679839361f4a60adc5f7434944fb17"}
experimental_model
Randomized placebo crossover vascular trial
exposure
Fifteen-day L-citrulline and placebo periods
limitations
Small surrogate trial; abstract reports unusual FMD units, so only the dimensionless ratio is extracted.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 30 coronary-artery-disease patients
plain_language
A vascular-response ratio improved in this selected patient group.
primary_references
[citrulline-p27648629] The Assessment of short-term effect of L-Citrulline on endothelial function via FMD to NMD ratio in known CAD patients: A randomized, cross-over clinical trial (Clinical trial number: NCT02638727). (2017). https://pubmed.ncbi.nlm.nih.gov/27648629/ DOI: 10.1515/rjim-2016-0045
tissue_or_cell_type
Brachial FMD/NMD ratio
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1230–1241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized placebo crossover vascular trial · source_derived_draft · unverified_draft
### citrulline-cad-ratio The FMD/NMD ratio increased by 0.12 with citrulline versus 0.01 with placebo in the CAD trial. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A vascular-response ratio improved in this selected patient group. organism: Human, 30 coronary-artery-disease patients tissue_or_cell_type: Brachial FMD/NMD ratio experimental_model: Randomized placebo crossover vascular trial limitations: Small surrogate trial; abstract reports unusual FMD units, so only the dimensionless ratio is extracted. exposure: Fifteen-day L-citrulline and placebo periods evidence_span: {"source_cache": "artifacts/citrulline-research/27648629.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7584e325856443da6067298d1c6ab31b95679839361f4a60adc5f7434944fb17", "start_char": 0, "end_char": 1848, "text_sha256": "7584e325856443da6067298d1c6ab31b95679839361f4a60adc5f7434944fb17"} [citrulline-p27648629] The Assessment of short-term effect of L-Citrulline on endothelial function via FMD to NMD ratio in known CAD patients: A randomized, cross-over clinical trial (Clinical trial number: NCT02638727). (2017). https://pubmed.ncbi.nlm.nih.gov/27648629/ DOI: 10.1515/rjim-2016-0045
Complete structured claim and evidence
Normal-range erection hardness was reported in 12/24 men during citrulline versus 2/24 during the preceding placebo month.
L-Citrulline → Erection hardness score source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/21195829.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b85dfbc0993e9d8f01bdc021151650d6466c9204a7d7158e488ce66416e1df74", "start_char": 0, "end_char": 1897, "text_sha256": "b85dfbc0993e9d8f01bdc021151650d6466c9204a7d7158e488ce66416e1df74"}
experimental_model
Single-blind fixed-sequence placebo then active pilot
exposure
One month placebo followed by one month L-citrulline 1.5 g/day
limitations
Not a randomized-order crossover; expectation, time and sequence effects cannot be excluded; no direct PDE5-inhibitor comparison.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human, 24 men with mild erectile dysfunction
plain_language
An encouraging pilot finding needs stronger trial confirmation.
primary_references
[citrulline-p21195829] Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. (2011). https://pubmed.ncbi.nlm.nih.gov/21195829/ DOI: 10.1016/j.urology.2010.08.028
tissue_or_cell_type
Erection hardness
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1243–1254
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-blind fixed-sequence placebo then active pilot · source_derived_draft · unverified_draft
### citrulline-erection-pilot Normal-range erection hardness was reported in 12/24 men during citrulline versus 2/24 during the preceding placebo month. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: An encouraging pilot finding needs stronger trial confirmation. organism: Human, 24 men with mild erectile dysfunction tissue_or_cell_type: Erection hardness experimental_model: Single-blind fixed-sequence placebo then active pilot limitations: Not a randomized-order crossover; expectation, time and sequence effects cannot be excluded; no direct PDE5-inhibitor comparison. exposure: One month placebo followed by one month L-citrulline 1.5 g/day evidence_span: {"source_cache": "artifacts/citrulline-research/21195829.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b85dfbc0993e9d8f01bdc021151650d6466c9204a7d7158e488ce66416e1df74", "start_char": 0, "end_char": 1897, "text_sha256": "b85dfbc0993e9d8f01bdc021151650d6466c9204a7d7158e488ce66416e1df74"} [citrulline-p21195829] Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. (2011). https://pubmed.ncbi.nlm.nih.gov/21195829/ DOI: 10.1016/j.urology.2010.08.028
Complete structured claim and evidence
Oral citrulline increased mortality in infected preterm pigs; intravenous exposure did not significantly change mortality.
L-Citrulline → Mortality in experimentally infected preterm pigs source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/38825026.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062", "start_char": 0, "end_char": 1404, "text_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062"}
experimental_model
Controlled infection experiment with oral or intravenous supplementation
exposure
Citrulline 1 g/kg followed by Staphylococcus epidermidis inoculation; 14-hour monitoring
limitations
Preclinical high-exposure neonatal infection model; does not establish harm from usual adult supplementation or benefit in human sepsis.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Preterm pigs; related cord-blood experiments
plain_language
Correcting a presumed precursor shortage did not improve this infection model.
primary_references
[citrulline-p38825026] Citrulline supplementation exacerbates sepsis severity in infected preterm piglets via early induced immunosuppression. (2024). https://pubmed.ncbi.nlm.nih.gov/38825026/ DOI: 10.1016/j.jnutbio.2024.109674
tissue_or_cell_type
Bacterial load, inflammation and survival
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1256–1267
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled infection experiment with oral or intravenous supplementation · source_derived_draft · unverified_draft
### citrulline-preterm-sepsis-mortality Oral citrulline increased mortality in infected preterm pigs; intravenous exposure did not significantly change mortality. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Correcting a presumed precursor shortage did not improve this infection model. organism: Preterm pigs; related cord-blood experiments tissue_or_cell_type: Bacterial load, inflammation and survival experimental_model: Controlled infection experiment with oral or intravenous supplementation limitations: Preclinical high-exposure neonatal infection model; does not establish harm from usual adult supplementation or benefit in human sepsis. exposure: Citrulline 1 g/kg followed by Staphylococcus epidermidis inoculation; 14-hour monitoring evidence_span: {"source_cache": "artifacts/citrulline-research/38825026.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062", "start_char": 0, "end_char": 1404, "text_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062"} [citrulline-p38825026] Citrulline supplementation exacerbates sepsis severity in infected preterm piglets via early induced immunosuppression. (2024). https://pubmed.ncbi.nlm.nih.gov/38825026/ DOI: 10.1016/j.jnutbio.2024.109674
Complete structured claim and evidence
Both oral and intravenous citrulline groups showed increased bacterial burden and inflammation.
L-Citrulline → Blood bacterial burden in infected preterm pigs source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/38825026.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062", "start_char": 0, "end_char": 1404, "text_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062"}
experimental_model
Controlled infection experiment with oral or intravenous supplementation
exposure
Citrulline 1 g/kg followed by Staphylococcus epidermidis inoculation; 14-hour monitoring
limitations
Preclinical high-exposure neonatal infection model; does not establish harm from usual adult supplementation or benefit in human sepsis.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Preterm pigs; related cord-blood experiments
plain_language
Effects on immunity and timing can matter beyond the NO pathway.
primary_references
[citrulline-p38825026] Citrulline supplementation exacerbates sepsis severity in infected preterm piglets via early induced immunosuppression. (2024). https://pubmed.ncbi.nlm.nih.gov/38825026/ DOI: 10.1016/j.jnutbio.2024.109674
tissue_or_cell_type
Bacterial load, inflammation and survival
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 1269–1280
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled infection experiment with oral or intravenous supplementation · source_derived_draft · unverified_draft
### citrulline-preterm-sepsis-burden Both oral and intravenous citrulline groups showed increased bacterial burden and inflammation. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Effects on immunity and timing can matter beyond the NO pathway. organism: Preterm pigs; related cord-blood experiments tissue_or_cell_type: Bacterial load, inflammation and survival experimental_model: Controlled infection experiment with oral or intravenous supplementation limitations: Preclinical high-exposure neonatal infection model; does not establish harm from usual adult supplementation or benefit in human sepsis. exposure: Citrulline 1 g/kg followed by Staphylococcus epidermidis inoculation; 14-hour monitoring evidence_span: {"source_cache": "artifacts/citrulline-research/38825026.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062", "start_char": 0, "end_char": 1404, "text_sha256": "a41a36f1d4539b1bb87cbfbd145f54655183855c1a4ad0061589bee0c13df062"} [citrulline-p38825026] Citrulline supplementation exacerbates sepsis severity in infected preterm piglets via early induced immunosuppression. (2024). https://pubmed.ncbi.nlm.nih.gov/38825026/ DOI: 10.1016/j.jnutbio.2024.109674
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
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
Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate.
Human cytosolic aspartate aminotransferase / GOT1 → L-Aspartate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified human cytosolic GOT1 and GPT; coupled kinetic assays
exposure
Kinetic assays at pH 7.4 and 37 C
limitations
Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
This B6-dependent enzyme links amino-acid and carbon metabolism.
primary_references
[b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 741–751
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic GOT1 and GPT; coupled kinetic assays · source_derived_draft · unverified_draft
### b6-met-got1-reaction Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent enzyme links amino-acid and carbon metabolism. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human cytosolic GOT1 and GPT; coupled kinetic assays limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. exposure: Kinetic assays at pH 7.4 and 37 C [b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398
Complete structured claim and evidence
Human RFK phosphorylates riboflavin to FMN using ATP, yielding ADP; this precedes FLAD1-mediated FAD synthesis.
Riboflavin kinase / RFK → Riboflavin (vitamin B2) source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract and product-bound structure
experimental_model
Human RFK structural and catalytic mechanism study
exposure
Purified RFK with flavin and adenine nucleotide ligands.
limitations
Reaction chemistry does not imply RFK controls every tissue flavin pool to the same extent.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
RFK performs the first activation step from riboflavin to FMN.
primary_references
[transport-rfk-2003] Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism. (2003). https://pubmed.ncbi.nlm.nih.gov/14580199/ DOI: 10.1021/bi035450t
tissue_or_cell_type
Purified protein
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 293–304
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RFK structural and catalytic mechanism study · source_derived_draft · unverified_draft
### transport-rfk-phosphorylation Human RFK phosphorylates riboflavin to FMN using ATP, yielding ADP; this precedes FLAD1-mediated FAD synthesis. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: RFK performs the first activation step from riboflavin to FMN. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human RFK structural and catalytic mechanism study limitations: Reaction chemistry does not imply RFK controls every tissue flavin pool to the same extent. exposure: Purified RFK with flavin and adenine nucleotide ligands. evidence_location: Abstract and product-bound structure [transport-rfk-2003] Ligand binding-induced conformational changes in riboflavin kinase: structural basis for the ordered mechanism. (2003). https://pubmed.ncbi.nlm.nih.gov/14580199/ DOI: 10.1021/bi035450t
Complete structured claim and evidence
Human COASY dephospho-CoA kinase activity phosphorylated dephospho-CoA to CoA using ATP; deleting the C-terminal domain retained PPAT but removed DPCK activity.
Coenzyme A synthase / COASY → 3′-Dephospho-coenzyme A source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution
exposure
DPCK assay: 5–100 micromolar dephospho-CoA, 1 mM ATP; coupled ADP readout and direct HPLC product analysis.
limitations
Recombinant enzyme and truncation studies define two distinct COASY activities; no whole-body nutritional threshold is measured.
nutrient_topic
Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)
organism
Homo sapiens
plain_language
The final COASY reaction completes CoA.
primary_references
[b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 587–598
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution · source_derived_draft · unverified_draft
### b5-bio-coasy-phosphorylation Human COASY dephospho-CoA kinase activity phosphorylated dephospho-CoA to CoA using ATP; deleting the C-terminal domain retained PPAT but removed DPCK activity. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: The final COASY reaction completes CoA. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human PPCS, PPCDC and COASY expressed in Escherichia coli; coupled enzyme assays and HPLC reconstitution limitations: Recombinant enzyme and truncation studies define two distinct COASY activities; no whole-body nutritional threshold is measured. exposure: DPCK assay: 5–100 micromolar dephospho-CoA, 1 mM ATP; coupled ADP readout and direct HPLC product analysis. cross_nutrient: false [b5-bio-daugherty2002] Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. (2002). https://pubmed.ncbi.nlm.nih.gov/11923312/ DOI: 10.1074/jbc.m201708200
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
GPX3 may help preserve nitric oxide's platelet-inhibitory signal.
Redox and platelet measurements support GPX3 preservation of NO-mediated platelet restraint.
GPX3 → NO source_derived_draftliterature_reviewed:supported_interpretation
Experimental context and source evidence
cell_type
plasma and platelets
experimental_model
Gpx3 knockout
limitations
Individual oxidant intermediates were not fully isolated.
organism
mouse
Selenium: literature corrections and mechanism additions · lines 714–724
Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Gpx3 knockout · secondary_verified · secondary_verified
## gpx3-supports-no-platelet-restraint GPX3 may help preserve nitric oxide's platelet-inhibitory signal. Redox and platelet measurements support GPX3 preservation of NO-mediated platelet restraint. Organism: mouse Cell type: plasma and platelets Experimental model: Gpx3 knockout Limitations: Individual oxidant intermediates were not fully isolated. Primary reference: [Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis in vivo](https://pmc.ncbi.nlm.nih.gov/articles/PMC3107543/)
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.

When the citrulline-producing enzyme is impaired

Condition: machinery_impairment · Experimental mutation of active-site residue D263.

Normal role: OTC catalyzes formation of citrulline.

Recorded consequence: Substantial loss of OTC activity without reduced protein stability.

Scope: Purified human enzyme experiment; not a dietary deficiency.

Inherited precursor failure can lower citrulline

Condition: machinery_impairment · Homozygous ALDH18A1 R84Q in two siblings.

Normal role: P5CS supplies precursors for ornithine and arginine metabolism.

Recorded consequence: Low citrulline, ornithine, arginine and proline accompanied hyperammonemia.

Scope: Rare human genetic disorder; not a dietary citrulline-deficiency syndrome.

ASL failure blocks more than arginine production

Condition: machinery_impairment · Human or mouse ASL deficiency.

Normal role: ASL supports arginine formation and assembly of a NO-producing complex.

Recorded consequence: NO synthesis falls and use of extracellular arginine is impaired.

Scope: Inherited human disease and matched experimental models; not ordinary dietary insufficiency.

Local arginine recycling can matter despite abundant extracellular arginine

Condition: machinery_impairment · ASS1 knockdown in bovine endothelial cells.

Normal role: Endothelial ASS1 helps regenerate arginine from citrulline.

Recorded consequence: Basal and stimulated NO production decline.

Scope: Bovine cultured endothelial cells, not a human supplementation trial.

When pterin recycling fails

Condition: machinery_impairment · DHFR inhibition or knockdown.

Normal role: DHFR helps maintain reduced BH4 relative to BH2.

Recorded consequence: Lower BH4/BH2 ratio and uncoupled eNOS with less NO and more superoxide.

Scope: Experimental mouse cell systems; not a diagnosis based on folate intake.

Citrulline can bypass a specific amino-acid transport defect

Condition: machinery_impairment · Lysinuric protein intolerance impairs diamino-acid transport.

Normal role: Intestinal absorption supplies arginine and ornithine.

Recorded consequence: Citrulline absorption is preserved despite impaired arginine/ornithine uptake.

Scope: Human genetic transport disorder; downstream enzymes must still function.

Low blood citrulline can reflect reduced functioning intestine

Condition: biomarker_context · Established short-bowel syndrome after the adaptive period.

Normal role: The intestinal mucosa contributes citrulline to circulation.

Recorded consequence: Lower plasma citrulline correlated with remaining bowel length and intestinal failure.

Scope: Adult short-bowel diagnostic cohort; renal function and clinical setting still matter.

Renal disease changes how blood citrulline is interpreted

Condition: biomarker_context · End-stage renal disease.

Normal role: Kidneys participate in citrulline utilization.

Recorded consequence: Citrulline concentration and flux rose, while whole-body arginine synthesis appeared preserved.

Scope: Small human isotope study; cannot infer individual renal or vascular function from the concentration alone.

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.

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-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
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Selenium: literature corrections and mechanism additionsMetabolic Ledger literature curation, 17 September 2026; primary papers linked individually · secondary_verifiedRead preserved source
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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.

Citrulline malate and soreness: lower in one trial, higher in anotherThe primary trials reported opposite directions for postexercise soreness. They used different exercise protocols, participants, observation windows and supplement characterization. The later trial measured a 1.11:1 citrulline-to-malate ratio. These differences are candidate explanations, not demonstrated causes of the reversal; the performance null by itself is not the conflict.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.

Which transporters dominate human intestinal absorption at nutritional versus supplemental doses?Renal SLC6A19/SLC7A9 evidence cannot by itself answer the intestinal question.
Which cofactor becomes limiting for citrulline-to-arginine conversion in a particular patient?Enzyme requirements do not establish clinical thresholds or show benefit from adding cofactors in replete people.
Does citrulline provide sustained muscle gain or broadly improve exercise performance?Acute protein fractions, training protocols and formulations yield different results; these endpoints are not equivalent to long-term hypertrophy.
Is a low plasma citrulline concentration a universal indication for supplementation?Intestinal production, renal handling, utilization and inherited blocks alter the meaning of the measurement; no universal dietary deficiency rule is established.
What clinically important interactions occur with nitrates, PDE5 inhibitors or antihypertensives?A shared vasodilator pathway suggests questions to test, but this collection does not establish a quantified interaction or a dosing adjustment.
Can citrulline meaningfully improve creatine production or other arginine branches in humans?A shared arginine precursor and enzyme pathway are not a demonstrated combination or clinical outcome.
Which citrulline/cofactor combinations improve patient outcomes?Most cofactor connections are enzyme or preclinical findings. The PAD trial provides preliminary, subgroup-dependent human BH4 evidence.
How much of a citrulline response depends on local recycling rather than the blood arginine pool?ASL disease and bovine ASS1 knockdown show compartmental constraints but do not quantify them across healthy human tissues.

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-Citrulline

The mechanisms

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

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

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

Cells expressing human endothelial NOS produced bioactive NO that increased guanylate cyclase activity in cocultured reporter cells.

Purified human eNOS showed an absolute BH4 requirement for the measured catalytic reaction.

The purified human eNOS preparation contained approximately 0.56 FAD equivalents per subunit.

Recombinant human soluble guanylate cyclase converted GTP to cGMP and pyrophosphate; both products inhibited enzyme activity in the kinetic assays.

Acetyl-CoA is a substrate for human NAGS-mediated N-acetylglutamate synthesis.

5-MTHF improved eNOS coupling and increased its dimer-to-monomer ratio and activity in the human vessel study.

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

Oral citrulline increased plasma arginine AUC and peak concentration dose-dependently, more effectively than the tested oral arginine regimens.

No treatment improved FMD over baseline in the healthy-volunteer study.

Aspartate is a substrate of human ASS1 and was resolved with citrulline in the enzyme structure.

The ASS1 reaction uses ATP cleavage to AMP and pyrophosphate.

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

Human OTC converts ornithine and carbamoyl phosphate into citrulline, releasing inorganic phosphate.

Mutation of human OTC D263 substantially reduced catalysis without reducing protein stability.

N-acetylglutamate binding reshaped human CPS1 and established the channel linking its two phosphorylation sites.

CPS1 uses two ATP-dependent phosphorylation steps to convert bicarbonate and ammonia into carbamoyl phosphate.

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

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

Human P5CS links glutamate to P5C synthesis through ATP- and NADPH-dependent chemistry.

P5CS requires NADPH for its reductive step in glutamate-to-P5C synthesis.

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

Human OAT bound pyridoxal phosphate through a Schiff base to Lys292.

OAT transfers the ornithine delta-amino group to 2-oxoglutarate, yielding glutamate and glutamate semialdehyde, which cyclizes to P5C.

Reconstituted citrin exchanged aspartate for glutamate plus a proton.

Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange.

Citrin overexpression increased malate-aspartate shuttle activity in transfected human cells.

Silencing SLC6A19 reduced citrulline uptake in human HK-2 renal cells.

Silencing SLC7A9 also reduced citrulline uptake in HK-2 cells.

HK-2 citrulline uptake included two sodium-dependent saturable components and one sodium-independent component.

In glutamine-supplemented surgical patients, 91% of total citrulline turnover was attributed to glutamine.

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.

The human eNOS preparation contained approximately 0.79 FMN equivalents per subunit.

Heme and protein-bound iron were detected in purified human eNOS by independent analytical methods.

Metal analysis detected approximately 0.43 zinc equivalents per human eNOS subunit.

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

Coexpressing human calmodulin stabilized eNOS and raised its specific activity; later calmodulin addition did not reproduce the gain.

The NOS2 zinc-tetrathiolate center supported intersubunit contacts and integrity of the BH4-binding site.

ASL deficiency reduced nitric-oxide synthesis in the studied humans and mice.

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

ASS1 knockdown reduced basal and stimulated NO despite saturating arginine in the culture medium.

ASS1 knockdown increased apoptotic indicators; an NO donor prevented the associated apoptosis.

NO binding to the beta1 H-NOX region drove structural changes that increased human soluble guanylate cyclase activity.

Ascorbate increased intracellular BH4 in porcine aortic endothelial cells.

Ascorbate increased arginine-to-citrulline conversion and NO-related output in porcine endothelial cells.

Ascorbate had no additional effect at high BH4 or after sepiapterin raised cellular BH4.

5-MTHF increased vascular BH4 and its proportion of total biopterin in human vessel experiments.

5-MTHF reduced vascular superoxide; the effect was not explained by direct superoxide scavenging or changed plasma homocysteine.

DHFR knockdown decreased intracellular BH4 and increased BH2 in the cell systems.

DHFR loss increased eNOS-dependent superoxide while reducing NO production.

BH4 oxidation accompanied eNOS uncoupling with increased ROS and reduced NO in hypertensive mouse aortas.

Combined citrulline and BH4 improved pulmonary vascular resistance more than either alone in hypoxic piglets.

Combination treatment improved eNOS dimer ratios and NO production more than either single intervention.

Citrulline plasma increments after oral loads were similar in LPI homozygotes and controls, unlike diamino-acid increments.

Oral citrulline raised plasma urea-cycle intermediates more than oral arginine or ornithine in the LPI report.

At 3 g twice daily, the arginine/ADMA ratio rose from 186 to 278.

The highest citrulline regimen increased urinary cGMP from 38 to 50 nmol/mmol creatinine.

The highest regimen increased urinary nitrate from 92 to 125 micromol/mmol creatinine.

At the largest doses, plasma citrulline accumulated while arginine rose less than expected.

Less than 5% of administered citrulline was excreted in urine, even at the higher tested doses.

Plasma insulin and growth hormone were not affected by the oral citrulline loads.

Mean plasma citrulline was 20 ± 13 micromolar in short-bowel patients versus 40 ± 10 in controls.

A 20 micromolar threshold classified permanent intestinal failure with 92% sensitivity and 90% specificity in this cohort.

ESRD patients had elevated plasma citrulline and citrulline flux compared with healthy adults.

Despite reduced renal function, whole-body de novo arginine synthesis appeared preserved in the ESRD patients.

Hypoxia and/or inflammation did not reduce citrulline production during the six-hour human explant experiment.

Mixed-muscle fractional synthesis was higher with citrulline than the comparator, 0.060 versus 0.049, P=0.03.

Mitochondrial protein synthesis and whole-body protein turnover did not differ between treatments.

Adding citrulline to 15 g whey did not augment myofibrillar protein synthesis compared with the nonessential-amino-acid addition.

Despite higher arginine, blood flow and muscle microvascular perfusion did not differ between treatments.

Citrulline supplementation increased plasma citrulline seventeenfold and arginine threefold in the SBS trial.

Whole-body synthesis estimated by nonoxidative leucine disposal did not significantly change in the overall SBS group.

CM increased repetitions in later bench-press sets; the reported final-set relative gain was 52.92%.

The trial reported approximately 40% lower soreness at 24 and 48 hours with CM.