Nutrient chapter

L-Histidine

80 recorded mechanisms · 11 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.

During histidine-deficient feeding, nitrogen balance became negative and albumin decreased in six of seven participants; repletion reversed nitrogen balance in six.
L-Histidine → Nitrogen balance during controlled histidine depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days.
limitations
Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Without adequate histidine, the body could not maintain its previous protein balance.
primary_references
Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 26–32
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. · source_derived_draft · unverified_draft
## histidine-diet-nitrogen Without adequate histidine, the body could not maintain its previous protein balance. During histidine-deficient feeding, nitrogen balance became negative and albumin decreased in six of seven participants; repletion reversed nitrogen balance in six. Model: Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. Limitations: Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose. Evidence access: Primary abstract Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
Complete structured claim and evidence
Histidine-deficient feeding reduced plasma histidine by 82 +/- 6 percent and muscle histidine by 62 +/- 19 percent; both rose with repletion.
L-Histidine → Plasma and muscle histidine during controlled depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days.
limitations
Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Blood and muscle pools both fell, but by different amounts.
primary_references
Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 34–40
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. · source_derived_draft · unverified_draft
## histidine-diet-pools Blood and muscle pools both fell, but by different amounts. Histidine-deficient feeding reduced plasma histidine by 82 +/- 6 percent and muscle histidine by 62 +/- 19 percent; both rose with repletion. Model: Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. Limitations: Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose. Evidence access: Primary abstract Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
Complete structured claim and evidence
Histidine-deficient feeding lowered hematocrit by 25 +/- 9 percent while serum iron rose; repletion produced reticulocytosis, higher hematocrit and a fall in serum iron.
L-Histidine → Erythropoiesis during controlled histidine depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days.
limitations
Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose. Changes do not identify the exact iron-handling mechanism.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Red-cell production failed despite more iron in serum.
primary_references
Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 42–48
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. · source_derived_draft · unverified_draft
## histidine-diet-erythropoiesis Red-cell production failed despite more iron in serum. Histidine-deficient feeding lowered hematocrit by 25 +/- 9 percent while serum iron rose; repletion produced reticulocytosis, higher hematocrit and a fall in serum iron. Model: Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. Limitations: Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose. Changes do not identify the exact iron-handling mechanism. Evidence access: Primary abstract Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
Complete structured claim and evidence
Five participants developed scaling, dryness and mild erythema during histidine-deficient feeding; these lesions and general symptoms resolved after repletion.
L-Histidine → Skin condition during controlled histidine depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days.
limitations
Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The controlled shortage also affected skin.
primary_references
Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 50–56
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. · source_derived_draft · unverified_draft
## histidine-diet-skin The controlled shortage also affected skin. Five participants developed scaling, dryness and mild erythema during histidine-deficient feeding; these lesions and general symptoms resolved after repletion. Model: Controlled sequential metabolic-unit feeding in four healthy and three chronically uremic men; histidine-deficient amino-acid diet for 35 +/- 2 days, followed by histidine-containing diet for 31 +/- 5 days. Limitations: Small historical nonrandomized sequential study; mixed renal status and artificial diet. Does not define a universal plasma cutoff, ordinary dietary prevalence or replacement dose. Evidence access: Primary abstract Evidence that histidine is an essential amino acid in normal and chronically uremic man. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1123426/ · DOI 10.1172/JCI108016
Complete structured claim and evidence
Reconstituted human LAT1 supported histidine antiport, including exchange with internal cysteine, tyrosine or glutamine; external histidine affinity exceeded internal affinity.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → L-Histidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human SiHa extracts and purified recombinant human LAT1 in proteoliposomes.
limitations
In-vitro exchange does not establish whole-body competition or supplement ratios.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The transporter exchanges substrates, so both sides of the membrane matter.
primary_references
LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004
transport_effect
depends Recorded as antiport, including exchange with internal cysteine, tyrosine or glutamine.
transport_pool
the cytosol across the plasma membrane Recorded as antiport, including exchange with internal cysteine, tyrosine or glutamine.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 58–64
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SiHa extracts and purified recombinant human LAT1 in proteoliposomes. · source_derived_draft · unverified_draft
## histidine-lat1-exchange The transporter exchanges substrates, so both sides of the membrane matter. Reconstituted human LAT1 supported histidine antiport, including exchange with internal cysteine, tyrosine or glutamine; external histidine affinity exceeded internal affinity. Model: Human SiHa extracts and purified recombinant human LAT1 in proteoliposomes. Limitations: In-vitro exchange does not establish whole-body competition or supplement ratios. Evidence access: Primary abstract LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004
Complete structured claim and evidence
Purified human LAT1 alone transported histidine in proteoliposomes; purified CD98 alone did not.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → Transport competence of reconstituted human LAT1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human LAT1 and CD98 reconstitution.
limitations
CD98 dispensability for this assay does not mean dispensability for membrane targeting in intact tissues.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The transport pore and its partnering protein have distinct roles.
primary_references
LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 66–72
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human LAT1 and CD98 reconstitution. · source_derived_draft · unverified_draft
## histidine-lat1-subunit The transport pore and its partnering protein have distinct roles. Purified human LAT1 alone transported histidine in proteoliposomes; purified CD98 alone did not. Model: Recombinant human LAT1 and CD98 reconstitution. Limitations: CD98 dispensability for this assay does not mean dispensability for membrane targeting in intact tissues. Evidence access: Primary abstract LAT1 is the transport competent unit of the LAT1/CD98 heterodimeric amino acid transporter. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26256001/ · DOI 10.1016/j.biocel.2015.08.004
Complete structured claim and evidence
Expressed human SN2 transported histidine with sodium dependence and strong pH sensitivity; the measured histidine Km was 0.6 +/- 0.1 mM.
Human system N transporter SN2 / SLC38A5 → L-Histidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cloned human liver-cell SN2 in mammalian expression assays.
limitations
Transporter kinetics do not supply a dietary sodium or histidine target.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A second uptake system depends on the ionic and pH environment.
primary_references
Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11243884/ · DOI 10.1006/bbrc.2001.4504
transport_effect
raises Sodium-dependent histidine transport with a measured Km of 0.6 mM.
transport_pool
the expressing cell Sodium-dependent histidine transport with a measured Km of 0.6 mM.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 74–80
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cloned human liver-cell SN2 in mammalian expression assays. · source_derived_draft · unverified_draft
## histidine-sn2-uptake A second uptake system depends on the ionic and pH environment. Expressed human SN2 transported histidine with sodium dependence and strong pH sensitivity; the measured histidine Km was 0.6 +/- 0.1 mM. Model: Cloned human liver-cell SN2 in mammalian expression assays. Limitations: Transporter kinetics do not supply a dietary sodium or histidine target. Evidence access: Primary abstract Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11243884/ · DOI 10.1006/bbrc.2001.4504
Complete structured claim and evidence
Purified human LAT1 transported Cu(His)2 without the internal counter-substrate required for ordinary amino-acid antiport.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → Copper(II) bis(L-histidinate) / Cu(His)2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate.
limitations
This in-vitro uniport finding does not establish human copper delivery, safety or treatment efficacy.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Binding copper changed how the histidine-containing species crossed this transporter.
primary_references
LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37692288/ · DOI 10.1016/j.isci.2023.107738
transport_effect
raises Transported without the internal counter-substrate ordinary antiport needs, so this record is a uniport measurement.
transport_pool
the proteoliposome interior Transported without the internal counter-substrate ordinary antiport needs, so this record is a uniport measurement.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 82–88
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate. · source_derived_draft · unverified_draft
## histidine-lat1-copper-complex Binding copper changed how the histidine-containing species crossed this transporter. Purified human LAT1 transported Cu(His)2 without the internal counter-substrate required for ordinary amino-acid antiport. Model: Reconstituted human LAT1; radiotracer uptake, copper mass spectrometry and mutagenesis; representative assay 40 micromolar histidine plus 20 micromolar copper sulfate. Limitations: This in-vitro uniport finding does not establish human copper delivery, safety or treatment efficacy. Evidence access: Primary full text LAT1 (SLC7A5) catalyzes copper(histidinate) transport switching from antiport to uniport mechanism. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37692288/ · DOI 10.1016/j.isci.2023.107738
Complete structured claim and evidence
Deleting Pht1 reduced histidine uptake in mouse brain slices by about half; Pept2 expression increased approximately twofold.
Mouse peptide/histidine transporter Pht1 / Slc15a4 → Histidine uptake into mouse brain slices source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Pht1-null and matched wild-type adult mice; brain slices and transporter expression.
limitations
Genetic deletion is not dietary histidine deficiency.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Loss of one transporter altered uptake even with a compensatory response.
primary_references
A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27845049/ · DOI 10.1016/j.bcp.2016.11.012
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 90–96
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pht1-null and matched wild-type adult mice; brain slices and transporter expression. · source_derived_draft · unverified_draft
## histidine-pht1-brain-uptake Loss of one transporter altered uptake even with a compensatory response. Deleting Pht1 reduced histidine uptake in mouse brain slices by about half; Pept2 expression increased approximately twofold. Model: Pht1-null and matched wild-type adult mice; brain slices and transporter expression. Limitations: Genetic deletion is not dietary histidine deficiency. Evidence access: Primary full text A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27845049/ · DOI 10.1016/j.bcp.2016.11.012
Complete structured claim and evidence
Five minutes after intravenous histidine, Pht1-null mouse brain parenchyma contained 28-48 percent less tracer-associated histidine than wild type, despite comparable plasma time courses and no corresponding CSF difference.
Mouse peptide/histidine transporter Pht1 / Slc15a4 → Brain-parenchymal histidine after intravenous dosing source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse knockout and intravenous pharmacokinetics.
limitations
Acute tracer distribution cannot define steady-state human brain deficiency.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A normal circulating profile did not guarantee the same tissue exposure.
primary_references
A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27845049/ · DOI 10.1016/j.bcp.2016.11.012
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 98–104
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout and intravenous pharmacokinetics. · source_derived_draft · unverified_draft
## histidine-pht1-compartments A normal circulating profile did not guarantee the same tissue exposure. Five minutes after intravenous histidine, Pht1-null mouse brain parenchyma contained 28-48 percent less tracer-associated histidine than wild type, despite comparable plasma time courses and no corresponding CSF difference. Model: Mouse knockout and intravenous pharmacokinetics. Limitations: Acute tracer distribution cannot define steady-state human brain deficiency. Evidence access: Primary full text A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27845049/ · DOI 10.1016/j.bcp.2016.11.012
Complete structured claim and evidence
HAL initiates histidine degradation by converting L-histidine to trans-urocanate with ammonia release.
Human histidine ammonia-lyase / HAL → trans-Urocanate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; pathway background
experimental_model
Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.
limitations
Reaction background is distinguished from the study-specific CRISPR findings below. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The first breakdown enzyme directs histidine toward urocanate.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 106–112
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft
## histidine-hal-reaction The first breakdown enzyme directs histidine toward urocanate. HAL initiates histidine degradation by converting L-histidine to trans-urocanate with ammonia release. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: Reaction background is distinguished from the study-specific CRISPR findings below. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text; pathway background Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
UROC1 hydrates urocanate to imidazolonepropionate in the histidine degradation pathway.
Human urocanate hydratase / UROC1 → 4-Imidazolone-5-propionate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; pathway background
experimental_model
Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.
limitations
Not a claim that added histidine can bypass UROC1 loss. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A second enzyme changes urocanate into the next intermediate.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 114–120
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft
## histidine-uroc-reaction A second enzyme changes urocanate into the next intermediate. UROC1 hydrates urocanate to imidazolonepropionate in the histidine degradation pathway. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: Not a claim that added histidine can bypass UROC1 loss. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text; pathway background Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
AMDHD1 hydrolyzes imidazolonepropionate to formiminoglutamate in the histidine degradation pathway.
Human imidazolonepropionase / AMDHD1 → N-Formimino-L-glutamate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; pathway background
experimental_model
Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.
limitations
Not interchangeable with bacterial imidazole-propionate synthesis. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
This step creates FIGLU, the intermediate that links to folate.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 122–128
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft
## histidine-amdhd-reaction This step creates FIGLU, the intermediate that links to folate. AMDHD1 hydrolyzes imidazolonepropionate to formiminoglutamate in the histidine degradation pathway. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: Not interchangeable with bacterial imidazole-propionate synthesis. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text; pathway background Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
The formiminotransferase domain of FTCD transfers the formimino group from FIGLU to THF, producing 5-formimino-THF and glutamate.
Human formimidoyltransferase cyclodeaminase / FTCD → 5-Formiminotetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.
limitations
The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Folate accepts a group from a histidine-derived intermediate.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 130–136
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft
## histidine-ftcd-transfer Folate accepts a group from a histidine-derived intermediate. The formiminotransferase domain of FTCD transfers the formimino group from FIGLU to THF, producing 5-formimino-THF and glutamate. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: The existing rat FTCD biochemical claim remains a separate species-specific record. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
The cyclodeaminase domain of FTCD converts 5-formimino-THF to 5,10-methenyl-THF.
Human formimidoyltransferase cyclodeaminase / FTCD → 5,10-Methenyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme.
limitations
Two catalytic activities are separately searchable; this does not establish folate depletion in a normally nourished person. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A second activity of the same enzyme hands the group into one-carbon metabolism.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 138–144
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. · source_derived_draft · unverified_draft
## histidine-ftcd-cyclodeamination A second activity of the same enzyme hands the group into one-carbon metabolism. The cyclodeaminase domain of FTCD converts 5-formimino-THF to 5,10-methenyl-THF. Model: Established reaction in the pathway map of a primary human cancer-cell study; genetic perturbation and metabolomics investigate pathway flux rather than purified kinetics of every individual enzyme. Limitations: Two catalytic activities are separately searchable; this does not establish folate depletion in a normally nourished person. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
CRISPR depletion of FTCD reduced methotrexate sensitivity in HEL, Ramos and LAMA84 cells; an sgRNA-resistant murine Ftcd construct restored sensitivity in the rescue experiment.
Human formimidoyltransferase cyclodeaminase / FTCD → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue.
limitations
Drug-exposed culture and cross-species rescue; not evidence that histidine is universally harmful or beneficial. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Removing this histidine-processing step made the tested cancer cells less sensitive to the drug.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 146–152
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue. · source_derived_draft · unverified_draft
## histidine-ftcd-loss-mtx Removing this histidine-processing step made the tested cancer cells less sensitive to the drug. CRISPR depletion of FTCD reduced methotrexate sensitivity in HEL, Ramos and LAMA84 cells; an sgRNA-resistant murine Ftcd construct restored sensitivity in the rescue experiment. Model: Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue. Limitations: Drug-exposed culture and cross-species rescue; not evidence that histidine is universally harmful or beneficial. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls.
Human formimidoyltransferase cyclodeaminase / FTCD → Tetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing.
limitations
Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 154–160
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. · source_derived_draft · unverified_draft
## histidine-ftcd-thf-sparing Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting. Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls. Model: Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. Limitations: Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
CRISPR depletion of HAL reduced methotrexate sensitivity in the tested human cancer cells.
Human histidine ammonia-lyase / HAL → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human hematopoietic cancer-cell CRISPR experiments.
limitations
Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
An upstream histidine-breakdown step also changed drug sensitivity.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 162–168
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human hematopoietic cancer-cell CRISPR experiments. · source_derived_draft · unverified_draft
## histidine-hal-loss-mtx An upstream histidine-breakdown step also changed drug sensitivity. CRISPR depletion of HAL reduced methotrexate sensitivity in the tested human cancer cells. Model: Human hematopoietic cancer-cell CRISPR experiments. Limitations: Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells.
Human imidazolonepropionase / AMDHD1 → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human hematopoietic cancer-cell CRISPR experiments.
limitations
Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
An upstream histidine-breakdown step also changed drug sensitivity.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 170–176
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human hematopoietic cancer-cell CRISPR experiments. · source_derived_draft · unverified_draft
## histidine-amdhd-loss-mtx An upstream histidine-breakdown step also changed drug sensitivity. CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells. Model: Human hematopoietic cancer-cell CRISPR experiments. Limitations: Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment.
L-Histidine → Methotrexate response of human leukemia xenografts in mice source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.
limitations
Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Changing substrate supply strengthened a drug effect in this animal model.
primary_references
Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 178–184
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. · source_derived_draft · unverified_draft
## histidine-histidine-mtx-xenograft Changing substrate supply strengthened a drug effect in this animal model. Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment. Model: NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. Limitations: Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
Complete structured claim and evidence
A girl with urocanic aciduria carried UROC1 L70P/R450C variants; expression and activity studies supported impaired enzyme function.
Human urocanate hydratase / UROC1 → Urocanate handling in human UROC1-associated aciduria source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Single human case plus variant expression, enzyme assays and computational interpretation.
limitations
The biochemical association is stronger than attribution of every neurological feature in a single patient.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A block at the second enzyme allowed an upstream metabolite to accumulate.
primary_references
Mutations in the urocanase gene UROC1 are associated with urocanic aciduria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19304569/ · DOI 10.1136/jmg.2008.060632
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 186–192
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single human case plus variant expression, enzyme assays and computational interpretation. · source_derived_draft · unverified_draft
## histidine-uroc-human-loss A block at the second enzyme allowed an upstream metabolite to accumulate. A girl with urocanic aciduria carried UROC1 L70P/R450C variants; expression and activity studies supported impaired enzyme function. Model: Single human case plus variant expression, enzyme assays and computational interpretation. Limitations: The biochemical association is stronger than attribution of every neurological feature in a single patient. Evidence access: Primary abstract Mutations in the urocanase gene UROC1 are associated with urocanic aciduria. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19304569/ · DOI 10.1136/jmg.2008.060632
Complete structured claim and evidence
Among 18 newborn-screen-detected FTCD-deficient patients, most were asymptomatic at mean 56-month follow-up; 3/18 had educationally significant developmental delay and 4/16 mild self-limited anemia.
Human FTCD deficiency → N-Formimino-L-glutamate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Retrospective two-center newborn-screen cohort.
limitations
Ascertainment differs from early severe case series; follow-up is limited and this does not exclude later or rare severe effects. Correction record: The 2019 publisher erratum corrects patient 4 genotypes to c.1366dupG (p.E456Gfs*56) and c.236A>C (p.Q79P). The imported cohort-outcome claim does not use the erroneous genotype labels. https://onlinelibrary.wiley.com/doi/10.1002/jimd.12145
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A biochemical processing defect did not uniformly produce severe disease.
primary_references
Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30740726/ · DOI 10.1002/jimd.12035
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 194–200
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Retrospective two-center newborn-screen cohort. · source_derived_draft · unverified_draft
## histidine-ftcd-screening-spectrum A biochemical processing defect did not uniformly produce severe disease. Among 18 newborn-screen-detected FTCD-deficient patients, most were asymptomatic at mean 56-month follow-up; 3/18 had educationally significant developmental delay and 4/16 mild self-limited anemia. Model: Retrospective two-center newborn-screen cohort. Limitations: Ascertainment differs from early severe case series; follow-up is limited and this does not exclude later or rare severe effects. Correction record: The 2019 publisher erratum corrects patient 4 genotypes to c.1366dupG (p.E456Gfs*56) and c.236A>C (p.Q79P). The imported cohort-outcome claim does not use the erroneous genotype labels. https://onlinelibrary.wiley.com/doi/10.1002/jimd.12145 Evidence access: Primary abstract Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30740726/ · DOI 10.1002/jimd.12035
Complete structured claim and evidence
Long-term follow-up of screen-detected histidinemia found normal growth, no relation of plasma histidine to DQ/IQ and no apparent benefit from early low-histidine diet.
Human histidinemia → Development and growth in screen-detected histidinemia source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
113 detected children, nine lost to follow-up; 47 historically treated before 1981, others untreated.
limitations
Observational and nonrandom treatment allocation; not a general high-dose supplement safety study.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Higher histidine from slow breakdown did not by itself predict developmental impairment in this cohort.
primary_references
Histidinaemia: a benign metabolic disorder. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8669938/ · DOI 10.1136/adc.74.4.343
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 202–208
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 113 detected children, nine lost to follow-up; 47 historically treated before 1981, others untreated. · source_derived_draft · unverified_draft
## histidine-histidinemia-followup Higher histidine from slow breakdown did not by itself predict developmental impairment in this cohort. Long-term follow-up of screen-detected histidinemia found normal growth, no relation of plasma histidine to DQ/IQ and no apparent benefit from early low-histidine diet. Model: 113 detected children, nine lost to follow-up; 47 historically treated before 1981, others untreated. Limitations: Observational and nonrandom treatment allocation; not a general high-dose supplement safety study. Evidence access: Primary abstract Histidinaemia: a benign metabolic disorder. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8669938/ · DOI 10.1136/adc.74.4.343
Complete structured claim and evidence
Human HNMT methylates histamine using SAM; structural complexes locate histamine and the reaction product SAH at the enzyme.
Human histamine N-methyltransferase / HNMT → N-tau-Methylhistamine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified recombinant human enzyme; ternary structures and steady-state kinetics.
limitations
A shared SAM requirement does not prove clinically important methyl depletion from histamine turnover.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Histamine disposal connects to the cellular methyl-donor system.
primary_references
Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 210–216
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified recombinant human enzyme; ternary structures and steady-state kinetics. · source_derived_draft · unverified_draft
## histidine-hnmt-methylation Histamine disposal connects to the cellular methyl-donor system. Human HNMT methylates histamine using SAM; structural complexes locate histamine and the reaction product SAH at the enzyme. Model: Purified recombinant human enzyme; ternary structures and steady-state kinetics. Limitations: A shared SAM requirement does not prove clinically important methyl depletion from histamine turnover. Evidence access: Primary abstract Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8
Complete structured claim and evidence
Recombinant Ile105 HNMT had about 16 percent lower specific activity and higher apparent Km for SAM and histamine than Thr105 across 25-45 degrees C.
Human HNMT Thr105Ile variation → Human histamine N-methyltransferase / HNMT source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human recombinant enzyme comparison.
limitations
Results paragraph reports increased Km; the abstract conclusion says lowered Km. Numerical results are retained as a source wording discrepancy, not two independent experiments. No clinical symptom prediction.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A common enzyme variant changed the measured reaction kinetics.
primary_references
Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 218–224
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant enzyme comparison. · source_derived_draft · unverified_draft
## histidine-hnmt-variant A common enzyme variant changed the measured reaction kinetics. Recombinant Ile105 HNMT had about 16 percent lower specific activity and higher apparent Km for SAM and histamine than Thr105 across 25-45 degrees C. Model: Human recombinant enzyme comparison. Limitations: Results paragraph reports increased Km; the abstract conclusion says lowered Km. Numerical results are retained as a source wording discrepancy, not two independent experiments. No clinical symptom prediction. Evidence access: Primary abstract Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11566133/ · DOI 10.1016/s0969-2126(01)00643-8
Complete structured claim and evidence
Histamine-bound human H1 receptor was resolved with an engineered Gq-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling.
Histamine → Human histamine H1 receptor / HRH1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays.
limitations
Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The same histidine-derived messenger can activate a distinct receptor route.
primary_references
Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 226–232
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. · source_derived_draft · unverified_draft
## histidine-h1-activation The same histidine-derived messenger can activate a distinct receptor route. Histamine-bound human H1 receptor was resolved with an engineered Gq-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling. Model: Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. Limitations: Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response. Evidence access: Primary full text Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
Complete structured claim and evidence
Histamine-bound human H2 receptor was resolved with an engineered Gs-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling.
Histamine → Human histamine H2 receptor / HRH2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays.
limitations
Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The same histidine-derived messenger can activate a distinct receptor route.
primary_references
Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 234–240
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. · source_derived_draft · unverified_draft
## histidine-h2-activation The same histidine-derived messenger can activate a distinct receptor route. Histamine-bound human H2 receptor was resolved with an engineered Gs-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling. Model: Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. Limitations: Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response. Evidence access: Primary full text Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
Complete structured claim and evidence
Histamine-bound human H3 receptor was resolved with an engineered Gi-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling.
Histamine → Human histamine H3 receptor / HRH3 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays.
limitations
Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The same histidine-derived messenger can activate a distinct receptor route.
primary_references
Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 242–248
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. · source_derived_draft · unverified_draft
## histidine-h3-activation The same histidine-derived messenger can activate a distinct receptor route. Histamine-bound human H3 receptor was resolved with an engineered Gi-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling. Model: Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. Limitations: Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response. Evidence access: Primary full text Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
Complete structured claim and evidence
Histamine-bound human H4 receptor was resolved with an engineered Gi-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling.
Histamine → Human histamine H4 receptor / HRH4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays.
limitations
Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The same histidine-derived messenger can activate a distinct receptor route.
primary_references
Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 250–256
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. · source_derived_draft · unverified_draft
## histidine-h4-activation The same histidine-derived messenger can activate a distinct receptor route. Histamine-bound human H4 receptor was resolved with an engineered Gi-family protein complex, with binding and functional mutagenesis supporting ligand recognition and coupling. Model: Engineered human receptor complexes produced in insect cells, cryo-EM and HEK293 binding/G-protein assays. Limitations: Structural stabilization, chimeric/mini G proteins and recombinant cells differ from native tissues; receptor engagement is not proof that oral histidine produces this response. Evidence access: Primary full text Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
Complete structured claim and evidence
Human H2 receptor W222A/V mutations abolished measured Gs activation while retaining Gq responses; the structural Gq complex used a G-alpha-s/q chimera.
Human histamine H2 receptor / HRH2 → Human H2 receptor Gq coupling source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Recombinant human receptor mutagenesis and G-protein dissociation assays.
limitations
Do not label H2 as exclusively Gs-coupled; chimera-supported structure and native Gq signaling are distinct evidence types.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A receptor can use more than one signaling partner, with separable structural requirements.
primary_references
Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 258–264
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human receptor mutagenesis and G-protein dissociation assays. · source_derived_draft · unverified_draft
## histidine-h2-coupling-selectivity A receptor can use more than one signaling partner, with separable structural requirements. Human H2 receptor W222A/V mutations abolished measured Gs activation while retaining Gq responses; the structural Gq complex used a G-alpha-s/q chimera. Model: Recombinant human receptor mutagenesis and G-protein dissociation assays. Limitations: Do not label H2 as exclusively Gs-coupled; chimera-supported structure and native Gq signaling are distinct evidence types. Evidence access: Primary full text Structural basis of ligand recognition and activation of the histamine receptor family. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39333117/ · DOI 10.1038/s41467-024-52585-y
Complete structured claim and evidence
Full-length and two-domain S. oneidensis UrdA converted urocanate to imidazole propionate and did not show the tested fumarate-reductase activity.
Shewanella oneidensis MR-1 urocanate reductase / UrdA → Imidazole propionate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Purified bacterial full-length/truncated proteins, activity assays and ligand-bound crystal structures.
limitations
This species is a structural model; abundance or flux in an individual human microbiome is not measured.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A bacterial enzyme sends a histidine-derived intermediate down a different branch.
primary_references
Structural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33649331/ · DOI 10.1038/s41467-021-21548-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 266–272
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial full-length/truncated proteins, activity assays and ligand-bound crystal structures. · source_derived_draft · unverified_draft
## histidine-urda-product A bacterial enzyme sends a histidine-derived intermediate down a different branch. Full-length and two-domain S. oneidensis UrdA converted urocanate to imidazole propionate and did not show the tested fumarate-reductase activity. Model: Purified bacterial full-length/truncated proteins, activity assays and ligand-bound crystal structures. Limitations: This species is a structural model; abundance or flux in an individual human microbiome is not measured. Evidence access: Primary full text Structural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33649331/ · DOI 10.1038/s41467-021-21548-y
Complete structured claim and evidence
The UrdA catalytic-domain structures contained FAD alongside substrate or product, and assays supported flavin-associated urocanate reduction.
FAD → Shewanella oneidensis MR-1 urocanate reductase / UrdA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Bacterial structural enzymology; FAD-supplemented enzyme assays.
limitations
Does not show that human riboflavin intake limits or increases microbial imidazole-propionate production.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
This microbial reaction uses a riboflavin-derived chemical tool.
primary_references
Structural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33649331/ · DOI 10.1038/s41467-021-21548-y
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 274–280
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bacterial structural enzymology; FAD-supplemented enzyme assays. · source_derived_draft · unverified_draft
## histidine-urda-flavin This microbial reaction uses a riboflavin-derived chemical tool. The UrdA catalytic-domain structures contained FAD alongside substrate or product, and assays supported flavin-associated urocanate reduction. Model: Bacterial structural enzymology; FAD-supplemented enzyme assays. Limitations: Does not show that human riboflavin intake limits or increases microbial imidazole-propionate production. Evidence access: Primary full text Structural characterization of the microbial enzyme urocanate reductase mediating imidazole propionate production. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33649331/ · DOI 10.1038/s41467-021-21548-y
Complete structured claim and evidence
Fecal microbiota from donors with type 2 diabetes generated more imidazole propionate from histidine in the gut simulator than microbiota from donors without diabetes.
L-Histidine → Imidazole propionate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human-donor fecal communities in a gut simulator.
limitations
Ex-vivo community behavior is not a controlled human histidine-feeding outcome.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The same substrate produced different output with different microbial communities.
primary_references
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 282–288
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-donor fecal communities in a gut simulator. · source_derived_draft · unverified_draft
## histidine-microbial-imp-generation The same substrate produced different output with different microbial communities. Fecal microbiota from donors with type 2 diabetes generated more imidazole propionate from histidine in the gut simulator than microbiota from donors without diabetes. Model: Human-donor fecal communities in a gut simulator. Limitations: Ex-vivo community behavior is not a controlled human histidine-feeding outcome. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
Complete structured claim and evidence
Circulating imidazole propionate was higher in the studied people with type 2 diabetes than comparison participants.
Imidazole propionate → Circulating imidazole propionate in type 2 diabetes source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human observational metabolomics.
limitations
Association alone does not establish direction, causality or an individual diagnostic threshold.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A histidine-derived microbial metabolite tracked a metabolic phenotype.
primary_references
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 290–296
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human observational metabolomics. · source_derived_draft · unverified_draft
## histidine-imp-human-association A histidine-derived microbial metabolite tracked a metabolic phenotype. Circulating imidazole propionate was higher in the studied people with type 2 diabetes than comparison participants. Model: Human observational metabolomics. Limitations: Association alone does not establish direction, causality or an individual diagnostic threshold. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
Complete structured claim and evidence
Administering imidazole propionate impaired glucose tolerance in the reported mouse experiments.
Imidazole propionate → Glucose tolerance after imidazole-propionate administration in mice source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse metabolite-administration study; dose details not extracted from accessed primary abstract.
limitations
Not a dietary-histidine intervention or a demonstrated human clinical effect.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Giving the microbial product affected glucose control in an animal experiment.
primary_references
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 298–304
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse metabolite-administration study; dose details not extracted from accessed primary abstract. · source_derived_draft · unverified_draft
## histidine-imp-mouse-tolerance Giving the microbial product affected glucose control in an animal experiment. Administering imidazole propionate impaired glucose tolerance in the reported mouse experiments. Model: Mouse metabolite-administration study; dose details not extracted from accessed primary abstract. Limitations: Not a dietary-histidine intervention or a demonstrated human clinical effect. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
Complete structured claim and evidence
The 2018 study linked imidazole-propionate-activated p38-gamma to p62 phosphorylation.
p38-gamma assay protein in the 2018 ImP study; species unresolved in accessed abstract → p62 assay protein in the 2018 ImP study; species unresolved in accessed abstract source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Biochemical/cellular experiments summarized in the primary abstract; study also contains mouse intervention and human observations.
limitations
The abstract does not resolve species and construct for each biochemical step; assay proteins are not silently assigned human identity.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A kinase relays the microbial-metabolite signal to an adaptor protein.
primary_references
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 306–312
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical/cellular experiments summarized in the primary abstract; study also contains mouse intervention and human observations. · source_derived_draft · unverified_draft
## histidine-imp-p38-p62 A kinase relays the microbial-metabolite signal to an adaptor protein. The 2018 study linked imidazole-propionate-activated p38-gamma to p62 phosphorylation. Model: Biochemical/cellular experiments summarized in the primary abstract; study also contains mouse intervention and human observations. Limitations: The abstract does not resolve species and construct for each biochemical step; assay proteins are not silently assigned human identity. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
Complete structured claim and evidence
The study connected p62 phosphorylation to mTORC1 activation and impaired signaling at insulin receptor substrate.
p62 assay protein in the 2018 ImP study; species unresolved in accessed abstract → Mechanistic target of rapamycin complex 1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Primary abstract-level biochemical/cellular pathway report.
limitations
Complete construct, dose and cell-specific mapping remains a follow-up; this route is distinct from ordinary dietary histidine intake.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The adaptor connects this branch to nutrient-sensitive signaling and insulin response.
primary_references
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 314–320
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary abstract-level biochemical/cellular pathway report. · source_derived_draft · unverified_draft
## histidine-imp-p62-mtor The adaptor connects this branch to nutrient-sensitive signaling and insulin response. The study connected p62 phosphorylation to mTORC1 activation and impaired signaling at insulin receptor substrate. Model: Primary abstract-level biochemical/cellular pathway report. Limitations: Complete construct, dose and cell-specific mapping remains a follow-up; this route is distinct from ordinary dietary histidine intake. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055
Complete structured claim and evidence
In HEK293 experiments, imidazole propionate increased basal Akt phosphorylation; p38-gamma knockdown blocked the Akt and inhibitory AMPK phosphorylation responses.
Imidazole propionate → AKT serine/threonine kinase family source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation.
limitations
Basal activation differs from insulin-stimulated activation. Recombinant assay construct species is not inferred from the human host cells.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A microbial product changed a kinase pathway, and removing one kinase interrupted the response.
primary_references
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 322–328
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation. · source_derived_draft · unverified_draft
## histidine-imp-akt A microbial product changed a kinase pathway, and removing one kinase interrupted the response. In HEK293 experiments, imidazole propionate increased basal Akt phosphorylation; p38-gamma knockdown blocked the Akt and inhibitory AMPK phosphorylation responses. Model: Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation. Limitations: Basal activation differs from insulin-stimulated activation. Recombinant assay construct species is not inferred from the human host cells. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
Complete structured claim and evidence
In HEK293 cells, imidazole propionate suppressed metformin-induced AMPK activation; expression of the study-labeled AMPK S485A mutant prevented suppression of activating T172 phosphorylation.
Imidazole propionate → Human AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
HEK293 expression and phosphorylation assays; the paper labels the construct site S485.
limitations
Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Changing the inhibitory phosphorylation site interrupted the measured drug interaction.
primary_references
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 330–336
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · HEK293 expression and phosphorylation assays; the paper labels the construct site S485. · source_derived_draft · unverified_draft
## histidine-imp-ampk Changing the inhibitory phosphorylation site interrupted the measured drug interaction. In HEK293 cells, imidazole propionate suppressed metformin-induced AMPK activation; expression of the study-labeled AMPK S485A mutant prevented suppression of activating T172 phosphorylation. Model: HEK293 expression and phosphorylation assays; the paper labels the construct site S485. Limitations: Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
Complete structured claim and evidence
The study distinguished p38-gamma-dependent basal Akt activation from mTORC1-dependent IRS loss; direct mTORC2 activation was not detected in the tested kinase assay.
Imidazole propionate → Imidazole-propionate-dependent basal Akt pathway source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human-cell signaling, kinase assays and inhibitor/knockdown experiments.
limitations
Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Two routes from the same metabolite have different timing and intermediates.
primary_references
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 338–344
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell signaling, kinase assays and inhibitor/knockdown experiments. · source_derived_draft · unverified_draft
## histidine-imp-mtor-boundary Two routes from the same metabolite have different timing and intermediates. The study distinguished p38-gamma-dependent basal Akt activation from mTORC1-dependent IRS loss; direct mTORC2 activation was not detected in the tested kinase assay. Model: Human-cell signaling, kinase assays and inhibitor/knockdown experiments. Limitations: Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
Complete structured claim and evidence
Imidazole-propionate pretreatment prevented the measured glucose-lowering response to metformin in mice.
Imidazole propionate → Glucose-lowering response to metformin in mice source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Mouse pretreatment and metformin experiments; separate from observational human plasma data.
limitations
Not evidence that histidine supplementation causes metformin failure in humans.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A microbial metabolite changed a drug response in an animal model.
primary_references
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 346–352
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse pretreatment and metformin experiments; separate from observational human plasma data. · source_derived_draft · unverified_draft
## histidine-imp-mouse-metformin A microbial metabolite changed a drug response in an animal model. Imidazole-propionate pretreatment prevented the measured glucose-lowering response to metformin in mice. Model: Mouse pretreatment and metformin experiments; separate from observational human plasma data. Limitations: Not evidence that histidine supplementation causes metformin failure in humans. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
Complete structured claim and evidence
Metformin-treated participants with high blood glucose had higher circulating imidazole propionate in the observational comparison.
Imidazole propionate → Poor glucose control among metformin-treated participants source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human type 2 diabetes plasma comparison.
limitations
Confounding and reverse causation remain possible; no randomized metabolite or histidine intervention.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The human association is consistent with a hypothesis but does not test the mechanism.
primary_references
Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 354–360
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human type 2 diabetes plasma comparison. · source_derived_draft · unverified_draft
## histidine-imp-human-metformin The human association is consistent with a hypothesis but does not test the mechanism. Metformin-treated participants with high blood glucose had higher circulating imidazole propionate in the observational comparison. Model: Human type 2 diabetes plasma comparison. Limitations: Confounding and reverse causation remain possible; no randomized metabolite or histidine intervention. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012
Complete structured claim and evidence
Slc15a4 loss disturbed mouse B-cell endolysosomal pH regulation and was associated with disrupted mTOR signaling and the IRF7/type-I-interferon circuit.
Mouse peptide/histidine transporter Pht1 / Slc15a4 → Endolysosomal pH regulation in mouse B cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse B-cell genetic experiments and lupus model.
limitations
v-ATPase integrity was proposed rather than definitively established as the sole cause. Histidine intake was not the manipulation.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Losing a transporter-associated system changed the local organelle environment and immune signaling.
primary_references
The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25238095/ · DOI 10.1016/j.immuni.2014.08.011
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 362–368
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse B-cell genetic experiments and lupus model. · source_derived_draft · unverified_draft
## histidine-slc15a4-mouse-ph Losing a transporter-associated system changed the local organelle environment and immune signaling. Slc15a4 loss disturbed mouse B-cell endolysosomal pH regulation and was associated with disrupted mTOR signaling and the IRF7/type-I-interferon circuit. Model: Mouse B-cell genetic experiments and lupus model. Limitations: v-ATPase integrity was proposed rather than definitively established as the sole cause. Histidine intake was not the manipulation. Evidence access: Primary abstract The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25238095/ · DOI 10.1016/j.immuni.2014.08.011
Complete structured claim and evidence
Mouse experiments attributed TLR-triggered cytokine production to functional Slc15a4 transport and linked Slc15a4 loss with reduced pathogenic antibody production.
Mouse peptide/histidine transporter Pht1 / Slc15a4 → TLR7-induced interferon and antibody output in mouse B cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse genetic/transport-function study.
limitations
Later human TASL-tethering experiments provide a scaffold bypass; this is not proof that dietary histidine controls autoimmunity.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The original model linked transporter function with the immune response.
primary_references
The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25238095/ · DOI 10.1016/j.immuni.2014.08.011
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 370–376
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic/transport-function study. · source_derived_draft · unverified_draft
## histidine-slc15a4-mouse-cytokines The original model linked transporter function with the immune response. Mouse experiments attributed TLR-triggered cytokine production to functional Slc15a4 transport and linked Slc15a4 loss with reduced pathogenic antibody production. Model: Mouse genetic/transport-function study. Limitations: Later human TASL-tethering experiments provide a scaffold bypass; this is not proof that dietary histidine controls autoimmunity. Evidence access: Primary abstract The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25238095/ · DOI 10.1016/j.immuni.2014.08.011
Complete structured claim and evidence
Human SLC15A4 interacted with TASL and was required for its endolysosomal localization and function in the tested cells.
Human peptide/histidine transporter PHT1 / SLC15A4 → Human TLR adaptor interacting with SLC15A4 / TASL source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Primary and transformed human immune cells; interaction mapping and mutagenesis.
limitations
Docking does not prove that the amount of histidine transported is the limiting signal.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The transporter also serves as a docking location for a signaling adaptor.
primary_references
TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 378–384
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary and transformed human immune cells; interaction mapping and mutagenesis. · source_derived_draft · unverified_draft
## histidine-tasl-recruitment The transporter also serves as a docking location for a signaling adaptor. Human SLC15A4 interacted with TASL and was required for its endolysosomal localization and function in the tested cells. Model: Primary and transformed human immune cells; interaction mapping and mutagenesis. Limitations: Docking does not prove that the amount of histidine transported is the limiting signal. Evidence access: Primary full text TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
Complete structured claim and evidence
The conserved TASL pLxIS motif mediated recruitment and activation of IRF5 downstream of endolysosomal TLR7/8/9 stimulation.
Human TLR adaptor interacting with SLC15A4 / TASL → Human interferon regulatory factor 5 / IRF5 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human immune-cell mutagenesis and signaling experiments.
limitations
A shared transporter node does not establish a nutritional intervention.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
An adaptor connects the membrane-associated system to a transcription factor.
primary_references
TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 386–392
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human immune-cell mutagenesis and signaling experiments. · source_derived_draft · unverified_draft
## histidine-tasl-irf5 An adaptor connects the membrane-associated system to a transcription factor. The conserved TASL pLxIS motif mediated recruitment and activation of IRF5 downstream of endolysosomal TLR7/8/9 stimulation. Model: Human immune-cell mutagenesis and signaling experiments. Limitations: A shared transporter node does not establish a nutritional intervention. Evidence access: Primary full text TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
Complete structured claim and evidence
Deleting TASL or SLC15A4 impaired the IRF response without abolishing the measured NF-kappaB or MAPK responses.
Human TLR adaptor interacting with SLC15A4 / TASL → Human endolysosomal TLR IRF signaling source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human immune-cell deletion experiments.
limitations
Does not imply all immune function is lost or a global histidine shortage.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Loss of the system selectively disrupted one signaling branch.
primary_references
TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 394–400
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human immune-cell deletion experiments. · source_derived_draft · unverified_draft
## histidine-tasl-loss-selectivity Loss of the system selectively disrupted one signaling branch. Deleting TASL or SLC15A4 impaired the IRF response without abolishing the measured NF-kappaB or MAPK responses. Model: Human immune-cell deletion experiments. Limitations: Does not imply all immune function is lost or a global histidine shortage. Evidence access: Primary full text TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32433612/ · DOI 10.1038/s41586-020-2282-0
Complete structured claim and evidence
Artificially tethering TASL to endolysosomes restored TLR7-9-induced IRF5 activation and interferon/cytokine production in SLC15A4-deficient human cells.
Human TLR adaptor interacting with SLC15A4 / TASL → Human endolysosomal TLR IRF signaling source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Engineered human-cell localization/rescue experiments.
limitations
Shows transport is dispensable with this bypass; does not show native transport is irrelevant in every cell, or replicate mouse IRF7 experiments under identical conditions.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A targeted scaffold bypass restored signaling without the transporter.
primary_references
SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37527038/ · DOI 10.1016/j.celrep.2023.112916
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 402–408
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered human-cell localization/rescue experiments. · source_derived_draft · unverified_draft
## histidine-tasl-bypass A targeted scaffold bypass restored signaling without the transporter. Artificially tethering TASL to endolysosomes restored TLR7-9-induced IRF5 activation and interferon/cytokine production in SLC15A4-deficient human cells. Model: Engineered human-cell localization/rescue experiments. Limitations: Shows transport is dispensable with this bypass; does not show native transport is irrelevant in every cell, or replicate mouse IRF7 experiments under identical conditions. Evidence access: Primary abstract SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37527038/ · DOI 10.1016/j.celrep.2023.112916
Complete structured claim and evidence
Adding L-histidine increased filaggrin monomer formation in the reported human keratinocyte/skin-equivalent experiments.
L-Histidine → Human filaggrin / FLG source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human keratinocyte differentiation and skin-equivalent models.
limitations
Culture response does not prove all eczema reflects histidine shortage or that FLG null variants can be repaired; one author was a director of a patent-owning company.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
More available substrate changed a skin-protein processing readout in culture.
primary_references
Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 410–416
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human keratinocyte differentiation and skin-equivalent models. · source_derived_draft · unverified_draft
## histidine-skin-flg-processing More available substrate changed a skin-protein processing readout in culture. Adding L-histidine increased filaggrin monomer formation in the reported human keratinocyte/skin-equivalent experiments. Model: Human keratinocyte differentiation and skin-equivalent models. Limitations: Culture response does not prove all eczema reflects histidine shortage or that FLG null variants can be repaired; one author was a director of a patent-owning company. Evidence access: Primary full text Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
Complete structured claim and evidence
Histidine supplementation improved the measured barrier readout in human skin-equivalent experiments.
L-Histidine → Barrier function in human skin-equivalent culture source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human skin-equivalent in-vitro assay.
limitations
Separate from oral clinical outcomes; no direct proof of the entire mediation chain in patients.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
The culture study also measured a functional barrier outcome.
primary_references
Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 418–424
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human skin-equivalent in-vitro assay. · source_derived_draft · unverified_draft
## histidine-skin-barrier The culture study also measured a functional barrier outcome. Histidine supplementation improved the measured barrier readout in human skin-equivalent experiments. Model: Human skin-equivalent in-vitro assay. Limitations: Separate from oral clinical outcomes; no direct proof of the entire mediation chain in patients. Evidence access: Primary full text Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
Complete structured claim and evidence
A 24-adult randomized blinded crossover pilot reported lower SCORAD and POEM after four weeks of 4 g/day oral histidine, with no corresponding improvement on placebo.
L-Histidine → Atopic-dermatitis scores in the histidine pilot source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Adult atopic-dermatitis pilot; 4 g histidine or erythritol daily, crossover after eight weeks.
limitations
Small pilot, carryover and generalizability limitations; patent/company interest disclosed. The culture mechanism was not proven to mediate the clinical change.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A small human study reported symptom-score improvement.
primary_references
Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 426–432
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Adult atopic-dermatitis pilot; 4 g histidine or erythritol daily, crossover after eight weeks. · source_derived_draft · unverified_draft
## histidine-skin-pilot A small human study reported symptom-score improvement. A 24-adult randomized blinded crossover pilot reported lower SCORAD and POEM after four weeks of 4 g/day oral histidine, with no corresponding improvement on placebo. Model: Adult atopic-dermatitis pilot; 4 g histidine or erythritol daily, crossover after eight weeks. Limitations: Small pilot, carryover and generalizability limitations; patent/company interest disclosed. The culture mechanism was not proven to mediate the clinical change. Evidence access: Primary full text Feeding filaggrin: effects of l-histidine supplementation in atopic dermatitis. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29042806/ · DOI 10.2147/CCID.S146760
Complete structured claim and evidence
UV exposure converted trans-urocanic-acid standard to cis isomer; UVB produced faster conversion than UVA under the tested conditions.
trans-Urocanate → cis-Urocanate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
In-vitro standards plus analytical measurement of histidine and urocanate isomers in skin washes from eight volunteers.
limitations
Photochemistry in standards does not establish a clinical sunscreen effect from oral histidine.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Light changes the shape of a histidine-derived skin molecule.
primary_references
Determination of histidine and urocanic acid isomers in the human skin by high-performance capillary electrophoresis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11129077/ · DOI 10.1016/s0378-4347(00)00376-5
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 434–440
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · In-vitro standards plus analytical measurement of histidine and urocanate isomers in skin washes from eight volunteers. · source_derived_draft · unverified_draft
## histidine-urocanate-uv Light changes the shape of a histidine-derived skin molecule. UV exposure converted trans-urocanic-acid standard to cis isomer; UVB produced faster conversion than UVA under the tested conditions. Model: In-vitro standards plus analytical measurement of histidine and urocanate isomers in skin washes from eight volunteers. Limitations: Photochemistry in standards does not establish a clinical sunscreen effect from oral histidine. Evidence access: Primary abstract Determination of histidine and urocanic acid isomers in the human skin by high-performance capillary electrophoresis. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11129077/ · DOI 10.1016/s0378-4347(00)00376-5
Complete structured claim and evidence
Histidase-deficient Peruvian mice retained skin-surface pH similar to matched controls.
Mouse histidine ammonia-lyase / Hal → Mouse stratum-corneum surface acidity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse histidase-deficiency comparison; surface pH measurement.
limitations
Does not negate urocanate chemistry or human skin-equivalent effects; distinct endpoint, species and manipulation.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Other systems could preserve skin acidity when this histidine-processing enzyme was absent.
primary_references
Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? · 2010 · https://pubmed.ncbi.nlm.nih.gov/20376063/ · DOI 10.1038/jid.2010.74
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 442–448
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse histidase-deficiency comparison; surface pH measurement. · source_derived_draft · unverified_draft
## histidine-skin-ph-redundancy Other systems could preserve skin acidity when this histidine-processing enzyme was absent. Histidase-deficient Peruvian mice retained skin-surface pH similar to matched controls. Model: Mouse histidase-deficiency comparison; surface pH measurement. Limitations: Does not negate urocanate chemistry or human skin-equivalent effects; distinct endpoint, species and manipulation. Evidence access: Primary full text Is the filaggrin-histidine-urocanic acid pathway essential for stratum corneum acidification? · 2010 · https://pubmed.ncbi.nlm.nih.gov/20376063/ · DOI 10.1038/jid.2010.74
Complete structured claim and evidence
In a randomized blinded trial of 100 obese women with metabolic syndrome, 4 g/day histidine for 12 weeks reduced HOMA-IR relative to placebo among 92 completers.
L-Histidine → HOMA-IR in the histidine metabolic-syndrome trial source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Women aged 33-51; 50 assigned per arm, 45 histidine and 47 placebo completed.
limitations
HOMA-IR is a surrogate; one population and duration. Separate adipocyte experiments do not prove the human mechanism; not a contradiction of isolated microbial-metabolite administration.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A human trial measured improved insulin-resistance-related outcomes in a selected group.
primary_references
Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23361591/ · DOI 10.1007/s00125-013-2839-7
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 450–456
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Women aged 33-51; 50 assigned per arm, 45 histidine and 47 placebo completed. · source_derived_draft · unverified_draft
## histidine-metabolic-human-trial A human trial measured improved insulin-resistance-related outcomes in a selected group. In a randomized blinded trial of 100 obese women with metabolic syndrome, 4 g/day histidine for 12 weeks reduced HOMA-IR relative to placebo among 92 completers. Model: Women aged 33-51; 50 assigned per arm, 45 histidine and 47 placebo completed. Limitations: HOMA-IR is a surrogate; one population and duration. Separate adipocyte experiments do not prove the human mechanism; not a contradiction of isolated microbial-metabolite administration. Evidence access: Primary abstract Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23361591/ · DOI 10.1007/s00125-013-2839-7
Complete structured claim and evidence
HARS1 ligates histidine to its cognate tRNA for protein synthesis.
Human cytosolic histidyl-tRNA synthetase / HARS1 → Human cytosolic histidyl-tRNA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Established enzymatic role in a primary HARS variant study.
limitations
Background chemistry rather than a new dietary intervention.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A charging enzyme connects free histidine to the protein-building machinery.
primary_references
A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 458–464
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established enzymatic role in a primary HARS variant study. · source_derived_draft · unverified_draft
## histidine-hars-charging A charging enzyme connects free histidine to the protein-building machinery. HARS1 ligates histidine to its cognate tRNA for protein synthesis. Model: Established enzymatic role in a primary HARS variant study. Limitations: Background chemistry rather than a new dietary intervention. Evidence access: Primary full text A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210
Complete structured claim and evidence
HARS1 Arg137Gln identified in a neuropathy screen showed loss of function in yeast complementation and neuronal toxicity in a worm expression model.
Human HARS1 Arg137Gln variant → Human cytosolic histidyl-tRNA synthetase / HARS1 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human variant discovery, orthologous yeast complementation and C. elegans functional assays.
limitations
The variant also occurred in additional sequenced people; functional findings do not establish penetrance or an effective histidine treatment.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
A defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix.
primary_references
A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 466–472
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human variant discovery, orthologous yeast complementation and C. elegans functional assays. · source_derived_draft · unverified_draft
## histidine-hars-variant A defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix. HARS1 Arg137Gln identified in a neuropathy screen showed loss of function in yeast complementation and neuronal toxicity in a worm expression model. Model: Human variant discovery, orthologous yeast complementation and C. elegans functional assays. Limitations: The variant also occurred in additional sequenced people; functional findings do not establish penetrance or an effective histidine treatment. Evidence access: Primary full text A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210
Complete structured claim and evidence
HARS2 provides histidyl-tRNA for mitochondrial translation; L200V and V368L variants reduced aminoacylation in the study assays.
Human mitochondrial histidyl-tRNA synthetase / HARS2 → Human mitochondrial histidyl-tRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human family study with recombinant activity, transcript analysis and yeast/worm experiments.
limitations
Background role and measured variant impairment are distinguished; direct respiratory-chain failure in every affected tissue is not established here.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
Mitochondria have a separate histidine-charging requirement.
primary_references
Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 474–480
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human family study with recombinant activity, transcript analysis and yeast/worm experiments. · source_derived_draft · unverified_draft
## histidine-hars2-charging Mitochondria have a separate histidine-charging requirement. HARS2 provides histidyl-tRNA for mitochondrial translation; L200V and V368L variants reduced aminoacylation in the study assays. Model: Human family study with recombinant activity, transcript analysis and yeast/worm experiments. Limitations: Background role and measured variant impairment are distinguished; direct respiratory-chain failure in every affected tissue is not established here. Evidence access: Primary abstract Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108
Complete structured claim and evidence
The nucleotide change encoding HARS2 L200V also generated a transcript lacking 12 codons; the deletion product was not stably expressed in mammalian mitochondria.
Human HARS2 L200V-associated altered splicing → Human mitochondrial histidyl-tRNA synthetase / HARS2 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Perrault-syndrome family, transcript analysis and expression assays.
limitations
A machinery defect is not evidence of dietary histidine deficiency.
nutrient_topic
L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
plain_language
One DNA change affected both the protein sequence and how its RNA was assembled.
primary_references
Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 482–488
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Perrault-syndrome family, transcript analysis and expression assays. · source_derived_draft · unverified_draft
## histidine-hars2-splicing One DNA change affected both the protein sequence and how its RNA was assembled. The nucleotide change encoding HARS2 L200V also generated a transcript lacking 12 codons; the deletion product was not stably expressed in mammalian mitochondria. Model: Perrault-syndrome family, transcript analysis and expression assays. Limitations: A machinery defect is not evidence of dietary histidine deficiency. Evidence access: Primary abstract Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21464306/ · DOI 10.1073/pnas.1103471108
Complete structured claim and evidence
Recombinant human HDC catalyzes PLP-dependent histidine decarboxylation to histamine.
Human histidine decarboxylase / HDC → Histamine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant engineered human HDC; crystallography and enzyme assays
exposure
Recombinant HDC enzyme-activity assays.
limitations
Engineered soluble HDC construct; histamine release and allergy outcomes were not tested.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
Activated B6 supports histamine synthesis.
primary_references
[komori-2012-hdc] Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3436558/ DOI: 10.1074/jbc.M112.381897
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1047–1057
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant engineered human HDC; crystallography and enzyme assays · source_derived_draft · unverified_draft
### b6-neuro-hdc-histamine Recombinant human HDC catalyzes PLP-dependent histidine decarboxylation to histamine. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activated B6 supports histamine synthesis. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant engineered human HDC; crystallography and enzyme assays limitations: Engineered soluble HDC construct; histamine release and allergy outcomes were not tested. exposure: Recombinant HDC enzyme-activity assays. [komori-2012-hdc] Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3436558/ DOI: 10.1074/jbc.M112.381897
Complete structured claim and evidence
The human HDC inhibitor complex resolved a PLP-histidine-methyl-ester external aldimine in its active site.
Human histidine decarboxylase / HDC → PLP source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant engineered human HDC; crystallography and enzyme assays
exposure
Histidine methyl ester co-crystallization.
limitations
Inhibitor-bound engineered protein; not direct observation of every physiological catalytic intermediate.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
The structure shows how HDC holds a B6-bound substrate mimic.
primary_references
[komori-2012-hdc] Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3436558/ DOI: 10.1074/jbc.M112.381897
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1059–1069
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant engineered human HDC; crystallography and enzyme assays · source_derived_draft · unverified_draft
### b6-neuro-hdc-external-aldimine The human HDC inhibitor complex resolved a PLP-histidine-methyl-ester external aldimine in its active site. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The structure shows how HDC holds a B6-bound substrate mimic. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant engineered human HDC; crystallography and enzyme assays limitations: Inhibitor-bound engineered protein; not direct observation of every physiological catalytic intermediate. exposure: Histidine methyl ester co-crystallization. [komori-2012-hdc] Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3436558/ DOI: 10.1074/jbc.M112.381897
Complete structured claim and evidence
The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate.
Rat formiminotransferase cyclodeaminase / FTCD → N-Formimino-L-glutamate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Histidine degradation supplies a folate-bound carbon group.
evidence_location
Introduction reaction definition; Figure 1 and FT-domain structural analysis.
experimental_model
Recombinant protein structure and functional analysis
exposure
Recombinant rat FTCD; FT-domain structural analysis.
limitations
Rat enzyme; no human histidine-loading response is inferred.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
This step brings histidine-derived carbon into folate chemistry.
primary_references
[mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1294–1306
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein structure and functional analysis · source_derived_draft · unverified_draft
### rat-ftcd-formimino-transfer The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This step brings histidine-derived carbon into folate chemistry. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein structure and functional analysis limitations: Rat enzyme; no human histidine-loading response is inferred. exposure: Recombinant rat FTCD; FT-domain structural analysis. cross_nutrient: Histidine degradation supplies a folate-bound carbon group. evidence_location: Introduction reaction definition; Figure 1 and FT-domain structural analysis. [mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
Complete structured claim and evidence
Adding histidine to the high-iron water solution attenuated inhibition, with zinc absorption of 47% compared with 34% at the high iron ratio without that ligand.
L-Histidine → Intestinal zinc absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Ferrous iron (competing_ion); Zinc(II) ion (absorbed_ion)
evidence_location
Indexed primary abstract.
evidence_span
{"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044}
experimental_model
Human 65Zn tracer study with whole-body counting after two weeks
exposure
Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons.
limitations
Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows.
nutrient_topic
Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc
organism
Homo sapiens
plain_language
A ligand changed the interaction between iron and zinc in this experiment.
primary_references
[zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411
tissue_or_cell_type
Intestinal absorption
Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1256–1269
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human 65Zn tracer study with whole-body counting after two weeks · source_derived_draft · unverified_draft
### zn-clin-histidine-iron Adding histidine to the high-iron water solution attenuated inhibition, with zinc absorption of 47% compared with 34% at the high iron ratio without that ligand. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A ligand changed the interaction between iron and zinc in this experiment. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Human 65Zn tracer study with whole-body counting after two weeks limitations: Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows. exposure: Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons. cross_nutrient: Ferrous iron (competing_ion); Zinc(II) ion (absorbed_ion) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044} [zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411
Complete structured claim and evidence
Human diamine oxidase has a substrate pocket adapted to diamines including histamine, distinct from that of AOC3.
Human diamine oxidase / AOC1 / DAO → Histamine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"}
experimental_model
Crystallography of recombinant human diamine oxidase and inhibitor complexes
exposure
Native structure and inhibitor binding
limitations
Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants.
nutrient_topic
Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper
organism
Human AOC1 expressed in insect cells
plain_language
Related copper enzymes process different amines.
primary_references
[copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192
tissue_or_cell_type
Purified protein
Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1027–1038
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystallography of recombinant human diamine oxidase and inhibitor complexes · source_derived_draft · unverified_draft
### copper-aoc1-histamine-specificity Human diamine oxidase has a substrate pocket adapted to diamines including histamine, distinct from that of AOC3. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Related copper enzymes process different amines. organism: Human AOC1 expressed in insect cells tissue_or_cell_type: Purified protein experimental_model: Crystallography of recombinant human diamine oxidase and inhibitor complexes limitations: Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants. exposure: Native structure and inhibitor binding evidence_span: {"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"} [copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192
Complete structured claim and evidence
Purified recombinant human CARNS1 joined beta-alanine and L-histidine to form carnosine in an ATP-containing assay.
Human carnosine synthase / CARNS1 (ATPGD1) → L-Carnosine / beta-alanyl-L-histidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and full-text enzyme methods
experimental_model
Human enzyme expressed in HEK293T cells.
limitations
An enzyme assay does not define dietary requirements.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
Two building blocks are assembled by a specific enzyme.
primary_references
Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 20–26
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme expressed in HEK293T cells. · source_derived_draft · unverified_draft
## carnosine-synthesis Two building blocks are assembled by a specific enzyme. Purified recombinant human CARNS1 joined beta-alanine and L-histidine to form carnosine in an ATP-containing assay. Model: Human enzyme expressed in HEK293T cells. Limitations: An enzyme assay does not define dietary requirements. Evidence access: Primary abstract and full-text enzyme methods Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505
Complete structured claim and evidence
Beta-alanine alone or with histidine increased muscle carnosine; histidine alone did not, and the combined group did not exceed beta-alanine alone.
Beta-alanine → Human skeletal-muscle carnosine content source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Thirty adults; 23 days; BA 6 g/day, histidine 3.5 g/day or both.
limitations
Study exposures, not personal dosing guidance.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
More of one precursor helped; adding the other did not further raise carnosine.
primary_references
Effects of Histidine and β-alanine Supplementation on Human Muscle Carnosine Storage. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28106620/ · DOI 10.1249/MSS.0000000000001213
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 108–114
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Thirty adults; 23 days; BA 6 g/day, histidine 3.5 g/day or both. · source_derived_draft · unverified_draft
## carnosine-histidine-loading More of one precursor helped; adding the other did not further raise carnosine. Beta-alanine alone or with histidine increased muscle carnosine; histidine alone did not, and the combined group did not exceed beta-alanine alone. Model: Thirty adults; 23 days; BA 6 g/day, histidine 3.5 g/day or both. Limitations: Study exposures, not personal dosing guidance. Evidence access: Primary abstract Effects of Histidine and β-alanine Supplementation on Human Muscle Carnosine Storage. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28106620/ · DOI 10.1249/MSS.0000000000001213
Complete structured claim and evidence
Beta-alanine supplementation lowered free histidine in muscle by 31.6% and plasma by 30.6%; simultaneous histidine prevented these declines.
Beta-alanine → Human skeletal-muscle free histidine content source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same 23-day study.
limitations
Physiological consequences of the declines were not established.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
Making more carnosine can draw on another amino-acid pool.
primary_references
Effects of Histidine and β-alanine Supplementation on Human Muscle Carnosine Storage. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28106620/ · DOI 10.1249/MSS.0000000000001213
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 116–122
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same 23-day study. · source_derived_draft · unverified_draft
## carnosine-histidine-cost Making more carnosine can draw on another amino-acid pool. Beta-alanine supplementation lowered free histidine in muscle by 31.6% and plasma by 30.6%; simultaneous histidine prevented these declines. Model: Same 23-day study. Limitations: Physiological consequences of the declines were not established. Evidence access: Primary abstract Effects of Histidine and β-alanine Supplementation on Human Muscle Carnosine Storage. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28106620/ · DOI 10.1249/MSS.0000000000001213
Complete structured claim and evidence
At pH 7.4, intact carnosine quenched HNE more effectively than histidine or N-acetylcarnosine, while beta-alanine was inactive.
L-Carnosine / beta-alanyl-L-histidine → 4-Hydroxy-2-nonenal / HNE source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cell-free comparison.
limitations
This molecular comparison is not proof of supplement synergy.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
The joined peptide has properties its separate parts do not reproduce.
primary_references
Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? · 2002 · https://pubmed.ncbi.nlm.nih.gov/12419310/ · DOI 10.1016/s0006-291x(02)02545-7
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 244–250
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cell-free comparison. · source_derived_draft · unverified_draft
## carnosine-hne-intact-peptide The joined peptide has properties its separate parts do not reproduce. At pH 7.4, intact carnosine quenched HNE more effectively than histidine or N-acetylcarnosine, while beta-alanine was inactive. Model: Cell-free comparison. Limitations: This molecular comparison is not proof of supplement synergy. Evidence access: Primary abstract Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? · 2002 · https://pubmed.ncbi.nlm.nih.gov/12419310/ · DOI 10.1016/s0006-291x(02)02545-7
Complete structured claim and evidence
Histidine increased DNA damage in the tested iron/peroxide/ascorbate system and weakened carnosine protection when combined with it.
L-Histidine → Cell-free metal/peroxide/ascorbate-induced DNA damage source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cell-free 10 mM amino-acid comparison.
limitations
Not evidence that dietary histidine damages human DNA.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
The breakdown product did not behave like the intact peptide.
primary_references
Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 316–322
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cell-free 10 mM amino-acid comparison. · source_derived_draft · unverified_draft
## carnosine-histidine-metal The breakdown product did not behave like the intact peptide. Histidine increased DNA damage in the tested iron/peroxide/ascorbate system and weakened carnosine protection when combined with it. Model: Cell-free 10 mM amino-acid comparison. Limitations: Not evidence that dietary histidine damages human DNA. Evidence access: Primary abstract Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x
Complete structured claim and evidence
Carns1 deletion made histidine-containing dipeptides undetectable in the primary olfactory system and skeletal muscle.
Mouse carnosine synthase / Carns1 → Mouse olfactory-system histidine dipeptide content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Genetic mouse knockout.
limitations
Machinery failure, not a human dietary-deficiency syndrome.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
Removing synthesis emptied the measured peptide pools.
primary_references
Carnosine synthase deficiency is compatible with normal skeletal muscle and olfactory function but causes reduced olfactory sensitivity in aging mice. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33040025/ · DOI 10.1074/jbc.RA120.014188
trigger_kind
machinery_impairment Imported condition classification; unverified.
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 396–402
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Genetic mouse knockout. · source_derived_draft · unverified_draft
## carnosine-mouse-loss Removing synthesis emptied the measured peptide pools. Carns1 deletion made histidine-containing dipeptides undetectable in the primary olfactory system and skeletal muscle. Model: Genetic mouse knockout. Limitations: Machinery failure, not a human dietary-deficiency syndrome. Evidence access: Primary abstract Carnosine synthase deficiency is compatible with normal skeletal muscle and olfactory function but causes reduced olfactory sensitivity in aging mice. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33040025/ · DOI 10.1074/jbc.RA120.014188
Complete structured claim and evidence
Carns1 deletion eliminated histidine dipeptides and produced lower cardiomyocyte calcium peaks with slower calcium removal.
Rat carnosine synthase / Carns1 → Rat cardiomyocyte calcium-transient kinetics source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Four-month-old male knockout rats.
limitations
Loss affects carnosine and anserine; cannot assign all effects to one peptide.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
Heart calcium handling changed when synthesis was absent.
primary_references
Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34038814/ · DOI 10.1016/j.redox.2021.102016
trigger_kind
machinery_impairment Imported condition classification; unverified.
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 436–442
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Four-month-old male knockout rats. · source_derived_draft · unverified_draft
## carnosine-rat-calcium Heart calcium handling changed when synthesis was absent. Carns1 deletion eliminated histidine dipeptides and produced lower cardiomyocyte calcium peaks with slower calcium removal. Model: Four-month-old male knockout rats. Limitations: Loss affects carnosine and anserine; cannot assign all effects to one peptide. Evidence access: Primary abstract Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34038814/ · DOI 10.1016/j.redox.2021.102016
Complete structured claim and evidence
Carnosine treatment reduced infarct size in both wild-type and histidine-decarboxylase-null mice after permanent MCAO.
L-Carnosine / beta-alanyl-L-histidine → Mouse cerebral infarct size after focal ischemia source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse cerebral ischemia with Hdc knockout.
limitations
Preclinical intervention; not stroke treatment guidance.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
Protection in this model did not require histamine synthesis.
primary_references
Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20043985/ · DOI 10.1016/j.freeradbiomed.2009.12.021
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 460–466
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse cerebral ischemia with Hdc knockout. · source_derived_draft · unverified_draft
## carnosine-ischemia-hdc Protection in this model did not require histamine synthesis. Carnosine treatment reduced infarct size in both wild-type and histidine-decarboxylase-null mice after permanent MCAO. Model: Mouse cerebral ischemia with Hdc knockout. Limitations: Preclinical intervention; not stroke treatment guidance. Evidence access: Primary abstract Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20043985/ · DOI 10.1016/j.freeradbiomed.2009.12.021
Complete structured claim and evidence
Mycobacterium smegmatis EgtD uses SAM-dependent methyl transfer to convert histidine into hercynine.
S-Adenosyl-L-methionine → Mycobacterium smegmatis EgtD source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Apo and ligand-bound enzyme structures.
limitations
No evidence that human ergothioneine consumption drains SAM; humans lack this established synthesis pathway.
nutrient_topic
Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine
plain_language
The microbial synthesis branch connects to methyl-donor chemistry.
primary_references
Structural insights into the histidine trimethylation activity of EgtD from Mycobacterium smegmatis. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25251321/ · DOI 10.1016/j.bbrc.2014.09.058
Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 552–558
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Apo and ligand-bound enzyme structures. · source_derived_draft · unverified_draft
## ergothioneine-egtd-sam The microbial synthesis branch connects to methyl-donor chemistry. Mycobacterium smegmatis EgtD uses SAM-dependent methyl transfer to convert histidine into hercynine. Model: Apo and ligand-bound enzyme structures. Limitations: No evidence that human ergothioneine consumption drains SAM; humans lack this established synthesis pathway. Evidence access: Primary abstract Structural insights into the histidine trimethylation activity of EgtD from Mycobacterium smegmatis. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25251321/ · DOI 10.1016/j.bbrc.2014.09.058
Complete structured claim and evidence
Elevated zinc stimulated human ZIP4 ubiquitination and degradation; a cytoplasmic histidine-rich region was required for this degradation response but dispensable for zinc-induced endocytosis.
Zinc(II) ion → ZIP4 protein degradation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Cultured cells expressing human ZIP4 with mutational analysis
exposure
Elevated zinc exposure; detailed concentration and cell lineage not specified in the abstract.
limitations
Abstract extraction; the region requirement does not mean every histidine acts as an independent sensor. This is zinc exposure, not demonstrated dietary deficiency.
nutrient_topic
Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc
organism
Human protein in cultured cells
plain_language
Human ZIP4 has a zinc-triggered disposal response that is separate from removal from the surface.
primary_references
[zinc-trans-17202136] A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. (2007). https://pubmed.ncbi.nlm.nih.gov/17202136/ DOI: 10.1074/jbc.m610552200
tissue_or_cell_type
Cellular zinc-uptake machinery
Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 258–269
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured cells expressing human ZIP4 with mutational analysis · source_derived_draft · unverified_draft
### zinc-trans-hzip4-degradation Elevated zinc stimulated human ZIP4 ubiquitination and degradation; a cytoplasmic histidine-rich region was required for this degradation response but dispensable for zinc-induced endocytosis. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human ZIP4 has a zinc-triggered disposal response that is separate from removal from the surface. organism: Human protein in cultured cells tissue_or_cell_type: Cellular zinc-uptake machinery experimental_model: Cultured cells expressing human ZIP4 with mutational analysis limitations: Abstract extraction; the region requirement does not mean every histidine acts as an independent sensor. This is zinc exposure, not demonstrated dietary deficiency. exposure: Elevated zinc exposure; detailed concentration and cell lineage not specified in the abstract. cross_nutrient: false [zinc-trans-17202136] A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. (2007). https://pubmed.ncbi.nlm.nih.gov/17202136/ DOI: 10.1074/jbc.m610552200
Complete structured claim and evidence
X-ray absorption analysis of human CA2 supported a zinc site with three histidine nitrogen ligands and most likely one water/hydroxide oxygen ligand in both isolated and reconstituted enzyme.
Zinc(II) ion → Human carbonic anhydrase II / CA2 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy
exposure
Zn K-edge XANES and EXAFS on isolated and zinc-reconstituted recombinant CA2.
limitations
Coordination assignment is spectroscopic; the oxygen ligand is most likely solvent-derived, not an independently measured dietary effect.
nutrient_topic
Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc
organism
Homo sapiens
plain_language
CA2 holds zinc with three histidines and a water-derived ligand at its active site.
primary_references
[zinc-enz-ca2-coordination2012] Revisiting zinc coordination in human carbonic anhydrase II. (2012). https://pubmed.ncbi.nlm.nih.gov/23030313/ DOI: 10.1021/ic301645j
tissue_or_cell_type
Purified protein; cell-free assay
Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 651–662
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy · source_derived_draft · unverified_draft
### zinc-enz-ca2-coordination X-ray absorption analysis of human CA2 supported a zinc site with three histidine nitrogen ligands and most likely one water/hydroxide oxygen ligand in both isolated and reconstituted enzyme. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: CA2 holds zinc with three histidines and a water-derived ligand at its active site. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Purified recombinant human CA2; metal reconstitution, ITC and X-ray absorption spectroscopy limitations: Coordination assignment is spectroscopic; the oxygen ligand is most likely solvent-derived, not an independently measured dietary effect. exposure: Zn K-edge XANES and EXAFS on isolated and zinc-reconstituted recombinant CA2. cross_nutrient: false [zinc-enz-ca2-coordination2012] Revisiting zinc coordination in human carbonic anhydrase II. (2012). https://pubmed.ncbi.nlm.nih.gov/23030313/ DOI: 10.1021/ic301645j
Complete structured claim and evidence
Oxyhemoglobin structures resolved hydrogen bonding between the oxygen ligand and distal histidine in both alpha and beta subunits.
Human adult hemoglobin A → Reversible oxygen binding by hemoglobin source_derived_draftungraded
Experimental context and source evidence
evidence_span
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experimental_model
High-resolution crystallographic comparison
exposure
1.25 angstrom structural refinement
limitations
Structural oxygen-ligand geometry, not a supplementation or oxygen-delivery clinical trial.
nutrient_topic
Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron
organism
Human hemoglobin A
plain_language
Hemoglobin holds oxygen at carefully organized heme sites so oxygen binding can be controlled.
primary_references
[iron-p16765986] 1.25 A resolution crystal structures of human haemoglobin in the oxy, deoxy and carbonmonoxy forms. (2006). https://pubmed.ncbi.nlm.nih.gov/16765986/ DOI: 10.1016/j.jmb.2006.05.036
tissue_or_cell_type
Purified oxy-, deoxy- and carbonmonoxyhemoglobin
Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 537–548
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-resolution crystallographic comparison · source_derived_draft · unverified_draft
### iron-hemoglobin-oxygen-site Oxyhemoglobin structures resolved hydrogen bonding between the oxygen ligand and distal histidine in both alpha and beta subunits. Condition category: normal nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Hemoglobin holds oxygen at carefully organized heme sites so oxygen binding can be controlled. organism: Human hemoglobin A tissue_or_cell_type: Purified oxy-, deoxy- and carbonmonoxyhemoglobin experimental_model: High-resolution crystallographic comparison limitations: Structural oxygen-ligand geometry, not a supplementation or oxygen-delivery clinical trial. exposure: 1.25 angstrom structural refinement evidence_span: {"source_cache": "artifacts/iron-research/16765986.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "177ab81c08f82c99c81c69d1cb582e52216234e290066ae5aa380a887fb0e38c", "start_char": 0, "end_char": 1284, "text_sha256": "177ab81c08f82c99c81c69d1cb582e52216234e290066ae5aa380a887fb0e38c"} [iron-p16765986] 1.25 A resolution crystal structures of human haemoglobin in the oxy, deoxy and carbonmonoxy forms. (2006). https://pubmed.ncbi.nlm.nih.gov/16765986/ DOI: 10.1016/j.jmb.2006.05.036
Complete structured claim and evidence
CARNMT1 methylated histidine-containing C3H zinc-finger substrates including U2AF1; cellular mass spectrometry supported these modifications.
Human carnosine N-methyltransferase / CARNMT1 → Human splicing factor U2AF1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cellular extracts, recombinant-enzyme assays and mass spectrometry.
limitations
This does not show that carnosine supplements alter RNA processing.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
The carnosine methylating enzyme also acts on proteins.
primary_references
Identification of substrates and sequence requirements for CARNMT1-mediated histidine methylation of C3H zinc fingers. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40473212/ · DOI 10.1016/j.jbc.2025.110335
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 156–162
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cellular extracts, recombinant-enzyme assays and mass spectrometry. · source_derived_draft · unverified_draft
## carnosine-carnmt1-protein The carnosine methylating enzyme also acts on proteins. CARNMT1 methylated histidine-containing C3H zinc-finger substrates including U2AF1; cellular mass spectrometry supported these modifications. Model: Human cellular extracts, recombinant-enzyme assays and mass spectrometry. Limitations: This does not show that carnosine supplements alter RNA processing. Evidence access: Primary abstract Identification of substrates and sequence requirements for CARNMT1-mediated histidine methylation of C3H zinc fingers. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40473212/ · DOI 10.1016/j.jbc.2025.110335
Complete structured claim and evidence
Substrate profiling identified RNF113A as a CARNMT1 histidine-methylation target.
Human carnosine N-methyltransferase / CARNMT1 → Human RNF113A source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Peptide-array and cellular methylation profiling.
limitations
Zinc-finger identity does not establish regulation by zinc intake.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
A shared enzyme creates another testable connection.
primary_references
Identification of substrates and sequence requirements for CARNMT1-mediated histidine methylation of C3H zinc fingers. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40473212/ · DOI 10.1016/j.jbc.2025.110335
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 164–170
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Peptide-array and cellular methylation profiling. · source_derived_draft · unverified_draft
## carnosine-carnmt1-new-target A shared enzyme creates another testable connection. Substrate profiling identified RNF113A as a CARNMT1 histidine-methylation target. Model: Peptide-array and cellular methylation profiling. Limitations: Zinc-finger identity does not establish regulation by zinc intake. Evidence access: Primary abstract Identification of substrates and sequence requirements for CARNMT1-mediated histidine methylation of C3H zinc fingers. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40473212/ · DOI 10.1016/j.jbc.2025.110335
Complete structured claim and evidence
Human AOC1 has one copper ion and a tyrosine-derived topaquinone in each of its two active sites.
Human diamine oxidase / AOC1 / DAO → Protein-derived topaquinone / TPQ cofactor source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"}
experimental_model
Crystallography of recombinant human diamine oxidase and inhibitor complexes
exposure
Native structure and inhibitor binding
limitations
Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants.
nutrient_topic
Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper
organism
Human AOC1 expressed in insect cells
plain_language
Histamine-processing machinery includes both a metal and a protein-derived cofactor.
primary_references
[copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192
tissue_or_cell_type
Purified protein
Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1014–1025
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystallography of recombinant human diamine oxidase and inhibitor complexes · source_derived_draft · unverified_draft
### copper-aoc1-copper-tpq Human AOC1 has one copper ion and a tyrosine-derived topaquinone in each of its two active sites. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Histamine-processing machinery includes both a metal and a protein-derived cofactor. organism: Human AOC1 expressed in insect cells tissue_or_cell_type: Purified protein experimental_model: Crystallography of recombinant human diamine oxidase and inhibitor complexes limitations: Copper/TPQ dependence is molecular evidence, not a trial of copper for histamine intolerance; DAO activity can have multiple determinants. exposure: Native structure and inhibitor binding evidence_span: {"source_cache": "artifacts/copper-research/19764817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6", "start_char": 0, "end_char": 1343, "text_sha256": "9a01d0dba5caec8a33a77fdbe7190d7a05bdd6e691a570a890eb6b19d4c692b6"} [copper-p19764817] Structure and inhibition of human diamine oxidase. (2009). https://pubmed.ncbi.nlm.nih.gov/19764817/ DOI: 10.1021/bi9014192
Complete structured claim and evidence
Purified human CARNS1 also synthesized homocarnosine using GABA, with lower catalytic efficiency than the beta-alanine reaction.
Human carnosine synthase / CARNS1 (ATPGD1) → Homocarnosine / GABA-L-histidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human enzyme substrate comparison.
limitations
Shared synthesis does not mean the two peptides have identical functions.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
The same enzyme can assemble a related GABA-containing peptide.
primary_references
Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 36–42
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human enzyme substrate comparison. · source_derived_draft · unverified_draft
## carnosine-homocarnosine The same enzyme can assemble a related GABA-containing peptide. Purified human CARNS1 also synthesized homocarnosine using GABA, with lower catalytic efficiency than the beta-alanine reaction. Model: Recombinant human enzyme substrate comparison. Limitations: Shared synthesis does not mean the two peptides have identical functions. Evidence access: Primary abstract Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). · 2010 · https://pubmed.ncbi.nlm.nih.gov/20097752/ · DOI 10.1074/jbc.M109.095505
Complete structured claim and evidence
Recombinant human CARNMT1 methylated carnosine to anserine; the reaction uses S-adenosylmethionine as methyl donor.
Human carnosine N-methyltransferase / CARNMT1 → Anserine / beta-alanyl-N-pi-methyl-L-histidine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract plus Reactome reaction R-HSA-8876789
experimental_model
Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789.
limitations
Does not establish methyl-donor depletion or benefit from folate/B12 supplements.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
A methyl group turns carnosine into a distinct peptide.
primary_references
UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26001783/ · DOI 10.1074/jbc.M115.640037
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 148–154
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789. · source_derived_draft · unverified_draft
## carnosine-methylation A methyl group turns carnosine into a distinct peptide. Recombinant human CARNMT1 methylated carnosine to anserine; the reaction uses S-adenosylmethionine as methyl donor. Model: Purified human enzyme; reaction identity also curated in Reactome R-HSA-8876789. Limitations: Does not establish methyl-donor depletion or benefit from folate/B12 supplements. Evidence access: Primary abstract plus Reactome reaction R-HSA-8876789 UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26001783/ · DOI 10.1074/jbc.M115.640037
Complete structured claim and evidence

Availability and dependencies

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

Low histidine supply impairs protein balance, erythropoiesis and skin

Condition: nutrient_deficiency · Controlled histidine-deficient amino-acid feeding for approximately five weeks.

Normal role: Histidine supports protein synthesis and distinct metabolic branches when transport, enzymes and reaction partners function.

Recorded consequence: Plasma/muscle histidine, nitrogen balance and hematocrit decline; repletion reverses measured changes.