Nutrient chapter

L-Tryptophan

109 recorded mechanisms · 17 availability situations · 9 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

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

Human LAT1 coexpressed with human SLC3A2/4F2hc in Xenopus oocytes transported large neutral amino acids; extracellular substrates exchanged intracellular leucine and glutamine.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → Human LAT1 neutral amino acid exchange source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected.
limitations
This is an exchange assay, not a direct human brain-uptake trial.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Transport depends on a partner protein and amino acids on both sides of the membrane.
primary_references
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 42–48
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. · source_derived_draft · unverified_draft
## tryptophan-lat1-partner Transport depends on a partner protein and amino acids on both sides of the membrane. Human LAT1 coexpressed with human SLC3A2/4F2hc in Xenopus oocytes transported large neutral amino acids; extracellular substrates exchanged intracellular leucine and glutamine. Model: Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. Limitations: This is an exchange assay, not a direct human brain-uptake trial. Evidence access: Primary abstract Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4
Complete structured claim and evidence
Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium.
Human TAT1 / SLC16A10 → L-Tryptophan source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cloned transporter; expression strongest in kidney and intestine.
limitations
The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Tryptophan also has an aromatic-amino-acid transport route.
primary_references
The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
transport_effect
raises An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
transport_pool
the expressing cell An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 50–56
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cloned transporter; expression strongest in kidney and intestine. · source_derived_draft · unverified_draft
## tryptophan-tat1-transport Tryptophan also has an aromatic-amino-acid transport route. Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium. Model: Human cloned transporter; expression strongest in kidney and intestine. Limitations: The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome. Evidence access: Primary abstract The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
Complete structured claim and evidence
In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone.
L-Leucine → Rat brain tryptophan content source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Overnight-fasted rats receiving defined meals with different amino-acid mixtures.
limitations
Not a validated universal human threshold or proof that protein-rich meals worsen mood.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A higher blood level need not mean more tryptophan reaches the brain.
primary_references
Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 58–64
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Overnight-fasted rats receiving defined meals with different amino-acid mixtures. · source_derived_draft · unverified_draft
## tryptophan-brain-competition A higher blood level need not mean more tryptophan reaches the brain. In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone. Model: Overnight-fasted rats receiving defined meals with different amino-acid mixtures. Limitations: Not a validated universal human threshold or proof that protein-rich meals worsen mood. Evidence access: Primary abstract Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759
Complete structured claim and evidence
Ace2 loss removed intestinal B0AT1 expression in mice; kidney B0AT1 regulation differed and depended on collectrin.
Mouse angiotensin-converting enzyme 2 / Ace2 → Mouse B0AT1 / Slc6a19 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, partner constructs and mouse tissue results
experimental_model
Mouse tissue expression and transporter-partner experiments.
limitations
Separate oocyte experiments combine human B0AT1 with mouse ACE2 or human collectrin; they are not an all-human ACE2 reconstruction.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The same amino-acid transporter needs different support in intestine and kidney.
primary_references
Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 66–72
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse tissue expression and transporter-partner experiments. · source_derived_draft · unverified_draft
## tryptophan-ace2-transporter The same amino-acid transporter needs different support in intestine and kidney. Ace2 loss removed intestinal B0AT1 expression in mice; kidney B0AT1 regulation differed and depended on collectrin. Model: Mouse tissue expression and transporter-partner experiments. Limitations: Separate oocyte experiments combine human B0AT1 with mouse ACE2 or human collectrin; they are not an all-human ACE2 reconstruction. Evidence access: Primary full text, partner constructs and mouse tissue results Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055
Complete structured claim and evidence
Gly-Trp feeding restored serum tryptophan and reduced DSS-colitis susceptibility in Ace2-deficient mice, bypassing loss of single-amino-acid uptake.
Glycyl-L-tryptophan / Gly-Trp dipeptide → Mouse susceptibility to chemically induced colitis in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, Figure 2 and rescue results
experimental_model
Ace2-mutant mouse dietary rescue.
limitations
Not a clinical Gly-Trp treatment recommendation or evidence that free tryptophan always bypasses transporter loss.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A dipeptide delivery route bypassed missing transport support.
primary_references
ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 74–80
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Ace2-mutant mouse dietary rescue. · source_derived_draft · unverified_draft
## tryptophan-glytrp-bypass A dipeptide delivery route bypassed missing transport support. Gly-Trp feeding restored serum tryptophan and reduced DSS-colitis susceptibility in Ace2-deficient mice, bypassing loss of single-amino-acid uptake. Model: Ace2-mutant mouse dietary rescue. Limitations: Not a clinical Gly-Trp treatment recommendation or evidence that free tryptophan always bypasses transporter loss. Evidence access: Primary full text, Figure 2 and rescue results ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Complete structured claim and evidence
A tryptophan-free diet reduced small-intestinal antimicrobial peptide expression and increased chemically induced colitis susceptibility in wild-type mice.
L-Tryptophan → Mouse intestinal antimicrobial peptide expression in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, diet experiments
experimental_model
Mouse tryptophan-free diet with DSS/TNBS challenges.
limitations
Induced susceptibility, not proof that every human colitis case is tryptophan deficiency.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Low dietary supply weakened a gut defense response in mice.
primary_references
ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 82–88
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse tryptophan-free diet with DSS/TNBS challenges. · source_derived_draft · unverified_draft
## tryptophan-trp-free-peptides Low dietary supply weakened a gut defense response in mice. A tryptophan-free diet reduced small-intestinal antimicrobial peptide expression and increased chemically induced colitis susceptibility in wild-type mice. Model: Mouse tryptophan-free diet with DSS/TNBS challenges. Limitations: Induced susceptibility, not proof that every human colitis case is tryptophan deficiency. Evidence access: Primary full text, diet experiments ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Complete structured claim and evidence
Nicotinamide supplementation markedly alleviated colitis and diarrhea in Ace2-deficient mice.
Nicotinamide → Mouse susceptibility to chemically induced colitis in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, Figure 2
experimental_model
Mouse Ace2 loss and DSS challenge.
limitations
Does not establish identical effects for nicotinic acid or human inflammatory bowel disease.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A downstream vitamin B3 form bypassed part of the disturbed pathway.
primary_references
ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 90–96
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Ace2 loss and DSS challenge. · source_derived_draft · unverified_draft
## tryptophan-nam-rescue A downstream vitamin B3 form bypassed part of the disturbed pathway. Nicotinamide supplementation markedly alleviated colitis and diarrhea in Ace2-deficient mice. Model: Mouse Ace2 loss and DSS challenge. Limitations: Does not establish identical effects for nicotinic acid or human inflammatory bowel disease. Evidence access: Primary full text, Figure 2 ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Complete structured claim and evidence
Rapamycin reduced mouse intestinal antimicrobial peptides, and nicotinamide did not rescue that reduction.
Mouse mechanistic target of rapamycin / Mtor → Mouse intestinal antimicrobial peptide expression in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, mTOR results and Supplementary Figure 22 description
experimental_model
Mouse mTOR inhibition in vivo.
limitations
Rapamycin affects multiple cell types; no human dietary threshold established.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
More precursor or downstream vitamin cannot replace every missing signal.
primary_references
ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 98–104
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse mTOR inhibition in vivo. · source_derived_draft · unverified_draft
## tryptophan-mtor-block-nam More precursor or downstream vitamin cannot replace every missing signal. Rapamycin reduced mouse intestinal antimicrobial peptides, and nicotinamide did not rescue that reduction. Model: Mouse mTOR inhibition in vivo. Limitations: Rapamycin affects multiple cell types; no human dietary threshold established. Evidence access: Primary full text, mTOR results and Supplementary Figure 22 description ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Complete structured claim and evidence
Microbiota transfer from Ace2-mutant mice transmitted increased colitis susceptibility to germ-free wild-type recipients.
Mouse angiotensin-converting enzyme 2 / Ace2 → Mouse susceptibility to chemically induced colitis in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, microbiota-transfer results
experimental_model
Mouse donor-to-recipient microbiota transfer.
limitations
Transfer does not isolate one bacterial species or one metabolite.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The altered microbial community carried part of the susceptibility.
primary_references
ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 106–112
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse donor-to-recipient microbiota transfer. · source_derived_draft · unverified_draft
## tryptophan-microbiota-transfer The altered microbial community carried part of the susceptibility. Microbiota transfer from Ace2-mutant mice transmitted increased colitis susceptibility to germ-free wild-type recipients. Model: Mouse donor-to-recipient microbiota transfer. Limitations: Transfer does not isolate one bacterial species or one metabolite. Evidence access: Primary full text, microbiota-transfer results ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22837003/ · DOI 10.1038/nature11228
Complete structured claim and evidence
Human WARS1 recognizes tryptophan and its cognate tRNA; ATP-dependent activation precedes transfer to tRNA in protein-synthesis aminoacylation.
Human cytosolic tryptophanyl-tRNA synthetase / WARS1 → Human tryptophanyl-tRNA-Trp source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, aminoacylation mechanism and structural results
experimental_model
Human WARS1–tRNA structural analysis and biochemical aminoacylation.
limitations
Cytosolic WARS1 is distinct from mitochondrial WARS2.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Tryptophan is a building block that must be attached to the correct transfer RNA.
primary_references
Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16798914/ · DOI 10.1093/nar/gkl441
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 114–120
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human WARS1–tRNA structural analysis and biochemical aminoacylation. · source_derived_draft · unverified_draft
## tryptophan-wars1-charging Tryptophan is a building block that must be attached to the correct transfer RNA. Human WARS1 recognizes tryptophan and its cognate tRNA; ATP-dependent activation precedes transfer to tRNA in protein-synthesis aminoacylation. Model: Human WARS1–tRNA structural analysis and biochemical aminoacylation. Limitations: Cytosolic WARS1 is distinct from mitochondrial WARS2. Evidence access: Primary full text, aminoacylation mechanism and structural results Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16798914/ · DOI 10.1093/nar/gkl441
Complete structured claim and evidence
Under IFN-gamma/IDO1-associated tryptophan shortage, human cancer cells continued translation with WARS1-associated phenylalanine incorporation at tryptophan positions.
Human cytosolic tryptophanyl-tRNA synthetase / WARS1 → Human cancer-cell tryptophan-to-phenylalanine translational substitution source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract; primary correction full text reviewed
experimental_model
Human cancer-cell depletion, molecular assays and tumor proteomics.
limitations
Not a DNA mutation or a universal consequence of a low-tryptophan meal. Tumor proteomic filtering was clarified in a correction. Correction record: The 2022 author correction adds omitted funding acknowledgements and clarifies that the maximum-sample peptide filter was used in the intra-tumour analysis (Fig. 3f) but not for W>F substitutants in the tumour-specific analysis (Fig. 3a). Authors report similar biological conclusions with both strategies. This is a publication correction, not an opposing mechanism claim. https://www.nature.com/articles/s41586-022-05097-y
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Severe local shortage can change what a cancer cell puts into a protein.
primary_references
Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35264796/ · DOI 10.1038/s41586-022-04499-2
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 122–128
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell depletion, molecular assays and tumor proteomics. · source_derived_draft · unverified_draft
## tryptophan-w-to-f-shortage Severe local shortage can change what a cancer cell puts into a protein. Under IFN-gamma/IDO1-associated tryptophan shortage, human cancer cells continued translation with WARS1-associated phenylalanine incorporation at tryptophan positions. Model: Human cancer-cell depletion, molecular assays and tumor proteomics. Limitations: Not a DNA mutation or a universal consequence of a low-tryptophan meal. Tumor proteomic filtering was clarified in a correction. Correction record: The 2022 author correction adds omitted funding acknowledgements and clarifies that the maximum-sample peptide filter was used in the intra-tumour analysis (Fig. 3f) but not for W>F substitutants in the tumour-specific analysis (Fig. 3a). Authors report similar biological conclusions with both strategies. This is a publication correction, not an opposing mechanism claim. https://www.nature.com/articles/s41586-022-05097-y Evidence access: Primary abstract; primary correction full text reviewed Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35264796/ · DOI 10.1038/s41586-022-04499-2
Complete structured claim and evidence
Tph2 knockout markedly reduced mouse brain serotonin while peripheral serotonin was not substantially reduced.
Mouse tryptophan hydroxylase 2 / Tph2 → Mouse brain serotonin abundance source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse Tph2 knockout versus wild type.
limitations
Mouse developmental knockout is not a human dietary depletion experiment.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The brain and peripheral serotonin factories are not interchangeable.
primary_references
Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18923670/ · DOI 10.1371/journal.pone.0003301
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 130–136
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Tph2 knockout versus wild type. · source_derived_draft · unverified_draft
## tryptophan-tph2-brain-loss The brain and peripheral serotonin factories are not interchangeable. Tph2 knockout markedly reduced mouse brain serotonin while peripheral serotonin was not substantially reduced. Model: Mouse Tph2 knockout versus wild type. Limitations: Mouse developmental knockout is not a human dietary depletion experiment. Evidence access: Primary abstract Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18923670/ · DOI 10.1371/journal.pone.0003301
Complete structured claim and evidence
Combined Tph1/Tph2 knockout reduced peripheral as well as central serotonin in mice.
Mouse tryptophan hydroxylase 1 / Tph1 → Mouse peripheral serotonin abundance source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse double knockout.
limitations
Viability and subtle behavioral findings prevent equating any serotonin reduction with one inevitable psychiatric syndrome.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Removing both enzyme systems affected both compartments.
primary_references
Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18923670/ · DOI 10.1371/journal.pone.0003301
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 138–144
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse double knockout. · source_derived_draft · unverified_draft
## tryptophan-tph-double-loss Removing both enzyme systems affected both compartments. Combined Tph1/Tph2 knockout reduced peripheral as well as central serotonin in mice. Model: Mouse double knockout. Limitations: Viability and subtle behavioral findings prevent equating any serotonin reduction with one inevitable psychiatric syndrome. Evidence access: Primary abstract Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18923670/ · DOI 10.1371/journal.pone.0003301
Complete structured claim and evidence
A tryptophan-free amino-acid drink lowered total and free plasma tryptophan by 70–80% after five hours in antidepressant responders.
L-Tryptophan → Human plasma tryptophan during acute depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Thirty human antidepressant responders in depletion and control sessions.
limitations
An experimentally unbalanced drink differs from ordinary meals; plasma values are not direct brain serotonin assays.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A research depletion drink rapidly lowered circulating supply.
primary_references
Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10418696/ · DOI 10.1016/s0006-3223(99)00014-1
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 146–152
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Thirty human antidepressant responders in depletion and control sessions. · source_derived_draft · unverified_draft
## tryptophan-clinical-depletion A research depletion drink rapidly lowered circulating supply. A tryptophan-free amino-acid drink lowered total and free plasma tryptophan by 70–80% after five hours in antidepressant responders. Model: Thirty human antidepressant responders in depletion and control sessions. Limitations: An experimentally unbalanced drink differs from ordinary meals; plasma values are not direct brain serotonin assays. Evidence access: Primary abstract Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10418696/ · DOI 10.1016/s0006-3223(99)00014-1
Complete structured claim and evidence
During depletion, 8/15 fluoxetine responders relapsed versus 1/15 desipramine responders; significant depressive symptoms did not occur in control sessions.
L-Tryptophan → Human depressive relapse during acute tryptophan depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Randomized antidepressant assignment followed by crossover depletion testing of responders.
limitations
Does not prove that depression generally results from low dietary tryptophan or that supplementation treats it.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The response depended on which treatment had produced remission.
primary_references
Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10418696/ · DOI 10.1016/s0006-3223(99)00014-1
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 154–160
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Randomized antidepressant assignment followed by crossover depletion testing of responders. · source_derived_draft · unverified_draft
## tryptophan-antidepressant-context The response depended on which treatment had produced remission. During depletion, 8/15 fluoxetine responders relapsed versus 1/15 desipramine responders; significant depressive symptoms did not occur in control sessions. Model: Randomized antidepressant assignment followed by crossover depletion testing of responders. Limitations: Does not prove that depression generally results from low dietary tryptophan or that supplementation treats it. Evidence access: Primary abstract Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10418696/ · DOI 10.1016/s0006-3223(99)00014-1
Complete structured claim and evidence
Acute tryptophan depletion impaired delayed paragraph recall in a pilot of recently recovered menopausal women, without depressive relapse or significant mood worsening.
L-Tryptophan → Human delayed verbal recall during acute tryptophan depletion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human pilot after estradiol, fluoxetine or combined treatment.
limitations
Different population and treatment context from the 1999 trial; no universal depletion response established.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Memory and mood did not respond identically.
primary_references
The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16891341/ · DOI 10.1177/0269881106067330
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 162–168
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human pilot after estradiol, fluoxetine or combined treatment. · source_derived_draft · unverified_draft
## tryptophan-menopause-recall Memory and mood did not respond identically. Acute tryptophan depletion impaired delayed paragraph recall in a pilot of recently recovered menopausal women, without depressive relapse or significant mood worsening. Model: Human pilot after estradiol, fluoxetine or combined treatment. Limitations: Different population and treatment context from the 1999 trial; no universal depletion response established. Evidence access: Primary abstract The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings. · 2007 · https://pubmed.ncbi.nlm.nih.gov/16891341/ · DOI 10.1177/0269881106067330
Complete structured claim and evidence
Human IDO1 uses heme-bound oxygen to cleave the tryptophan indole ring, incorporating both oxygen atoms during N-formylkynurenine formation.
Human indoleamine 2,3-dioxygenase 1 / IDO1 → N-Formyl-L-kynurenine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human IDO1 structure and mutagenesis.
limitations
Catalytic heme dependence does not establish benefit from extra dietary iron.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
An immune-regulated enzyme opens a different route for tryptophan.
primary_references
Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16477023/ · DOI 10.1073/pnas.0508996103
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 170–176
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human IDO1 structure and mutagenesis. · source_derived_draft · unverified_draft
## tryptophan-ido-ring-cleavage An immune-regulated enzyme opens a different route for tryptophan. Human IDO1 uses heme-bound oxygen to cleave the tryptophan indole ring, incorporating both oxygen atoms during N-formylkynurenine formation. Model: Human IDO1 structure and mutagenesis. Limitations: Catalytic heme dependence does not establish benefit from extra dietary iron. Evidence access: Primary abstract Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16477023/ · DOI 10.1073/pnas.0508996103
Complete structured claim and evidence
Human IDO1 F226A, F227A and R231A mutants retained substrate binding but lacked catalytic activity.
Human indoleamine 2,3-dioxygenase 1 / IDO1 → N-Formyl-L-kynurenine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human enzyme site-directed mutagenesis.
limitations
Engineered mutants, not a characterized common dietary disorder.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Binding the nutrient is not enough to process it.
primary_references
Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16477023/ · DOI 10.1073/pnas.0508996103
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 178–184
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme site-directed mutagenesis. · source_derived_draft · unverified_draft
## tryptophan-ido-binding-not-catalysis Binding the nutrient is not enough to process it. Human IDO1 F226A, F227A and R231A mutants retained substrate binding but lacked catalytic activity. Model: Human enzyme site-directed mutagenesis. Limitations: Engineered mutants, not a characterized common dietary disorder. Evidence access: Primary abstract Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16477023/ · DOI 10.1073/pnas.0508996103
Complete structured claim and evidence
Recombinant mouse Afmid hydrolyzed N-formyl-L-kynurenine with a Km of 0.18–0.19 mM, matching native mouse cytosolic enzyme.
Mouse arylformamidase / Afmid → L-Kynurenine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse liver enzyme expressed in E. coli.
limitations
This experiment is mouse enzyme evidence, not direct human AFMID validation.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A second enzyme removes the formyl group to produce kynurenine.
primary_references
Cloning, expression, and catalytic triad of recombinant arylformamidase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15935693/ · DOI 10.1016/j.pep.2005.04.013
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 186–192
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver enzyme expressed in E. coli. · source_derived_draft · unverified_draft
## tryptophan-afmid-hydrolysis A second enzyme removes the formyl group to produce kynurenine. Recombinant mouse Afmid hydrolyzed N-formyl-L-kynurenine with a Km of 0.18–0.19 mM, matching native mouse cytosolic enzyme. Model: Mouse liver enzyme expressed in E. coli. Limitations: This experiment is mouse enzyme evidence, not direct human AFMID validation. Evidence access: Primary abstract Cloning, expression, and catalytic triad of recombinant arylformamidase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15935693/ · DOI 10.1016/j.pep.2005.04.013
Complete structured claim and evidence
S162A, D247A or H279A substitutions in mouse Afmid each removed more than 99% of measured enzyme activity.
Mouse arylformamidase / Afmid → L-Kynurenine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Recombinant mouse enzyme mutations.
limitations
Does not quantify human variant effects or prove a clinical repletion failure.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
One defective catalytic residue can block the next step despite available substrate.
primary_references
Cloning, expression, and catalytic triad of recombinant arylformamidase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15935693/ · DOI 10.1016/j.pep.2005.04.013
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 194–200
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant mouse enzyme mutations. · source_derived_draft · unverified_draft
## tryptophan-afmid-triad One defective catalytic residue can block the next step despite available substrate. S162A, D247A or H279A substitutions in mouse Afmid each removed more than 99% of measured enzyme activity. Model: Recombinant mouse enzyme mutations. Limitations: Does not quantify human variant effects or prove a clinical repletion failure. Evidence access: Primary abstract Cloning, expression, and catalytic triad of recombinant arylformamidase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15935693/ · DOI 10.1016/j.pep.2005.04.013
Complete structured claim and evidence
Human KAT-II/AADAT is a PLP-dependent homodimer; the structure shows a PLP–Lys263 aldimine at its catalytic site.
AADAT / KAT II → PLP source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human KAT-II crystal structure at 1.83 angstrom resolution.
limitations
Cofactor dependence alone does not define clinical B6 requirements or benefit from excess B6.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Vitamin B6 participates in a branch enzyme, not only the serotonin route.
primary_references
Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27023527/ · DOI 10.3390/ijms17040446
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 202–208
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human KAT-II crystal structure at 1.83 angstrom resolution. · source_derived_draft · unverified_draft
## tryptophan-kat2-plp Vitamin B6 participates in a branch enzyme, not only the serotonin route. Human KAT-II/AADAT is a PLP-dependent homodimer; the structure shows a PLP–Lys263 aldimine at its catalytic site. Model: Human KAT-II crystal structure at 1.83 angstrom resolution. Limitations: Cofactor dependence alone does not define clinical B6 requirements or benefit from excess B6. Evidence access: Primary abstract Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27023527/ · DOI 10.3390/ijms17040446
Complete structured claim and evidence
Human KAT-II transaminates kynurenine to an intermediate that leads to kynurenic acid.
AADAT / KAT II → Kynurenic acid source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human enzyme structural study and catalytic characterization.
limitations
The enzyme performs transamination; it does not directly perform every subsequent chemical rearrangement.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Kynurenine can be diverted into a neuroactive branch.
primary_references
Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27023527/ · DOI 10.3390/ijms17040446
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 210–216
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme structural study and catalytic characterization. · source_derived_draft · unverified_draft
## tryptophan-kat2-kyna Kynurenine can be diverted into a neuroactive branch. Human KAT-II transaminates kynurenine to an intermediate that leads to kynurenic acid. Model: Human enzyme structural study and catalytic characterization. Limitations: The enzyme performs transamination; it does not directly perform every subsequent chemical rearrangement. Evidence access: Primary abstract Structure of the PLP-Form of the Human Kynurenine Aminotransferase II in a Novel Spacegroup at 1.83 Å Resolution. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27023527/ · DOI 10.3390/ijms17040446
Complete structured claim and evidence
Recombinant human ACMSD activity increased with incorporated zinc; adding free metal to purified enzyme did not restore or increase activity.
Human ACMS decarboxylase / ACMSD → Zinc(II) ion source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, metal incorporation and kinetics
experimental_model
Human enzyme expression, metal analysis, kinetics and crystallography.
limitations
Copper-substituted protein was used for spectroscopy; this does not make copper its preferred physiological cofactor.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The enzyme needs properly incorporated zinc, not simply zinc added later.
primary_references
Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722
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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme expression, metal analysis, kinetics and crystallography. · source_derived_draft · unverified_draft
## tryptophan-acmsd-zinc The enzyme needs properly incorporated zinc, not simply zinc added later. Recombinant human ACMSD activity increased with incorporated zinc; adding free metal to purified enzyme did not restore or increase activity. Model: Human enzyme expression, metal analysis, kinetics and crystallography. Limitations: Copper-substituted protein was used for spectroscopy; this does not make copper its preferred physiological cofactor. Evidence access: Primary full text, metal incorporation and kinetics Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722
Complete structured claim and evidence
Human ACMSD decarboxylates unstable ACMS, competing with its spontaneous conversion toward quinolinate in the NAD synthesis pathway.
Human ACMS decarboxylase / ACMSD → 2-Aminomuconate-6-semialdehyde / AMS source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, pathway and enzyme results
experimental_model
Human recombinant enzyme biochemistry.
limitations
Not evidence that zinc intake universally lowers NAD or that inhibiting this branch is always desirable.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A branch enzyme diverts material away from the quinolinate-to-NAD route.
primary_references
Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 226–232
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant enzyme biochemistry. · source_derived_draft · unverified_draft
## tryptophan-acmsd-diversion A branch enzyme diverts material away from the quinolinate-to-NAD route. Human ACMSD decarboxylates unstable ACMS, competing with its spontaneous conversion toward quinolinate in the NAD synthesis pathway. Model: Human recombinant enzyme biochemistry. Limitations: Not evidence that zinc intake universally lowers NAD or that inhibiting this branch is always desirable. Evidence access: Primary full text, pathway and enzyme results Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD): a structural and mechanistic unveiling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25392945/ · DOI 10.1002/prot.24722
Complete structured claim and evidence
ACMSD inhibition increased de novo NAD synthesis and SIRT1-related mitochondrial function in the mouse experiments.
Mouse ACMS decarboxylase / Acmsd → NAD+ source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse genetic/pharmacological work within a study also using C. elegans.
limitations
Not a human longevity outcome or evidence for tryptophan megadoses.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Restricting one exit route increased flow toward NAD in a preclinical model.
primary_references
De novo NAD+ synthesis enhances mitochondrial function and improves health. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30356218/ · DOI 10.1038/s41586-018-0645-6
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 234–240
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic/pharmacological work within a study also using C. elegans. · source_derived_draft · unverified_draft
## tryptophan-acmsd-inhibition-nad Restricting one exit route increased flow toward NAD in a preclinical model. ACMSD inhibition increased de novo NAD synthesis and SIRT1-related mitochondrial function in the mouse experiments. Model: Mouse genetic/pharmacological work within a study also using C. elegans. Limitations: Not a human longevity outcome or evidence for tryptophan megadoses. Evidence access: Primary abstract De novo NAD+ synthesis enhances mitochondrial function and improves health. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30356218/ · DOI 10.1038/s41586-018-0645-6
Complete structured claim and evidence
Mouse acute kidney injury reduced renal QPRT and NAD while quinolinate accumulated.
Mouse quinolinate phosphoribosyltransferase / Qprt → Mouse renal NAD abundance source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse acute kidney injury measurements.
limitations
Co-occurrence alone is not the complete causal test; Qprt dosage manipulation is recorded separately.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
An upstream metabolite can rise while the useful downstream product falls.
primary_references
De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 242–248
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse acute kidney injury measurements. · source_derived_draft · unverified_draft
## tryptophan-qprt-injury An upstream metabolite can rise while the useful downstream product falls. Mouse acute kidney injury reduced renal QPRT and NAD while quinolinate accumulated. Model: Mouse acute kidney injury measurements. Limitations: Co-occurrence alone is not the complete causal test; Qprt dosage manipulation is recorded separately. Evidence access: Primary abstract De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
Complete structured claim and evidence
Qprt-heterozygous mice had higher quinolinate, lower NAD and greater acute kidney injury susceptibility.
Mouse quinolinate phosphoribosyltransferase / Qprt → Mouse acute kidney injury susceptibility source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse Qprt heterozygous deletion.
limitations
No inference that more tryptophan fixes the blocked step.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Less conversion machinery increased vulnerability despite accumulated precursor.
primary_references
De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 250–256
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Qprt heterozygous deletion. · source_derived_draft · unverified_draft
## tryptophan-qprt-dosage Less conversion machinery increased vulnerability despite accumulated precursor. Qprt-heterozygous mice had higher quinolinate, lower NAD and greater acute kidney injury susceptibility. Model: Mouse Qprt heterozygous deletion. Limitations: No inference that more tryptophan fixes the blocked step. Evidence access: Primary abstract De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
Complete structured claim and evidence
In critically ill humans, a higher urinary quinolinate/tryptophan ratio predicted acute kidney injury and adverse outcomes; reduced QPRT was a mechanistic interpretation informed by mouse work.
Human urinary quinolinate-to-tryptophan ratio → Human acute kidney injury risk source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human observational metabolomics with separate mouse mechanistic experiments.
limitations
The mouse-QPRT experiments inform interpretation; human QPRT activity was not directly measured here.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A urine ratio was a risk marker, not a direct human enzyme measurement.
primary_references
De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
trigger_kind
biomarker_context Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 258–264
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human observational metabolomics with separate mouse mechanistic experiments. · source_derived_draft · unverified_draft
## tryptophan-urinary-qa-ratio A urine ratio was a risk marker, not a direct human enzyme measurement. In critically ill humans, a higher urinary quinolinate/tryptophan ratio predicted acute kidney injury and adverse outcomes; reduced QPRT was a mechanistic interpretation informed by mouse work. Model: Human observational metabolomics with separate mouse mechanistic experiments. Limitations: The mouse-QPRT experiments inform interpretation; human QPRT activity was not directly measured here. Evidence access: Primary abstract De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
Complete structured claim and evidence
A phase-1 placebo-controlled oral nicotinamide study showed dose-related increases in circulating NAD metabolites and an exploratory association with less acute kidney injury.
Nicotinamide → Human circulating NAD metabolites after nicotinamide source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human phase-1 study.
limitations
Not a definitive kidney-protection trial or proof that every blocked de novo step can be clinically bypassed.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
An alternate NAD precursor reached downstream metabolism in a human pilot.
primary_references
De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 266–272
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human phase-1 study. · source_derived_draft · unverified_draft
## tryptophan-nam-clinical An alternate NAD precursor reached downstream metabolism in a human pilot. A phase-1 placebo-controlled oral nicotinamide study showed dose-related increases in circulating NAD metabolites and an exploratory association with less acute kidney injury. Model: Human phase-1 study. Limitations: Not a definitive kidney-protection trial or proof that every blocked de novo step can be clinically bypassed. Evidence access: Primary abstract De novo NAD+ biosynthetic impairment in acute kidney injury in humans. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30127395/ · DOI 10.1038/s41591-018-0138-z
Complete structured claim and evidence
Quinolinate at 75 micromolar opened NMDA channels in cultured rat hippocampal neurons in calcium-containing, magnesium-free recording solution.
Quinolinic acid → Rat NMDA-type glutamate receptors, subunits unresolved source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat CA1 neuronal single-channel recording; 1.8 mM calcium.
limitations
Quinolinate is not tryptophan itself; bath concentration is not a dietary dose.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
One downstream metabolite activates an excitatory receptor.
primary_references
Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 274–280
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat CA1 neuronal single-channel recording; 1.8 mM calcium. · source_derived_draft · unverified_draft
## tryptophan-quinolinate-nmda One downstream metabolite activates an excitatory receptor. Quinolinate at 75 micromolar opened NMDA channels in cultured rat hippocampal neurons in calcium-containing, magnesium-free recording solution. Model: Rat CA1 neuronal single-channel recording; 1.8 mM calcium. Limitations: Quinolinate is not tryptophan itself; bath concentration is not a dietary dose. Evidence access: Primary abstract Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t
Complete structured claim and evidence
Adding 30 micromolar magnesium reduced quinolinate-activated NMDA channel mean open time to about one-third at minus 100 mV.
Mg2+ → Rat NMDA-type glutamate receptors, subunits unresolved source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat hippocampal patch-clamp experiment.
limitations
Does not establish that oral magnesium prevents quinolinate-related disease.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Magnesium and membrane voltage changed the receptor response.
primary_references
Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 282–288
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat hippocampal patch-clamp experiment. · source_derived_draft · unverified_draft
## tryptophan-magnesium-nmda Magnesium and membrane voltage changed the receptor response. Adding 30 micromolar magnesium reduced quinolinate-activated NMDA channel mean open time to about one-third at minus 100 mV. Model: Rat hippocampal patch-clamp experiment. Limitations: Does not establish that oral magnesium prevents quinolinate-related disease. Evidence access: Primary abstract Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t
Complete structured claim and evidence
Kynurenic acid inhibited alpha7 nicotinic responses in cultured rat hippocampal neurons after at least four minutes, with an IC50 near 7 micromolar.
Kynurenic acid → Rat alpha7-containing nicotinic acetylcholine receptors source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat hippocampal culture and slice electrophysiology.
limitations
Direct alpha7 inhibition is disputed by a later slice study; retain assay context rather than treating it as universal.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
One laboratory reported suppression of an acetylcholine receptor.
primary_references
The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11567036/ · DOI 10.1523/JNEUROSCI.21-19-07463.2001
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 290–296
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat hippocampal culture and slice electrophysiology. · source_derived_draft · unverified_draft
## tryptophan-kyna-alpha7-positive One laboratory reported suppression of an acetylcholine receptor. Kynurenic acid inhibited alpha7 nicotinic responses in cultured rat hippocampal neurons after at least four minutes, with an IC50 near 7 micromolar. Model: Rat hippocampal culture and slice electrophysiology. Limitations: Direct alpha7 inhibition is disputed by a later slice study; retain assay context rather than treating it as universal. Evidence access: Primary abstract The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11567036/ · DOI 10.1523/JNEUROSCI.21-19-07463.2001
Complete structured claim and evidence
Kynurenic acid did not inhibit choline-evoked alpha7 currents in rat hippocampal slice interneurons, contrasting with earlier reports.
Kynurenic acid → Rat alpha7-containing nicotinic acetylcholine receptors source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Adolescent rat stratum-radiatum interneurons in acute slices.
limitations
Slice age, temperature, agonist delivery and receptor environment are candidate explanations, not a demonstrated resolution.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Another experiment did not reproduce the claimed receptor block.
primary_references
Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22848433/ · DOI 10.1371/journal.pone.0041108
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 298–304
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Adolescent rat stratum-radiatum interneurons in acute slices. · source_derived_draft · unverified_draft
## tryptophan-kyna-alpha7-rat-null Another experiment did not reproduce the claimed receptor block. Kynurenic acid did not inhibit choline-evoked alpha7 currents in rat hippocampal slice interneurons, contrasting with earlier reports. Model: Adolescent rat stratum-radiatum interneurons in acute slices. Limitations: Slice age, temperature, agonist delivery and receptor environment are candidate explanations, not a demonstrated resolution. Evidence access: Primary abstract Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22848433/ · DOI 10.1371/journal.pone.0041108
Complete structured claim and evidence
Mouse hippocampal alpha7 currents remained insensitive to kynurenic acid, including slices prepared and stored in 1 mM for over 90 minutes, although glutamatergic currents were blocked.
Kynurenic acid → Mouse alpha7-containing nicotinic acetylcholine receptors source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse hilar and stratum-radiatum interneuron recordings.
limitations
Does not mean kynurenic acid has no neural effects.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The negative receptor result persisted with prolonged high exposure and a positive pharmacological control.
primary_references
Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22848433/ · DOI 10.1371/journal.pone.0041108
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 306–312
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse hilar and stratum-radiatum interneuron recordings. · source_derived_draft · unverified_draft
## tryptophan-kyna-alpha7-mouse-null The negative receptor result persisted with prolonged high exposure and a positive pharmacological control. Mouse hippocampal alpha7 currents remained insensitive to kynurenic acid, including slices prepared and stored in 1 mM for over 90 minutes, although glutamatergic currents were blocked. Model: Mouse hilar and stratum-radiatum interneuron recordings. Limitations: Does not mean kynurenic acid has no neural effects. Evidence access: Primary abstract Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22848433/ · DOI 10.1371/journal.pone.0041108
Complete structured claim and evidence
Kynurenic-acid NMDA-blocking IC50 shifted from about 15 to 235 micromolar when 10 micromolar glycine was present.
Glycine → Rat NMDA-type glutamate receptors, subunits unresolved source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat neuronal electrophysiological assay.
limitations
An assay co-agonist effect does not show that glycine supplements change human disease outcomes.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A second amino acid changed how strongly the metabolite blocked a receptor.
primary_references
The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11567036/ · DOI 10.1523/JNEUROSCI.21-19-07463.2001
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 314–320
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat neuronal electrophysiological assay. · source_derived_draft · unverified_draft
## tryptophan-glycine-kyna-nmda A second amino acid changed how strongly the metabolite blocked a receptor. Kynurenic-acid NMDA-blocking IC50 shifted from about 15 to 235 micromolar when 10 micromolar glycine was present. Model: Rat neuronal electrophysiological assay. Limitations: An assay co-agonist effect does not show that glycine supplements change human disease outcomes. Evidence access: Primary abstract The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11567036/ · DOI 10.1523/JNEUROSCI.21-19-07463.2001
Complete structured claim and evidence
IFN-gamma induced IDO activity and depleted almost all culture-medium tryptophan over two to three days in responsive human KB and WiDr cells.
Human interferon gamma / IFNG → Human indoleamine 2,3-dioxygenase 1 / IDO1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cancer-cell cultures.
limitations
Other tested cell lines lacked this induced enzyme response; not a universal effect of every interferon exposure.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
An immune signal can locally consume the available amino acid.
primary_references
Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 322–328
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell cultures. · source_derived_draft · unverified_draft
## tryptophan-ifng-ido-depletion An immune signal can locally consume the available amino acid. IFN-gamma induced IDO activity and depleted almost all culture-medium tryptophan over two to three days in responsive human KB and WiDr cells. Model: Human cancer-cell cultures. Limitations: Other tested cell lines lacked this induced enzyme response; not a universal effect of every interferon exposure. Evidence access: Primary abstract Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
Complete structured claim and evidence
Adding tryptophan reversed IFN-gamma-associated growth suppression in KB cells in a dose- and time-dependent manner.
L-Tryptophan → Proliferation of human KB cells source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human KB culture after IFN-gamma.
limitations
Not a recommendation to support tumor growth with supplementation.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Replacement helped where deprivation was the limiting mechanism.
primary_references
Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 330–336
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human KB culture after IFN-gamma. · source_derived_draft · unverified_draft
## tryptophan-kb-repletion Replacement helped where deprivation was the limiting mechanism. Adding tryptophan reversed IFN-gamma-associated growth suppression in KB cells in a dose- and time-dependent manner. Model: Human KB culture after IFN-gamma. Limitations: Not a recommendation to support tumor growth with supplementation. Evidence access: Primary abstract Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
Complete structured claim and evidence
Added tryptophan did not reverse IFN-gamma growth suppression in WiDr cells despite induced tryptophan catabolism.
L-Tryptophan → Proliferation of human WiDr cells source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human WiDr culture.
limitations
This experimentally observed context difference is not a contradiction requiring a universal single explanation.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Another cell type retained suppression after the nutrient was replaced.
primary_references
Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 338–344
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human WiDr culture. · source_derived_draft · unverified_draft
## tryptophan-widr-repletion-fails Another cell type retained suppression after the nutrient was replaced. Added tryptophan did not reverse IFN-gamma growth suppression in WiDr cells despite induced tryptophan catabolism. Model: Human WiDr culture. Limitations: This experimentally observed context difference is not a contradiction requiring a universal single explanation. Evidence access: Primary abstract Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. · 1988 · https://pubmed.ncbi.nlm.nih.gov/3124115/ · DOI 10.1073/pnas.85.4.1242
Complete structured claim and evidence
CD40 ligand increased IFN-gamma-driven tryptophan catabolism in human monocyte-derived macrophages.
Human CD40 ligand / CD40LG → Human indoleamine 2,3-dioxygenase 1 / IDO1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 5
experimental_model
Human macrophage and activated-T-cell coculture.
limitations
Not evidence that systemic tryptophan intake determines every immune response.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Two immune signals jointly increased local consumption.
primary_references
Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 346–352
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human macrophage and activated-T-cell coculture. · source_derived_draft · unverified_draft
## tryptophan-cd40-ifng-ido Two immune signals jointly increased local consumption. CD40 ligand increased IFN-gamma-driven tryptophan catabolism in human monocyte-derived macrophages. Model: Human macrophage and activated-T-cell coculture. Limitations: Not evidence that systemic tryptophan intake determines every immune response. Evidence access: Primary full text, Figure 5 Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
Complete structured claim and evidence
Human T cells activated without tryptophan arrested in mid-G1 while retaining early activation and some protein synthesis.
L-Tryptophan → Human activated T-cell proliferation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, cell-cycle results
experimental_model
Human purified T cells activated with anti-CD3/CD28.
limitations
Not synonymous with immediate cell death or complete cessation of protein synthesis.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Cells could begin activation but could not complete the division program.
primary_references
Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 354–360
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human purified T cells activated with anti-CD3/CD28. · source_derived_draft · unverified_draft
## tryptophan-tcell-arrest Cells could begin activation but could not complete the division program. Human T cells activated without tryptophan arrested in mid-G1 while retaining early activation and some protein synthesis. Model: Human purified T cells activated with anti-CD3/CD28. Limitations: Not synonymous with immediate cell death or complete cessation of protein synthesis. Evidence access: Primary full text, cell-cycle results Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
Complete structured claim and evidence
After tryptophan-sensitive arrest, human T cells required renewed T-cell-receptor signaling as well as tryptophan to resume division.
L-Tryptophan → Human activated T-cell proliferation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, TCR-dependence results
experimental_model
Human T-cell withdrawal, add-back and receptor-restimulation experiments.
limitations
A cell-cycle checkpoint experiment, not a general human supplementation rule.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Replacing the nutrient alone did not restore the lost activation commitment.
primary_references
Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 362–368
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human T-cell withdrawal, add-back and receptor-restimulation experiments. · source_derived_draft · unverified_draft
## tryptophan-tcell-restimulation Replacing the nutrient alone did not restore the lost activation commitment. After tryptophan-sensitive arrest, human T cells required renewed T-cell-receptor signaling as well as tryptophan to resume division. Model: Human T-cell withdrawal, add-back and receptor-restimulation experiments. Limitations: A cell-cycle checkpoint experiment, not a general human supplementation rule. Evidence access: Primary full text, TCR-dependence results Inhibition of T cell proliferation by macrophage tryptophan catabolism. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10224276/ · DOI 10.1084/jem.189.9.1363
Complete structured claim and evidence
GCN2-deficient mouse T cells resisted suppression and anergy imposed by IDO-expressing dendritic cells in the 2005 study.
Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments.
limitations
A later genetic study reports arrest without GCN2; necessity is not universal across the available evidence.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
One study found this nutrient-stress sensor necessary for suppression.
primary_references
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15894280/ · DOI 10.1016/j.immuni.2005.03.013
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 370–376
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments. · source_derived_draft · unverified_draft
## tryptophan-gcn2-required One study found this nutrient-stress sensor necessary for suppression. GCN2-deficient mouse T cells resisted suppression and anergy imposed by IDO-expressing dendritic cells in the 2005 study. Model: Mouse Gcn2 knockout, IDO-positive plasmacytoid/tumor-draining dendritic-cell experiments. Limitations: A later genetic study reports arrest without GCN2; necessity is not universal across the available evidence. Evidence access: Primary abstract GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15894280/ · DOI 10.1016/j.immuni.2005.03.013
Complete structured claim and evidence
GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study.
Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation.
limitations
Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Another study found the division block persisted without that sensor.
primary_references
Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 378–384
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. · source_derived_draft · unverified_draft
## tryptophan-gcn2-not-required Another study found the division block persisted without that sensor. GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study. Model: Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. Limitations: Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model. Evidence access: Primary abstract Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
Complete structured claim and evidence
GCN2 loss prevented induction of stress-target genes such as CHOP even though amino-acid-limited CD8 cells still arrested.
Mouse GCN2 / Eif2ak4 → Mouse CHOP / Ddit3 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse Gcn2-deficient CD8 T-cell experiments.
limitations
Does not make GCN2 dispensable for T-cell fitness; proliferation and trafficking defects were also observed.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A stress gene response and the division checkpoint could be separated.
primary_references
Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 386–392
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Gcn2-deficient CD8 T-cell experiments. · source_derived_draft · unverified_draft
## tryptophan-gcn2-chop A stress gene response and the division checkpoint could be separated. GCN2 loss prevented induction of stress-target genes such as CHOP even though amino-acid-limited CD8 cells still arrested. Model: Mouse Gcn2-deficient CD8 T-cell experiments. Limitations: Does not make GCN2 dispensable for T-cell fitness; proliferation and trafficking defects were also observed. Evidence access: Primary abstract Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079
Complete structured claim and evidence
Donor mouse T cells lacking GCN2 still responded to IDO-mediated suppression in graft-versus-host disease experiments.
Mouse GCN2 / Eif2ak4 → Mouse T-cell proliferation under tryptophan limitation or IDO exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse allogeneic transplantation and donor T-cell genetics.
limitations
The authors favor metabolite-mediated suppression; it does not prove which single metabolite explains all models.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
In a transplant model, IDO suppression also persisted without GCN2.
primary_references
Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19828695/ · DOI 10.1182/blood-2009-06-227587
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 394–400
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse allogeneic transplantation and donor T-cell genetics. · source_derived_draft · unverified_draft
## tryptophan-gcn2-gvhd In a transplant model, IDO suppression also persisted without GCN2. Donor mouse T cells lacking GCN2 still responded to IDO-mediated suppression in graft-versus-host disease experiments. Model: Mouse allogeneic transplantation and donor T-cell genetics. Limitations: The authors favor metabolite-mediated suppression; it does not prove which single metabolite explains all models. Evidence access: Primary abstract Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19828695/ · DOI 10.1182/blood-2009-06-227587
Complete structured claim and evidence
IFN-gamma/IDO-driven tryptophan depletion reduced S6K phosphorylation in human HeLa cells; tryptophan repletion restored the mTOR readout.
Human indoleamine 2,3-dioxygenase 1 / IDO1 → Human mechanistic target of rapamycin kinase / MTOR source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, Figure 2
experimental_model
Human HeLa cells, depleted media and amino-acid add-back.
limitations
S6K phosphorylation is a pathway readout, not direct tryptophan binding to MTOR.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Local depletion reduced a growth signal as well as changing metabolite supply.
primary_references
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 402–408
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HeLa cells, depleted media and amino-acid add-back. · source_derived_draft · unverified_draft
## tryptophan-trp-mtor Local depletion reduced a growth signal as well as changing metabolite supply. IFN-gamma/IDO-driven tryptophan depletion reduced S6K phosphorylation in human HeLa cells; tryptophan repletion restored the mTOR readout. Model: Human HeLa cells, depleted media and amino-acid add-back. Limitations: S6K phosphorylation is a pathway readout, not direct tryptophan binding to MTOR. Evidence access: Primary full text, Figure 2 IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
Complete structured claim and evidence
Tryptophan deprivation increased LC3-based autophagy readouts in human HeLa cells; tryptophan or D-1-methyltryptophan reversed those readouts.
L-Tryptophan → Autophagic response to tryptophan deprivation in human cells source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, Figure 4
experimental_model
Human HeLa LC3 imaging and immunoblotting.
limitations
LC3 measures do not establish every component of autophagic flux; the drug is not equivalent to nutrient replacement.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A shortage changed cellular recycling signals.
primary_references
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 410–416
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HeLa LC3 imaging and immunoblotting. · source_derived_draft · unverified_draft
## tryptophan-trp-autophagy A shortage changed cellular recycling signals. Tryptophan deprivation increased LC3-based autophagy readouts in human HeLa cells; tryptophan or D-1-methyltryptophan reversed those readouts. Model: Human HeLa LC3 imaging and immunoblotting. Limitations: LC3 measures do not establish every component of autophagic flux; the drug is not equivalent to nutrient replacement. Evidence access: Primary full text, Figure 4 IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
Complete structured claim and evidence
Tryptophan add-back restored activating phosphorylation of ectopically expressed GST–PKC-theta after deprivation in human MCF-7 cells.
L-Tryptophan → Phosphorylation of ectopically expressed PKC-theta in human MCF-7 cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 5
experimental_model
Human cancer-cell expression assay.
limitations
Not a direct demonstration of endogenous PKC-theta regulation in patient T cells.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The response extended to a second signaling branch.
primary_references
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 418–424
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell expression assay. · source_derived_draft · unverified_draft
## tryptophan-trp-pkc The response extended to a second signaling branch. Tryptophan add-back restored activating phosphorylation of ectopically expressed GST–PKC-theta after deprivation in human MCF-7 cells. Model: Human cancer-cell expression assay. Limitations: Not a direct demonstration of endogenous PKC-theta regulation in patient T cells. Evidence access: Primary full text, Figure 5 IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
Complete structured claim and evidence
Human tumor-cell TDO-derived kynurenine supported AHR-dependent survival and motility in the study.
L-Kynurenine → Human aryl hydrocarbon receptor / AHR source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human tumor-cell experiments with human brain-tumor associations.
limitations
The chemical identity of the active ligand requires care: later work identified potent trace kynurenine condensation products.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The catabolic route could feed a tumor-associated signal.
primary_references
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21976023/ · DOI 10.1038/nature10491
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 426–432
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human tumor-cell experiments with human brain-tumor associations. · source_derived_draft · unverified_draft
## tryptophan-tdo-ahr The catabolic route could feed a tumor-associated signal. Human tumor-cell TDO-derived kynurenine supported AHR-dependent survival and motility in the study. Model: Human tumor-cell experiments with human brain-tumor associations. Limitations: The chemical identity of the active ligand requires care: later work identified potent trace kynurenine condensation products. Evidence access: Primary abstract An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21976023/ · DOI 10.1038/nature10491
Complete structured claim and evidence
Incubation or storage increased kynurenine-solution AHR potency by 100–1000-fold; isolated trace condensation products accounted for potent activity.
L-Kynurenine → Kynurenine-derived trace extended aromatic condensation products / TEACOPs source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Chemical purification, synthesis and mouse-AHR reporter/ligand-pocket experiments.
limitations
Does not quantify TEACOP concentrations in human tumors or prove every kynurenine-associated effect is caused by these products.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
What forms from a metabolite in solution can matter more than the nominal starting compound.
primary_references
Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29279331/ · DOI 10.1074/jbc.RA117.000631
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 434–440
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Chemical purification, synthesis and mouse-AHR reporter/ligand-pocket experiments. · source_derived_draft · unverified_draft
## tryptophan-teacop-formation What forms from a metabolite in solution can matter more than the nominal starting compound. Incubation or storage increased kynurenine-solution AHR potency by 100–1000-fold; isolated trace condensation products accounted for potent activity. Model: Chemical purification, synthesis and mouse-AHR reporter/ligand-pocket experiments. Limitations: Does not quantify TEACOP concentrations in human tumors or prove every kynurenine-associated effect is caused by these products. Evidence access: Primary abstract Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29279331/ · DOI 10.1074/jbc.RA117.000631
Complete structured claim and evidence
Purified kynurenine-derived TEACOPs activated mouse AHR at low picomolar concentrations in the reported assays.
Kynurenine-derived trace extended aromatic condensation products / TEACOPs → Mouse aryl hydrocarbon receptor / Ahr source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and primary full text, Figure 1 and receptor constructs
experimental_model
Mouse AHR constructs in chemical pharmacology experiments.
limitations
Mouse receptor evidence must not be silently converted into a measured human physiological concentration.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Tiny amounts of a derivative can change receptor signaling.
primary_references
Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29279331/ · DOI 10.1074/jbc.RA117.000631
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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse AHR constructs in chemical pharmacology experiments. · source_derived_draft · unverified_draft
## tryptophan-teacop-ahr Tiny amounts of a derivative can change receptor signaling. Purified kynurenine-derived TEACOPs activated mouse AHR at low picomolar concentrations in the reported assays. Model: Mouse AHR constructs in chemical pharmacology experiments. Limitations: Mouse receptor evidence must not be silently converted into a measured human physiological concentration. Evidence access: Primary abstract and primary full text, Figure 1 and receptor constructs Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29279331/ · DOI 10.1074/jbc.RA117.000631
Complete structured claim and evidence
IL4I1 generated indole metabolites and kynurenic acid that activated AHR in the cancer study.
Human interleukin-4-induced protein 1 / IL4I1 → Human aryl hydrocarbon receptor / AHR source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cancer/biochemical work with separate mouse CLL experiments.
limitations
This abstract groups several products; their individual concentrations and relative causal contributions are not resolved here.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Another enzyme can feed the same receptor through different metabolites.
primary_references
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32818467/ · DOI 10.1016/j.cell.2020.07.038
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 450–456
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cancer/biochemical work with separate mouse CLL experiments. · source_derived_draft · unverified_draft
## tryptophan-il4i1-route Another enzyme can feed the same receptor through different metabolites. IL4I1 generated indole metabolites and kynurenic acid that activated AHR in the cancer study. Model: Human cancer/biochemical work with separate mouse CLL experiments. Limitations: This abstract groups several products; their individual concentrations and relative causal contributions are not resolved here. Evidence access: Primary abstract IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32818467/ · DOI 10.1016/j.cell.2020.07.038
Complete structured claim and evidence
IDO1 inhibitors did not block IL4I1 in the study, leaving an alternative route to AHR activation.
Human interleukin-4-induced protein 1 / IL4I1 → Human aryl hydrocarbon receptor / AHR source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cancer-mechanism experiments.
limitations
An explanation proposed for clinical trial failure, not proof that IL4I1 caused failure in every patient.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Blocking one enzyme does not necessarily close a parallel route.
primary_references
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32818467/ · DOI 10.1016/j.cell.2020.07.038
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 458–464
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cancer-mechanism experiments. · source_derived_draft · unverified_draft
## tryptophan-ido-drug-bypass Blocking one enzyme does not necessarily close a parallel route. IDO1 inhibitors did not block IL4I1 in the study, leaving an alternative route to AHR activation. Model: Cancer-mechanism experiments. Limitations: An explanation proposed for clinical trial failure, not proof that IL4I1 caused failure in every patient. Evidence access: Primary abstract IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32818467/ · DOI 10.1016/j.cell.2020.07.038
Complete structured claim and evidence
The studied lactobacilli produced indole-3-aldehyde when using tryptophan as an energy source.
Lactobacillus isolates in the 2013 tryptophan study → Indole-3-aldehyde source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Bacterial metabolic experiments in a mouse mucosal-immunity study.
limitations
Strain- and substrate-dependent; not every Lactobacillus preparation has the same capacity.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Microbes can turn the nutrient into a local immune signal.
primary_references
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 466–472
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Bacterial metabolic experiments in a mouse mucosal-immunity study. · source_derived_draft · unverified_draft
## tryptophan-microbial-aldehyde Microbes can turn the nutrient into a local immune signal. The studied lactobacilli produced indole-3-aldehyde when using tryptophan as an energy source. Model: Bacterial metabolic experiments in a mouse mucosal-immunity study. Limitations: Strain- and substrate-dependent; not every Lactobacillus preparation has the same capacity. Evidence access: Primary abstract Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Complete structured claim and evidence
Microbial indole-3-aldehyde supported Ahr-dependent Il22 transcription in mice.
Indole-3-aldehyde → Mouse interleukin-22 / Il22 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse mucosal immunity and microbial metabolite experiments.
limitations
Not a direct human supplementation outcome.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A microbial product connected the amino acid to an epithelial-defense cytokine.
primary_references
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 474–480
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse mucosal immunity and microbial metabolite experiments. · source_derived_draft · unverified_draft
## tryptophan-aldehyde-ahr A microbial product connected the amino acid to an epithelial-defense cytokine. Microbial indole-3-aldehyde supported Ahr-dependent Il22 transcription in mice. Model: Mouse mucosal immunity and microbial metabolite experiments. Limitations: Not a direct human supplementation outcome. Evidence access: Primary abstract Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Complete structured claim and evidence
IL-22-dependent mucosal responses supported Candida colonization resistance and protection from inflammation in the mouse microbial-tryptophan study.
Mouse interleukin-22 / Il22 → Mouse susceptibility to chemically induced colitis in tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse fungal colonization and mucosal inflammation models.
limitations
This protective model does not establish a universally beneficial effect of sustained AHR or IL-22 activation.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The downstream cytokine helped organize mucosal defense.
primary_references
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 482–488
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse fungal colonization and mucosal inflammation models. · source_derived_draft · unverified_draft
## tryptophan-il22-protection The downstream cytokine helped organize mucosal defense. IL-22-dependent mucosal responses supported Candida colonization resistance and protection from inflammation in the mouse microbial-tryptophan study. Model: Mouse fungal colonization and mucosal inflammation models. Limitations: This protective model does not establish a universally beneficial effect of sustained AHR or IL-22 activation. Evidence access: Primary abstract Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23973224/ · DOI 10.1016/j.immuni.2013.08.003
Complete structured claim and evidence
Disrupting fldC in C. sporogenes abolished indolepropionate accumulation in culture and altered aromatic-amino-acid metabolism.
Clostridium sporogenes FldC → Indole-3-propionic acid / indolepropionate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, Figures 1–3
experimental_model
C. sporogenes ClosTron mutant and LC–MS/MS.
limitations
The mutation affects phenylalanine and tyrosine products as well; effects cannot all be assigned to indolepropionate.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A missing microbial enzyme stopped production despite available tryptophan.
primary_references
A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 490–496
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · C. sporogenes ClosTron mutant and LC–MS/MS. · source_derived_draft · unverified_draft
## tryptophan-fldc-loss A missing microbial enzyme stopped production despite available tryptophan. Disrupting fldC in C. sporogenes abolished indolepropionate accumulation in culture and altered aromatic-amino-acid metabolism. Model: C. sporogenes ClosTron mutant and LC–MS/MS. Limitations: The mutation affects phenylalanine and tyrosine products as well; effects cannot all be assigned to indolepropionate. Evidence access: Primary full text, Figures 1–3 A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
Complete structured claim and evidence
C. sporogenes fldH disruption impaired the reductive metabolism of aromatic amino acids needed for indolepropionate production.
Clostridium sporogenes FldH → Indole-3-propionic acid / indolepropionate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, Figure 3
experimental_model
Bacterial targeted-mutant metabolomics.
limitations
Genetic pathway necessity is not a purified-enzyme substrate-specificity measurement.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The microbial route needs more than one enzyme.
primary_references
A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 498–504
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Bacterial targeted-mutant metabolomics. · source_derived_draft · unverified_draft
## tryptophan-fldh-loss The microbial route needs more than one enzyme. C. sporogenes fldH disruption impaired the reductive metabolism of aromatic amino acids needed for indolepropionate production. Model: Bacterial targeted-mutant metabolomics. Limitations: Genetic pathway necessity is not a purified-enzyme substrate-specificity measurement. Evidence access: Primary full text, Figure 3 A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
Complete structured claim and evidence
C. sporogenes acdA disruption impaired the reductive aromatic-amino-acid pathway leading to indolepropionate.
Clostridium sporogenes AcdA → Indole-3-propionic acid / indolepropionate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, Figure 3
experimental_model
Bacterial targeted-mutant metabolomics.
limitations
Do not equate a host ACAD gene with this microbial enzyme.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A later reduction step is another potential production bottleneck.
primary_references
A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 506–512
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Bacterial targeted-mutant metabolomics. · source_derived_draft · unverified_draft
## tryptophan-acda-loss A later reduction step is another potential production bottleneck. C. sporogenes acdA disruption impaired the reductive aromatic-amino-acid pathway leading to indolepropionate. Model: Bacterial targeted-mutant metabolomics. Limitations: Do not equate a host ACAD gene with this microbial enzyme. Evidence access: Primary full text, Figure 3 A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
Complete structured claim and evidence
Gnotobiotic mice colonized with the fldC-mutant strain had reduced gut and circulating indolepropionate and increased intestinal permeability compared with wild-type colonization.
Clostridium sporogenes FldC → Mouse intestinal permeability in microbial tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, host colonization results
experimental_model
Gnotobiotic mouse colonization.
limitations
Several metabolites changed; this comparison alone does not prove indolepropionate is the sole mediator.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A microbial genetic change altered a host barrier phenotype.
primary_references
A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 514–520
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Gnotobiotic mouse colonization. · source_derived_draft · unverified_draft
## tryptophan-fldc-host-effect A microbial genetic change altered a host barrier phenotype. Gnotobiotic mice colonized with the fldC-mutant strain had reduced gut and circulating indolepropionate and increased intestinal permeability compared with wild-type colonization. Model: Gnotobiotic mouse colonization. Limitations: Several metabolites changed; this comparison alone does not prove indolepropionate is the sole mediator. Evidence access: Primary full text, host colonization results A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29168502/ · DOI 10.1038/nature24661
Complete structured claim and evidence
Indolepropionate activated mouse PXR with an EC50 near 0.55 micromolar in the reporter assay.
Indole-3-propionic acid / indolepropionate → Mouse pregnane X receptor / Pxr / Nr1i2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 1
experimental_model
Mouse PXR expressed in 293T cells.
limitations
Expression host does not make the receptor human; potency differed sharply for human PXR.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The mouse receptor was sensitive to this microbial product.
primary_references
Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 522–528
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse PXR expressed in 293T cells. · source_derived_draft · unverified_draft
## tryptophan-ipa-mouse-pxr The mouse receptor was sensitive to this microbial product. Indolepropionate activated mouse PXR with an EC50 near 0.55 micromolar in the reporter assay. Model: Mouse PXR expressed in 293T cells. Limitations: Expression host does not make the receptor human; potency differed sharply for human PXR. Evidence access: Primary full text, Figure 1 Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
Complete structured claim and evidence
Indolepropionate alone weakly activated human PXR, with an EC50 near 120 micromolar; adding 1 mM indole enhanced activation.
Indole-3-propionic acid / indolepropionate → Human pregnane X receptor / SXR / PXR / NR1I2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 1
experimental_model
Human PXR reporter in 293T cells.
limitations
Millimolar indole is an assay condition, not a verified systemic human exposure.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A partner microbial metabolite changed the human receptor response.
primary_references
Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 530–536
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human PXR reporter in 293T cells. · source_derived_draft · unverified_draft
## tryptophan-ipa-human-pxr A partner microbial metabolite changed the human receptor response. Indolepropionate alone weakly activated human PXR, with an EC50 near 120 micromolar; adding 1 mM indole enhanced activation. Model: Human PXR reporter in 293T cells. Limitations: Millimolar indole is an assay condition, not a verified systemic human exposure. Evidence access: Primary full text, Figure 1 Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
Complete structured claim and evidence
Nr1i2-deficient mice had a barrier defect with increased TLR4-related signaling; additional Tlr4 deletion corrected the permeability phenotype.
Mouse pregnane X receptor / Pxr / Nr1i2 → Mouse intestinal permeability in microbial tryptophan experiments source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text, genetic barrier experiments
experimental_model
Mouse Nr1i2 and Tlr4 genetic perturbations.
limitations
Does not demonstrate the same causal chain in human patients.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Receptor status and inflammatory sensing determined the barrier outcome.
primary_references
Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 538–544
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse Nr1i2 and Tlr4 genetic perturbations. · source_derived_draft · unverified_draft
## tryptophan-pxr-tlr4-barrier Receptor status and inflammatory sensing determined the barrier outcome. Nr1i2-deficient mice had a barrier defect with increased TLR4-related signaling; additional Tlr4 deletion corrected the permeability phenotype. Model: Mouse Nr1i2 and Tlr4 genetic perturbations. Limitations: Does not demonstrate the same causal chain in human patients. Evidence access: Primary full text, genetic barrier experiments Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25065623/ · DOI 10.1016/j.immuni.2014.06.014
Complete structured claim and evidence
Purified C. sporogenes CLOSPO_02083 catalyzed tryptophan decarboxylation to tryptamine as a PLP-dependent enzyme.
Clostridium sporogenes CLOSPO_02083 tryptophan decarboxylase → Tryptamine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, enzyme identification and biochemical assays
experimental_model
Recombinant bacterial enzyme biochemistry.
limitations
Does not establish that B6 supplementation increases this product in humans.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A bacterial B6-dependent enzyme sends tryptophan down another branch.
primary_references
Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25263219/ · DOI 10.1016/j.chom.2014.09.001
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 546–552
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Recombinant bacterial enzyme biochemistry. · source_derived_draft · unverified_draft
## tryptophan-clostridial-tryptamine A bacterial B6-dependent enzyme sends tryptophan down another branch. Purified C. sporogenes CLOSPO_02083 catalyzed tryptophan decarboxylation to tryptamine as a PLP-dependent enzyme. Model: Recombinant bacterial enzyme biochemistry. Limitations: Does not establish that B6 supplementation increases this product in humans. Evidence access: Primary full text, enzyme identification and biochemical assays Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25263219/ · DOI 10.1016/j.chom.2014.09.001
Complete structured claim and evidence
Purified R. gnavus RUMGNA_01526 robustly decarboxylated tryptophan despite only 26% sequence identity to the C. sporogenes enzyme.
Ruminococcus gnavus RUMGNA_01526 tryptophan decarboxylase → Tryptamine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, enzyme screening and purification
experimental_model
Purified bacterial enzyme assays.
limitations
Enzyme presence and activity are not universal across human gut communities.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Different microbes can reach the same metabolite with distinct proteins.
primary_references
Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25263219/ · DOI 10.1016/j.chom.2014.09.001
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 554–560
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial enzyme assays. · source_derived_draft · unverified_draft
## tryptophan-ruminococcal-tryptamine Different microbes can reach the same metabolite with distinct proteins. Purified R. gnavus RUMGNA_01526 robustly decarboxylated tryptophan despite only 26% sequence identity to the C. sporogenes enzyme. Model: Purified bacterial enzyme assays. Limitations: Enzyme presence and activity are not universal across human gut communities. Evidence access: Primary full text, enzyme screening and purification Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25263219/ · DOI 10.1016/j.chom.2014.09.001
Complete structured claim and evidence
Tryptamine increased epithelial ionic flux and colonoid fluid secretion through 5-HT4 receptors in mice.
Tryptamine → Mouse colonic ionic and fluid secretion after tryptamine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Germ-free and human-stool-colonized mouse tissue/colonoids.
limitations
Humanized microbiota does not make the host tissue human.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A microbial tryptophan product can change intestinal fluid movement.
primary_references
Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 562–568
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Germ-free and human-stool-colonized mouse tissue/colonoids. · source_derived_draft · unverified_draft
## tryptophan-tryptamine-secretion A microbial tryptophan product can change intestinal fluid movement. Tryptamine increased epithelial ionic flux and colonoid fluid secretion through 5-HT4 receptors in mice. Model: Germ-free and human-stool-colonized mouse tissue/colonoids. Limitations: Humanized microbiota does not make the host tissue human. Evidence access: Primary abstract Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
Complete structured claim and evidence
Htr4 knockout or receptor antagonism removed the secretory response to tryptamine.
Mouse serotonin receptor 4 / Htr4 → Mouse colonic ionic and fluid secretion after tryptamine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse knockout and pharmacological blockade.
limitations
Not a universal receptor requirement for every action of tryptamine.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The metabolite could not produce this response without its receptor.
primary_references
Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 570–576
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout and pharmacological blockade. · source_derived_draft · unverified_draft
## tryptophan-htr4-loss The metabolite could not produce this response without its receptor. Htr4 knockout or receptor antagonism removed the secretory response to tryptamine. Model: Mouse knockout and pharmacological blockade. Limitations: Not a universal receptor requirement for every action of tryptamine. Evidence access: Primary abstract Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
Complete structured claim and evidence
Colonizing germ-free mice with B. thetaiotaomicron engineered to produce tryptamine accelerated gastrointestinal transit.
Tryptamine → Mouse gastrointestinal transit after microbial tryptamine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Engineered bacterium in gnotobiotic mice.
limitations
Not evidence that tryptophan supplements have the same effect in humans.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Changing microbial production changed movement through the gut.
primary_references
Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 578–584
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Engineered bacterium in gnotobiotic mice. · source_derived_draft · unverified_draft
## tryptophan-tryptamine-transit Changing microbial production changed movement through the gut. Colonizing germ-free mice with B. thetaiotaomicron engineered to produce tryptamine accelerated gastrointestinal transit. Model: Engineered bacterium in gnotobiotic mice. Limitations: Not evidence that tryptophan supplements have the same effect in humans. Evidence access: Primary abstract Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29902441/ · DOI 10.1016/j.chom.2018.05.004
Complete structured claim and evidence
Rat liver microsomal induction/inhibition experiments implicated CYP2E1 as the major enzyme oxidizing indole to indoxyl with NADPH support.
Indole → Indoxyl / 3-hydroxyindole source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat liver microsomes with inducer/inhibitor profiling.
limitations
CYP2E1 assignment is supported by convergent microsomal tests rather than exclusive purified-enzyme proof.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A gut-derived indole can enter a liver oxidation route.
primary_references
Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11808865/ · DOI 10.1007/BF03226377
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 586–592
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat liver microsomes with inducer/inhibitor profiling. · source_derived_draft · unverified_draft
## tryptophan-indole-oxidation A gut-derived indole can enter a liver oxidation route. Rat liver microsomal induction/inhibition experiments implicated CYP2E1 as the major enzyme oxidizing indole to indoxyl with NADPH support. Model: Rat liver microsomes with inducer/inhibitor profiling. Limitations: CYP2E1 assignment is supported by convergent microsomal tests rather than exclusive purified-enzyme proof. Evidence access: Primary abstract Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11808865/ · DOI 10.1007/BF03226377
Complete structured claim and evidence
Recombinant human SULT1A1*2 converted indoxyl to indoxyl sulfate using PAPS; apparent indoxyl Km was 5.6 ± 1.8 micromolar.
Human sulfotransferase 1A1 / SULT1A1 → Indoxyl sulfate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human recombinant allozyme and liver cytosol kinetic comparison.
limitations
Sulfation does not necessarily make a retained metabolite harmless; no inference that sulfur intake controls clinical toxicity.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A human sulfation enzyme adds a sulfur-containing group to the metabolite.
primary_references
Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12064372/ · DOI 10.1007/BF03190428
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 594–600
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human recombinant allozyme and liver cytosol kinetic comparison. · source_derived_draft · unverified_draft
## tryptophan-indoxyl-sulfation A human sulfation enzyme adds a sulfur-containing group to the metabolite. Recombinant human SULT1A1*2 converted indoxyl to indoxyl sulfate using PAPS; apparent indoxyl Km was 5.6 ± 1.8 micromolar. Model: Human recombinant allozyme and liver cytosol kinetic comparison. Limitations: Sulfation does not necessarily make a retained metabolite harmless; no inference that sulfur intake controls clinical toxicity. Evidence access: Primary abstract Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12064372/ · DOI 10.1007/BF03190428
Complete structured claim and evidence
Indoxyl sulfate entered human HK-2 proximal-tubule cells through organic-anion transport and induced Nrf2 activation consistent with intracellular oxidative stress.
Indoxyl sulfate → Human HK-2 cellular indoxyl-sulfate uptake and Nrf2 response source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human proximal-tubule-derived HK-2 cell experiments.
limitations
Accessed abstract does not resolve each transporter isoform in this cell assay; Nrf2 activation is not itself proof of clinical renal injury.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Transport into kidney cells can expose them to a downstream metabolite.
primary_references
Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24958931/ · DOI 10.1093/toxsci/kfu119
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 602–608
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human proximal-tubule-derived HK-2 cell experiments. · source_derived_draft · unverified_draft
## tryptophan-indoxyl-cell-uptake Transport into kidney cells can expose them to a downstream metabolite. Indoxyl sulfate entered human HK-2 proximal-tubule cells through organic-anion transport and induced Nrf2 activation consistent with intracellular oxidative stress. Model: Human proximal-tubule-derived HK-2 cell experiments. Limitations: Accessed abstract does not resolve each transporter isoform in this cell assay; Nrf2 activation is not itself proof of clinical renal injury. Evidence access: Primary abstract Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24958931/ · DOI 10.1093/toxsci/kfu119
Complete structured claim and evidence
The PGC-1alpha1–PPAR-alpha/delta program increased muscle kynurenine aminotransferases and conversion of kynurenine to kynurenic acid.
Mouse PGC-1alpha1 / Ppargc1a isoform 1 → Mouse skeletal-muscle kynurenine aminotransferases; multiple enzymes source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse skeletal-muscle transgenic and stress experiments.
limitations
Multiple aminotransferases are involved; do not assign the entire effect to human AADAT alone.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Muscle metabolism can change which tryptophan products remain in circulation.
primary_references
Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25259918/ · DOI 10.1016/j.cell.2014.07.051
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 610–616
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse skeletal-muscle transgenic and stress experiments. · source_derived_draft · unverified_draft
## tryptophan-muscle-kat-program Muscle metabolism can change which tryptophan products remain in circulation. The PGC-1alpha1–PPAR-alpha/delta program increased muscle kynurenine aminotransferases and conversion of kynurenine to kynurenic acid. Model: Mouse skeletal-muscle transgenic and stress experiments. Limitations: Multiple aminotransferases are involved; do not assign the entire effect to human AADAT alone. Evidence access: Primary abstract Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25259918/ · DOI 10.1016/j.cell.2014.07.051
Complete structured claim and evidence
Muscle-specific PGC-1alpha1 transgenic mice resisted depression-like changes induced by chronic mild stress or kynurenine administration as peripheral kynurenine handling shifted.
Mouse PGC-1alpha1 / Ppargc1a isoform 1 → Mouse stress/kynurenine-associated depression-like behavior source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse genetic overexpression and behavioral challenges.
limitations
Not proof that this is the sole human exercise–mood mechanism or that kynurenic acid freely enters the brain.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A peripheral metabolic change altered a brain-related behavioral response.
primary_references
Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25259918/ · DOI 10.1016/j.cell.2014.07.051
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 618–624
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic overexpression and behavioral challenges. · source_derived_draft · unverified_draft
## tryptophan-muscle-brain-context A peripheral metabolic change altered a brain-related behavioral response. Muscle-specific PGC-1alpha1 transgenic mice resisted depression-like changes induced by chronic mild stress or kynurenine administration as peripheral kynurenine handling shifted. Model: Mouse genetic overexpression and behavioral challenges. Limitations: Not proof that this is the sole human exercise–mood mechanism or that kynurenic acid freely enters the brain. Evidence access: Primary abstract Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25259918/ · DOI 10.1016/j.cell.2014.07.051
Complete structured claim and evidence
Carbidopa inhibition of kynurenine aminotransferase activity impaired aspartate synthesis and mitochondrial respiration and reduced mouse exercise performance and muscle force.
Mouse skeletal-muscle kynurenine aminotransferases; multiple enzymes → Mouse muscle aspartate synthesis and mitochondrial respiration during kynurenine metabolism source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse muscle/exercise experiments within a PGC-1alpha1 and malate–aspartate-shuttle study.
limitations
Carbidopa is not specific to a single KAT isoform; mouse exposures do not establish the same effect at a clinical human dose.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The branch can support muscle energy handling as well as alter circulating metabolites.
primary_references
Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31235694/ · DOI 10.1038/s41467-019-10712-0
trigger_kind
machinery_impairment Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 626–632
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse muscle/exercise experiments within a PGC-1alpha1 and malate–aspartate-shuttle study. · source_derived_draft · unverified_draft
## tryptophan-muscle-kat-inhibition The branch can support muscle energy handling as well as alter circulating metabolites. Carbidopa inhibition of kynurenine aminotransferase activity impaired aspartate synthesis and mitochondrial respiration and reduced mouse exercise performance and muscle force. Model: Mouse muscle/exercise experiments within a PGC-1alpha1 and malate–aspartate-shuttle study. Limitations: Carbidopa is not specific to a single KAT isoform; mouse exposures do not establish the same effect at a clinical human dose. Evidence access: Primary abstract Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31235694/ · DOI 10.1038/s41467-019-10712-0
Complete structured claim and evidence
Purified E. coli BW25113 TnaA converted L-tryptophan to indole in a PLP-containing assay; tryptophan Km was 0.19 ± 0.009 mM.
Escherichia coli BW25113 tryptophanase / TnaA → Indole source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 2 and enzyme-kinetics methods
experimental_model
Purified bacterial enzyme kinetics.
limitations
Culture kinetics do not predict a person’s production rate.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A bacterial enzyme creates the indole that can enter host liver metabolism.
primary_references
Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 634–640
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified bacterial enzyme kinetics. · source_derived_draft · unverified_draft
## tryptophan-tnaa-indole A bacterial enzyme creates the indole that can enter host liver metabolism. Purified E. coli BW25113 TnaA converted L-tryptophan to indole in a PLP-containing assay; tryptophan Km was 0.19 ± 0.009 mM. Model: Purified bacterial enzyme kinetics. Limitations: Culture kinetics do not predict a person’s production rate. Evidence access: Primary full text, Figure 2 and enzyme-kinetics methods Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Complete structured claim and evidence
TnaA also converted 5-HTP to 5-hydroxyindole, with lower catalytic efficiency than for tryptophan.
Escherichia coli BW25113 tryptophanase / TnaA → 5-Hydroxyindole source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 2
experimental_model
Purified E. coli enzyme and tnaA-mutant experiments.
limitations
5-HTP and tryptophan are distinct substrates, not interchangeable supplement exposures.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
The serotonin precursor can instead become a microbial product.
primary_references
Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 642–648
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified E. coli enzyme and tnaA-mutant experiments. · source_derived_draft · unverified_draft
## tryptophan-tnaa-hydroxyindole The serotonin precursor can instead become a microbial product. TnaA also converted 5-HTP to 5-hydroxyindole, with lower catalytic efficiency than for tryptophan. Model: Purified E. coli enzyme and tnaA-mutant experiments. Limitations: 5-HTP and tryptophan are distinct substrates, not interchangeable supplement exposures. Evidence access: Primary full text, Figure 2 Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Complete structured claim and evidence
5-Hydroxyindole stimulated rat colonic contraction, and 1 micromolar nifedipine inhibited the response.
5-Hydroxyindole → Rat colonic contractility after 5-hydroxyindole source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text, Figure 5
experimental_model
Rat ex-vivo colon organ-bath pharmacology.
limitations
Pharmacological dependence does not establish a direct binding site or a specific calcium-channel isoform.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A downstream microbial product acted through a calcium-channel-dependent mechanism.
primary_references
Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 650–656
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat ex-vivo colon organ-bath pharmacology. · source_derived_draft · unverified_draft
## tryptophan-hydroxyindole-calcium A downstream microbial product acted through a calcium-channel-dependent mechanism. 5-Hydroxyindole stimulated rat colonic contraction, and 1 micromolar nifedipine inhibited the response. Model: Rat ex-vivo colon organ-bath pharmacology. Limitations: Pharmacological dependence does not establish a direct binding site or a specific calcium-channel isoform. Evidence access: Primary full text, Figure 5 Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070
Complete structured claim and evidence
Purified recombinant human NMNAT2 has adenylyltransferase activity toward nicotinic acid mononucleotide, supporting NaAD formation.
Human nicotinamide mononucleotide adenylyltransferase 2 / NMNAT2 → Nicotinic acid adenine dinucleotide source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"}
experimental_model
Cloned, expressed and purified recombinant human NMNAT2
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
The same human isozyme processes either the amidated or deamidated mononucleotide.
primary_references
[b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 315–326
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloned, expressed and purified recombinant human NMNAT2 · source_derived_draft · unverified_draft
### b3-pre-nmnat2-namn Purified recombinant human NMNAT2 has adenylyltransferase activity toward nicotinic acid mononucleotide, supporting NaAD formation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same human isozyme processes either the amidated or deamidated mononucleotide. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Cloned, expressed and purified recombinant human NMNAT2 limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nmnat2002.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 826, "file_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477", "text_sha256": "5064cc6a7b31875eeaea8def5544c3cce75a971f73aa74f332d89e06c3c54477"} [b3-pre-nmnat2002] Identification of a novel human nicotinamide mononucleotide adenylyltransferase. (2002). https://pubmed.ncbi.nlm.nih.gov/12359228/ DOI: 10.1016/s0006-291x(02)02285-4
Complete structured claim and evidence
Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study.
Human methionine adenosyltransferase 2A / MAT2A → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"}
experimental_model
Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography
exposure
ATP/methionine reactions and PNPNP ligand complexes
limitations
Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand.
nutrient_topic
Phosphorus research collection; topical membership is not evidence of a direct dietary effect. · Phosphorus
organism
Human recombinant enzyme
plain_language
Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry.
primary_references
[phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998
tissue_or_cell_type
Purified MAT2A active site
Phosphorus: metabolism, signaling and nutrient connections (2026-09-17) · lines 633–644
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography · source_derived_draft · unverified_draft
### phosphorus-mat-sam Human MAT2A formed S-adenosylmethionine before rapid triphosphate hydrolysis and product release in the kinetic study. Condition category: normal nutrient_topic: Phosphorus research collection; topical membership is not evidence of a direct dietary effect. plain_language: Making the methyl donor SAM is coupled to ATP-derived phosphate chemistry. organism: Human recombinant enzyme tissue_or_cell_type: Purified MAT2A active site experimental_model: Human MAT2A kinetics, isotope exchange and inhibitor-bound crystallography limitations: Phosphoryl chemistry is not evidence that phosphate supplements boost methylation. Metal contacts were resolved with an experimental ATP-site ligand. exposure: ATP/methionine reactions and PNPNP ligand complexes evidence_span: {"source_cache": "artifacts/phosphorus-research/33656855.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38", "start_char": 0, "end_char": 1520, "text_sha256": "1d45073f7187a06cfb9b2d630f94fa651239f0a9a5ae353b37d9af90750f2f38"} [phosphorus-p33656855] Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. (2021). https://pubmed.ncbi.nlm.nih.gov/33656855/ DOI: 10.1021/acs.biochem.0c00998
Complete structured claim and evidence
Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF.
Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate methyl transfer requires B12.
experimental_model
Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
limitations
Chemistry, not dietary response.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
B12-dependent MTR recycles both homocysteine and folate.
primary_references
[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 482–492
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft
### folate-methyl-mtr-methyl-transfer Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12-dependent MTR recycles both homocysteine and folate. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Chemistry, not dietary response. cross_nutrient: Folate methyl transfer requires B12. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
Complete structured claim and evidence
Human PANK3 catalyzes ATP-dependent conversion of pantothenate to 4′-phosphopantothenate.
Human pantothenate kinase 3 / PANK3 → Pantothenate (vitamin B5) source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments
exposure
In-vitro biochemical exposure; concentrations not extracted.
limitations
Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here.
nutrient_topic
Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)
organism
Homo sapiens
plain_language
PANK3 starts vitamin B5 activation by adding phosphate.
primary_references
[b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 483–494
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments · source_derived_draft · unverified_draft
### b5-bio-pank3-phosphorylation Human PANK3 catalyzes ATP-dependent conversion of pantothenate to 4′-phosphopantothenate. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: PANK3 starts vitamin B5 activation by adding phosphate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human PANK3, crystallography and biochemical ligand-binding/heterodimer experiments limitations: Abstract-level structural and biochemical findings; no diet or Mg-repletion experiment. Substrate concentrations not established here. exposure: In-vitro biochemical exposure; concentrations not extracted. cross_nutrient: true [b5-bio-pank3allosteric] Allosteric Regulation of Mammalian Pantothenate Kinase. (2016). https://pubmed.ncbi.nlm.nih.gov/27555321/ DOI: 10.1074/jbc.m116.748061
Complete structured claim and evidence
SLC6A19 functioned as a sodium-dependent, chloride-independent neutral amino acid transporter.
Human neutral amino acid transporter B0AT1 / SLC6A19 → Neutral amino acids (assay substrates specified per claim) source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sodium-research/15286788.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14", "start_char": 0, "end_char": 1040, "text_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14"}
experimental_model
Human genetic mapping and heterologous transport-function tests
exposure
Hartnup-associated variants versus normal transporter
limitations
Not every clinical feature of Hartnup disorder was explained; no direct test here of niacin supplementation or sodium shortage.
nutrient_topic
Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium
organism
Human SLC6A19
plain_language
Sodium coupling is also used to absorb or recover some amino acids.
primary_references
[sodium-p15286788] Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. (2004). https://pubmed.ncbi.nlm.nih.gov/15286788/ DOI: 10.1038/ng1406
tissue_or_cell_type
Kidney/intestine transporter; expression assays
transport_effect
raises Sodium-dependent neutral amino acid transport, which is inward.
transport_pool
the expressing cell Sodium-dependent neutral amino acid transport, which is inward.
Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 590–601
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human genetic mapping and heterologous transport-function tests · source_derived_draft · unverified_draft
### sodium-b0at1-transport SLC6A19 functioned as a sodium-dependent, chloride-independent neutral amino acid transporter. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Sodium coupling is also used to absorb or recover some amino acids. organism: Human SLC6A19 tissue_or_cell_type: Kidney/intestine transporter; expression assays experimental_model: Human genetic mapping and heterologous transport-function tests limitations: Not every clinical feature of Hartnup disorder was explained; no direct test here of niacin supplementation or sodium shortage. exposure: Hartnup-associated variants versus normal transporter evidence_span: {"source_cache": "artifacts/sodium-research/15286788.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14", "start_char": 0, "end_char": 1040, "text_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14"} [sodium-p15286788] Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. (2004). https://pubmed.ncbi.nlm.nih.gov/15286788/ DOI: 10.1038/ng1406
Complete structured claim and evidence
Tested Hartnup-associated SLC6A19 variants reduced neutral amino acid transport in vitro.
Human neutral amino acid transporter B0AT1 / SLC6A19 → Intestinal and renal neutral amino acid transport source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sodium-research/15286788.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14", "start_char": 0, "end_char": 1040, "text_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14"}
experimental_model
Human genetic mapping and heterologous transport-function tests
exposure
Hartnup-associated variants versus normal transporter
limitations
Not every clinical feature of Hartnup disorder was explained; no direct test here of niacin supplementation or sodium shortage.
nutrient_topic
Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium
organism
Human SLC6A19
plain_language
Even with sodium and food present, a damaged transporter can limit nutrient transport.
primary_references
[sodium-p15286788] Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. (2004). https://pubmed.ncbi.nlm.nih.gov/15286788/ DOI: 10.1038/ng1406
tissue_or_cell_type
Kidney/intestine transporter; expression assays
trigger_kind
machinery_impairment Imported condition classification; unverified.
Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 603–614
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human genetic mapping and heterologous transport-function tests · source_derived_draft · unverified_draft
### sodium-b0at1-loss Tested Hartnup-associated SLC6A19 variants reduced neutral amino acid transport in vitro. Condition category: machinery_impairment nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even with sodium and food present, a damaged transporter can limit nutrient transport. organism: Human SLC6A19 tissue_or_cell_type: Kidney/intestine transporter; expression assays experimental_model: Human genetic mapping and heterologous transport-function tests limitations: Not every clinical feature of Hartnup disorder was explained; no direct test here of niacin supplementation or sodium shortage. exposure: Hartnup-associated variants versus normal transporter evidence_span: {"source_cache": "artifacts/sodium-research/15286788.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14", "start_char": 0, "end_char": 1040, "text_sha256": "72277489510231d6da07dacf086404f5f069094a47d7a1a2de9a8392556c3a14"} [sodium-p15286788] Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. (2004). https://pubmed.ncbi.nlm.nih.gov/15286788/ DOI: 10.1038/ng1406
Complete structured claim and evidence
The human PNPO structure localized tightly bound FMN at the conserved catalytic site of the homodimer.
Flavin mononucleotide → Pyridoxine 5-prime-phosphate oxidase / PNPO source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-FMN is a cofactor for B6 activation.
evidence_location
Results: kinetic properties; Table 1; FMN-binding structure
experimental_model
Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C.
exposure
Purified-enzyme assay
limitations
Biochemical evidence does not establish a dietary threshold or supplementation benefit.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
PNPO uses the FMN form of vitamin B2.
primary_references
[musayev2003] Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase. (2003). https://pubmed.ncbi.nlm.nih.gov/12824491/ DOI: 10.1110/ps.0356203
tissue_or_cell_type
Purified recombinant enzyme; no intact tissue
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1136–1148
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C. · source_derived_draft · unverified_draft
### b2-pnpo-fmn-binding The human PNPO structure localized tightly bound FMN at the conserved catalytic site of the homodimer. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: PNPO uses the FMN form of vitamin B2. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FMN is a cofactor for B6 activation. evidence_location: Results: kinetic properties; Table 1; FMN-binding structure [musayev2003] Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase. (2003). https://pubmed.ncbi.nlm.nih.gov/12824491/ DOI: 10.1110/ps.0356203
Complete structured claim and evidence
Purified human PNPO converted PNP to PLP with a turnover number of 0.19 per second at 37 C.
Pyridoxine 5-prime-phosphate oxidase / PNPO → Pyridoxine 5-prime-phosphate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-dependent oxidation activates one B6 precursor.
evidence_location
Results: kinetic properties; Table 1; FMN-binding structure
experimental_model
Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C.
exposure
Purified-enzyme assay
limitations
Biochemical evidence does not establish a dietary threshold or supplementation benefit.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
PNPO changes phosphorylated pyridoxine into active B6.
primary_references
[musayev2003] Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase. (2003). https://pubmed.ncbi.nlm.nih.gov/12824491/ DOI: 10.1110/ps.0356203
tissue_or_cell_type
Purified recombinant enzyme; no intact tissue
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1150–1162
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C. · source_derived_draft · unverified_draft
### b2-pnpo-pnp-oxidation Purified human PNPO converted PNP to PLP with a turnover number of 0.19 per second at 37 C. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: PNPO changes phosphorylated pyridoxine into active B6. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human PNPO expressed in E. coli; crystallography and purified-enzyme kinetics at 37 C. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-dependent oxidation activates one B6 precursor. evidence_location: Results: kinetic properties; Table 1; FMN-binding structure [musayev2003] Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase. (2003). https://pubmed.ncbi.nlm.nih.gov/12824491/ DOI: 10.1110/ps.0356203
Complete structured claim and evidence
Human PDXK assays directly measured ATP-dependent conversion of pyridoxal to PLP, a reaction distinct from PNPO oxidation.
Pyridoxal kinase / PDXK → Pyridoxal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Separates the B6 phosphorylation step from the B2-dependent oxidation step.
evidence_location
Abstract
experimental_model
Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures.
exposure
Purified-enzyme assay
limitations
This biochemical route does not establish that dietary pyridoxal bypasses all consequences of PNPO disease.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
Not every route to active B6 passes through PNPO.
primary_references
[safo2007] Crystal Structure of human pyridoxal kinase: structural basis of M(+) and M(2+) activation. (2007). https://pubmed.ncbi.nlm.nih.gov/17766369/ DOI: 10.1110/ps.073022107
tissue_or_cell_type
Purified recombinant enzyme; no intact tissue
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1192–1204
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures. · source_derived_draft · unverified_draft
### b2-pdxk-pyridoxal-route Human PDXK assays directly measured ATP-dependent conversion of pyridoxal to PLP, a reaction distinct from PNPO oxidation. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Not every route to active B6 passes through PNPO. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human PDXK expressed in E. coli; PL-to-PLP kinetics and unliganded/MgATP-bound structures. limitations: This biochemical route does not establish that dietary pyridoxal bypasses all consequences of PNPO disease. exposure: Purified-enzyme assay cross_nutrient: Separates the B6 phosphorylation step from the B2-dependent oxidation step. evidence_location: Abstract [safo2007] Crystal Structure of human pyridoxal kinase: structural basis of M(+) and M(2+) activation. (2007). https://pubmed.ncbi.nlm.nih.gov/17766369/ DOI: 10.1110/ps.073022107
Complete structured claim and evidence
Human KMO membrane assays measured kynurenine conversion to 3-hydroxykynurenine with NADPH; at 200 micromolar NADPH, kynurenine Km was 2 micromolar.
Human kynurenine 3-monooxygenase / KMO → L-Kynurenine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-FAD and nicotinamide-containing NADPH support a branch upstream of de novo niacin synthesis.
evidence_location
Fig 2f and Methods: kinetic assays; interpret species separately
experimental_model
Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography.
exposure
Purified-enzyme assay
limitations
Human functional assays and bacterial structures are distinct evidence; this experiment did not test dietary B2 restriction or total NAD synthesis.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
A flavin enzyme directs tryptophan-derived kynurenine into the hydroxylated branch.
primary_references
[hutchinson2017] Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. (2017). https://pubmed.ncbi.nlm.nih.gov/28604669/ DOI: 10.1038/ncomms15827
tissue_or_cell_type
Sf9 membrane fraction expressing human KMO
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1234–1246
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography. · source_derived_draft · unverified_draft
### b2-kmo-kynurenine-hydroxylation Human KMO membrane assays measured kynurenine conversion to 3-hydroxykynurenine with NADPH; at 200 micromolar NADPH, kynurenine Km was 2 micromolar. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A flavin enzyme directs tryptophan-derived kynurenine into the hydroxylated branch. organism: Homo sapiens tissue_or_cell_type: Sf9 membrane fraction expressing human KMO experimental_model: Human KMO in Sf9 membrane preparations; mass-spectrometry kinetics; separate P. fluorescens KMO crystallography. limitations: Human functional assays and bacterial structures are distinct evidence; this experiment did not test dietary B2 restriction or total NAD synthesis. exposure: Purified-enzyme assay cross_nutrient: B2-FAD and nicotinamide-containing NADPH support a branch upstream of de novo niacin synthesis. evidence_location: Fig 2f and Methods: kinetic assays; interpret species separately [hutchinson2017] Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. (2017). https://pubmed.ncbi.nlm.nih.gov/28604669/ DOI: 10.1038/ncomms15827
Complete structured claim and evidence
Kmo knockout reduced quinolinate to about 3% of wild-type liver content but about 80% of wild-type brain content.
Mouse kynurenine 3-monooxygenase / Kmo → Quinolinic acid source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
A B2-dependent step feeds the tryptophan-to-niacin pathway with tissue-specific dependence.
evidence_location
Results: liver Fig 4 and brain Fig 7; matching abstract conclusion
experimental_model
Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays.
exposure
Constitutive Kmo deletion
limitations
Genetic deletion; alternative routes were proposed but not all directly traced.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Mus musculus
plain_language
Removing this enzyme affected downstream metabolites differently across tissues.
primary_references
[giorgini2013] Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. (2013). https://pubmed.ncbi.nlm.nih.gov/24189070/ DOI: 10.1074/jbc.m113.503813
tissue_or_cell_type
Liver and brain
trigger_kind
machinery_impairment Imported condition classification; unverified.
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1248–1260
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays. · source_derived_draft · unverified_draft
### b2-kmo-loss-quinolinate-tissue Kmo knockout reduced quinolinate to about 3% of wild-type liver content but about 80% of wild-type brain content. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing this enzyme affected downstream metabolites differently across tissues. organism: Mus musculus tissue_or_cell_type: Liver and brain experimental_model: Constitutive Kmo knockout and wild-type mice, approximately two months old; liver and brain metabolite assays. limitations: Genetic deletion; alternative routes were proposed but not all directly traced. exposure: Constitutive Kmo deletion cross_nutrient: A B2-dependent step feeds the tryptophan-to-niacin pathway with tissue-specific dependence. evidence_location: Results: liver Fig 4 and brain Fig 7; matching abstract conclusion [giorgini2013] Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. (2013). https://pubmed.ncbi.nlm.nih.gov/24189070/ DOI: 10.1074/jbc.m113.503813
Complete structured claim and evidence
Human kynureninase crystallography resolves the PLP-containing active-site architecture.
PLP → Human kynureninase / KYNU source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B6-dependent KYNU acts in the pathway leading from tryptophan toward niacin/NAD precursors.
experimental_model
Recombinant human KYNU crystallography and biochemical characterization
limitations
Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
KYNU uses active B6 in the tryptophan pathway.
primary_references
[b6-kynu-2007] Crystal Structure of Homo Sapiens Kynureninase (2007). https://pmc.ncbi.nlm.nih.gov/articles/PMC2531291/ DOI: 10.1021/bi0616697
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 873–883
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human KYNU crystallography and biochemical characterization · source_derived_draft · unverified_draft
### b6-met-kynu-plp Human kynureninase crystallography resolves the PLP-containing active-site architecture. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: KYNU uses active B6 in the tryptophan pathway. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human KYNU crystallography and biochemical characterization limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: B6-dependent KYNU acts in the pathway leading from tryptophan toward niacin/NAD precursors. [b6-kynu-2007] Crystal Structure of Homo Sapiens Kynureninase (2007). https://pmc.ncbi.nlm.nih.gov/articles/PMC2531291/ DOI: 10.1021/bi0616697
Complete structured claim and evidence
Human KYNU cleaves 3-hydroxykynurenine to 3-hydroxyanthranilate and alanine using PLP.
Human kynureninase / KYNU → 3-Hydroxy-L-kynurenine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
PLP-dependent KYNU follows the FAD-dependent KMO step, connecting B6 and B2 with tryptophan-niacin metabolism.
existing_related_claim_ids
["5570a502-6ebf-5397-bf2a-0148727e7695"]
experimental_model
Recombinant human KYNU crystallography and biochemical characterization
limitations
KYNU does not directly make NAD; subsequent enzymes and dietary niacin also contribute.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
This B6-dependent step processes the product of upstream KMO chemistry.
primary_references
[b6-kynu-2007] Crystal Structure of Homo Sapiens Kynureninase (2007). https://pmc.ncbi.nlm.nih.gov/articles/PMC2531291/ DOI: 10.1021/bi0616697
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 885–896
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human KYNU crystallography and biochemical characterization · source_derived_draft · unverified_draft
### b6-met-kynu-hydrolysis Human KYNU cleaves 3-hydroxykynurenine to 3-hydroxyanthranilate and alanine using PLP. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent step processes the product of upstream KMO chemistry. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human KYNU crystallography and biochemical characterization limitations: KYNU does not directly make NAD; subsequent enzymes and dietary niacin also contribute. cross_nutrient: PLP-dependent KYNU follows the FAD-dependent KMO step, connecting B6 and B2 with tryptophan-niacin metabolism. existing_related_claim_ids: ["5570a502-6ebf-5397-bf2a-0148727e7695"] [b6-kynu-2007] Crystal Structure of Homo Sapiens Kynureninase (2007). https://pmc.ncbi.nlm.nih.gov/articles/PMC2531291/ DOI: 10.1021/bi0616697
Complete structured claim and evidence
Under niacin-free feeding, B6-free rats had lower apparent tryptophan-to-niacin conversion than rats receiving B6.
Vitamin B6 → Apparent tryptophan-to-niacin conversion from urinary metabolites source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Dietary B6 status affected apparent tryptophan-to-niacin conversion.
experimental_model
Young male Wistar rats; four controlled diets for 19 days
exposure
Young male Wistar rats; 19-day diets; conversion contrast within niacin-free groups
limitations
Apparent urinary conversion, not net synthesis or a human requirement.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Rattus norvegicus
plain_language
B6 shortage reduced this dietary study's estimate of niacin production from tryptophan.
primary_references
[b6-niacin-1995] Effects of Vitamin B6 Deficiency on the Conversion Ratio of Tryptophan to Niacin (1995). https://doi.org/10.1271/bbb.59.2060 DOI: 10.1271/bbb.59.2060
tissue_or_cell_type
Whole-animal dietary intake and urine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 898–909
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young male Wistar rats; four controlled diets for 19 days · source_derived_draft · unverified_draft
### b6-met-rat-niacin-conversion Under niacin-free feeding, B6-free rats had lower apparent tryptophan-to-niacin conversion than rats receiving B6. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6 shortage reduced this dietary study's estimate of niacin production from tryptophan. organism: Rattus norvegicus tissue_or_cell_type: Whole-animal dietary intake and urine experimental_model: Young male Wistar rats; four controlled diets for 19 days limitations: Apparent urinary conversion, not net synthesis or a human requirement. cross_nutrient: Dietary B6 status affected apparent tryptophan-to-niacin conversion. exposure: Young male Wistar rats; 19-day diets; conversion contrast within niacin-free groups [b6-niacin-1995] Effects of Vitamin B6 Deficiency on the Conversion Ratio of Tryptophan to Niacin (1995). https://doi.org/10.1271/bbb.59.2060 DOI: 10.1271/bbb.59.2060
Complete structured claim and evidence
Expressed human DDC decarboxylated 5-hydroxy-L-tryptophan; added PLP enhanced the measured activity.
Human aromatic L-amino acid decarboxylase / DDC → Serotonin source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human DDC expressed in monkey COS cells; enzyme assays
exposure
PLP addition to transfected COS-cell enzyme incubations.
limitations
An expression-system response is not proof that supplements increase brain monoamines.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Human DDC expressed in monkey COS cells
plain_language
B6 cofactor supports this monoamine-producing step.
primary_references
[sumi-1990-ddc] Characterization of recombinant human aromatic L-amino acid decarboxylase expressed in COS cells (1990). https://doi.org/10.1111/j.1471-4159.1990.tb04601.x DOI: 10.1111/j.1471-4159.1990.tb04601.x
tissue_or_cell_type
COS-cell expression system
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1011–1021
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DDC expressed in monkey COS cells; enzyme assays · source_derived_draft · unverified_draft
### b6-neuro-ddc-serotonin Expressed human DDC decarboxylated 5-hydroxy-L-tryptophan; added PLP enhanced the measured activity. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6 cofactor supports this monoamine-producing step. organism: Human DDC expressed in monkey COS cells tissue_or_cell_type: COS-cell expression system experimental_model: Human DDC expressed in monkey COS cells; enzyme assays limitations: An expression-system response is not proof that supplements increase brain monoamines. exposure: PLP addition to transfected COS-cell enzyme incubations. [sumi-1990-ddc] Characterization of recombinant human aromatic L-amino acid decarboxylase expressed in COS cells (1990). https://doi.org/10.1111/j.1471-4159.1990.tb04601.x DOI: 10.1111/j.1471-4159.1990.tb04601.x
Complete structured claim and evidence
3-Hydroxykynurenine increased 39% fasting and 34% after meals; kynurenic acid decreased 22% and 20%, respectively.
Vitamin B6 → 3-Hydroxy-L-kynurenine source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
B6-dependent kynurenine reactions intersect the tryptophan-to-niacin network; conversion to NAD was not measured.
experimental_model
Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling.
exposure
28 days below 0.35 mg/day B6. Related restriction research program; do not count paper totals as independent trial replications.
limitations
Does not measure brain neurotransmitters, tissue NAD synthesis or diagnose niacin deficiency.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
Different branches of tryptophan processing left a detectable blood pattern.
primary_references
[b6-dasilva2013] Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women (2013). https://pubmed.ncbi.nlm.nih.gov/23966327/ DOI: 10.3945/jn.113.180588
tissue_or_cell_type
Human blood and whole-body measurements
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1436–1447
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling. · source_derived_draft · unverified_draft
### b6-restriction-kynurenine-profile 3-Hydroxykynurenine increased 39% fasting and 34% after meals; kynurenic acid decreased 22% and 20%, respectively. Condition category: nutrient_deficiency nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different branches of tryptophan processing left a detectable blood pattern. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Twenty-three healthy adults; paired pre/postprandial LC-MS/MS metabolite profiling. limitations: Does not measure brain neurotransmitters, tissue NAD synthesis or diagnose niacin deficiency. exposure: 28 days below 0.35 mg/day B6. Related restriction research program; do not count paper totals as independent trial replications. cross_nutrient: B6-dependent kynurenine reactions intersect the tryptophan-to-niacin network; conversion to NAD was not measured. [b6-dasilva2013] Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women (2013). https://pubmed.ncbi.nlm.nih.gov/23966327/ DOI: 10.3945/jn.113.180588
Complete structured claim and evidence
Human TDO2 substrate and product structures support oxidative conversion of L-tryptophan and oxygen to N-formylkynurenine.
Human tryptophan 2,3-dioxygenase / TDO2 → N-Formyl-L-kynurenine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Tryptophan provides the carbon framework entering the de novo niacin pathway; downstream steps remain necessary.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/tdo2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 9–9 (0-based)", "start_char": 8003, "end_char": 9136, "file_sha256": "3f91886745b8ff9fb808232c839dd346b03605dd025d5fa682a3de4f81338ec5", "text_sha256": "b39e2ce5d405e5eb8fde25aec369c306954365d7ec2b448fe5a5689e89785e2a"}
experimental_model
Purified human TDO2 crystallography and spectroscopy; substrate/product complexes
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
TDO2 opens the tryptophan ring at the beginning of the kynurenine route.
primary_references
[b3-pre-tdo2016] Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. (2016). https://pubmed.ncbi.nlm.nih.gov/27762317/ DOI: 10.1038/srep35169
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 479–491
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human TDO2 crystallography and spectroscopy; substrate/product complexes · source_derived_draft · unverified_draft
### b3-pre-tdo-reaction Human TDO2 substrate and product structures support oxidative conversion of L-tryptophan and oxygen to N-formylkynurenine. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: TDO2 opens the tryptophan ring at the beginning of the kynurenine route. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human TDO2 crystallography and spectroscopy; substrate/product complexes limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Tryptophan provides the carbon framework entering the de novo niacin pathway; downstream steps remain necessary. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/tdo2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 9–9 (0-based)", "start_char": 8003, "end_char": 9136, "file_sha256": "3f91886745b8ff9fb808232c839dd346b03605dd025d5fa682a3de4f81338ec5", "text_sha256": "b39e2ce5d405e5eb8fde25aec369c306954365d7ec2b448fe5a5689e89785e2a"} [b3-pre-tdo2016] Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. (2016). https://pubmed.ncbi.nlm.nih.gov/27762317/ DOI: 10.1038/srep35169
Complete structured claim and evidence
In the human TDO2 substrate complex, molecular oxygen was coordinated to the heme iron next to the L-tryptophan substrate.
Heme → Human tryptophan 2,3-dioxygenase / TDO2 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Heme iron participates in a tryptophan-to-niacin upstream enzyme; the structure does not establish a dietary iron threshold.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/tdo2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5512, "end_char": 7250, "file_sha256": "3f91886745b8ff9fb808232c839dd346b03605dd025d5fa682a3de4f81338ec5", "text_sha256": "057137936657c739cdef730f5d10b930ec40af5e09f0ed4e2abbd813f26db9f0"}
experimental_model
Purified human TDO2 crystallography and spectroscopy; substrate/product complexes
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
Iron held in heme positions oxygen for this precursor reaction.
primary_references
[b3-pre-tdo2016] Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. (2016). https://pubmed.ncbi.nlm.nih.gov/27762317/ DOI: 10.1038/srep35169
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 493–505
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human TDO2 crystallography and spectroscopy; substrate/product complexes · source_derived_draft · unverified_draft
### b3-pre-tdo-heme-oxygen In the human TDO2 substrate complex, molecular oxygen was coordinated to the heme iron next to the L-tryptophan substrate. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron held in heme positions oxygen for this precursor reaction. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human TDO2 crystallography and spectroscopy; substrate/product complexes limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Heme iron participates in a tryptophan-to-niacin upstream enzyme; the structure does not establish a dietary iron threshold. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/tdo2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 7–7 (0-based)", "start_char": 5512, "end_char": 7250, "file_sha256": "3f91886745b8ff9fb808232c839dd346b03605dd025d5fa682a3de4f81338ec5", "text_sha256": "057137936657c739cdef730f5d10b930ec40af5e09f0ed4e2abbd813f26db9f0"} [b3-pre-tdo2016] Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. (2016). https://pubmed.ncbi.nlm.nih.gov/27762317/ DOI: 10.1038/srep35169
Complete structured claim and evidence
Human HAAO expressed in HEK-293 cells was enzymatically active toward 3-hydroxyanthranilate, with an apparent substrate Km near 2 micromolar in the study of the quinolinate-producing pathway step.
Human 3-hydroxyanthranilate 3,4-dioxygenase / HAAO → Quinolinic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
This step follows the canonical PLP-dependent KYNU reaction and uses a nonheme iron enzyme.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/haao1994.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 1874, "file_sha256": "a79697b138bcb2957b0eff9580266c7879a1c5853aba34898f891559b4e435f8", "text_sha256": "a79697b138bcb2957b0eff9580266c7879a1c5853aba34898f891559b4e435f8"}
experimental_model
Human HAAO cDNA from HepG2 library, expressed in HEK-293 cells and assayed biochemically
exposure
Biochemical or structural assay; no dietary intervention
limitations
The immediate HAAO product is ACMS, which cyclizes to quinolinate; the indexed abstract uses pathway-level quinolinate wording. This claim does not assert direct NAD+ synthesis.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
Expressed human HAAO processed the product made by B6-dependent KYNU.
primary_references
[b3-pre-haao1994] Molecular cloning and functional expression of human 3-hydroxyanthranilic-acid dioxygenase. (1994). https://pubmed.ncbi.nlm.nih.gov/7514594/ DOI: 10.1016/s0021-9258(17)36717-0 [b3-pre-haao2017] Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metals bound in the active site. (2017). https://pubmed.ncbi.nlm.nih.gov/28375145/ DOI: 10.1107/s2059798317002029
supporting_evidence_spans
[{"source_cache": "artifacts/niacin-precursors-sources/haao2017.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 4395, "end_char": 7197, "file_sha256": "d02386a59595104ccae2e62943e69030930da86ec005769b469f2001e31a6eb5", "text_sha256": "3b52b56d1b671c24721b47204cd30d19cd004f8a461fecd4875e94d3f491dbf6"}]
tissue_or_cell_type
HEK-293 cells expressing human HAAO; biochemical activity assay
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 521–535
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HAAO cDNA from HepG2 library, expressed in HEK-293 cells and assayed biochemically · source_derived_draft · unverified_draft
### b3-pre-haao-human-activity Human HAAO expressed in HEK-293 cells was enzymatically active toward 3-hydroxyanthranilate, with an apparent substrate Km near 2 micromolar in the study of the quinolinate-producing pathway step. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Expressed human HAAO processed the product made by B6-dependent KYNU. organism: Homo sapiens tissue_or_cell_type: HEK-293 cells expressing human HAAO; biochemical activity assay experimental_model: Human HAAO cDNA from HepG2 library, expressed in HEK-293 cells and assayed biochemically limitations: The immediate HAAO product is ACMS, which cyclizes to quinolinate; the indexed abstract uses pathway-level quinolinate wording. This claim does not assert direct NAD+ synthesis. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: This step follows the canonical PLP-dependent KYNU reaction and uses a nonheme iron enzyme. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/haao1994.abstract.txt", "locator": "Indexed primary abstract", "start_char": 0, "end_char": 1874, "file_sha256": "a79697b138bcb2957b0eff9580266c7879a1c5853aba34898f891559b4e435f8", "text_sha256": "a79697b138bcb2957b0eff9580266c7879a1c5853aba34898f891559b4e435f8"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/haao2017.paragraphs.txt", "locator": "Normalized full-text paragraphs 14–14 (0-based)", "start_char": 4395, "end_char": 7197, "file_sha256": "d02386a59595104ccae2e62943e69030930da86ec005769b469f2001e31a6eb5", "text_sha256": "3b52b56d1b671c24721b47204cd30d19cd004f8a461fecd4875e94d3f491dbf6"}] [b3-pre-haao1994] Molecular cloning and functional expression of human 3-hydroxyanthranilic-acid dioxygenase. (1994). https://pubmed.ncbi.nlm.nih.gov/7514594/ DOI: 10.1016/s0021-9258(17)36717-0 [b3-pre-haao2017] Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metals bound in the active site. (2017). https://pubmed.ncbi.nlm.nih.gov/28375145/ DOI: 10.1107/s2059798317002029
Complete structured claim and evidence
Crystallography and metal characterization identified iron in the active site of human HAAO, with spectroscopic behavior consistent with the ferrous preparation before air oxidation.
Ferrous iron → Human 3-hydroxyanthranilate 3,4-dioxygenase / HAAO source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Nonheme iron participates in a downstream tryptophan/niacin pathway enzyme; nutritional iron restriction was not tested.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/haao2017.paragraphs.txt", "locator": "Normalized full-text paragraphs 33–33 (0-based)", "start_char": 22514, "end_char": 24337, "file_sha256": "d02386a59595104ccae2e62943e69030930da86ec005769b469f2001e31a6eb5", "text_sha256": "4c47aa3f5cdc1fd3c776752c345f1d60e4833d0e3b7e8227c574ae086c3b1783"}
experimental_model
Purified human HAAO metal-containing crystal structures and ICP-MS/XRF/EPR characterization
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
A second iron-containing enzyme acts farther along the tryptophan route.
primary_references
[b3-pre-haao2017] Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metals bound in the active site. (2017). https://pubmed.ncbi.nlm.nih.gov/28375145/ DOI: 10.1107/s2059798317002029
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 507–519
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human HAAO metal-containing crystal structures and ICP-MS/XRF/EPR characterization · source_derived_draft · unverified_draft
### b3-pre-haao-iron Crystallography and metal characterization identified iron in the active site of human HAAO, with spectroscopic behavior consistent with the ferrous preparation before air oxidation. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second iron-containing enzyme acts farther along the tryptophan route. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human HAAO metal-containing crystal structures and ICP-MS/XRF/EPR characterization limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Nonheme iron participates in a downstream tryptophan/niacin pathway enzyme; nutritional iron restriction was not tested. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/haao2017.paragraphs.txt", "locator": "Normalized full-text paragraphs 33–33 (0-based)", "start_char": 22514, "end_char": 24337, "file_sha256": "d02386a59595104ccae2e62943e69030930da86ec005769b469f2001e31a6eb5", "text_sha256": "4c47aa3f5cdc1fd3c776752c345f1d60e4833d0e3b7e8227c574ae086c3b1783"} [b3-pre-haao2017] Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metals bound in the active site. (2017). https://pubmed.ncbi.nlm.nih.gov/28375145/ DOI: 10.1107/s2059798317002029
Complete structured claim and evidence
Human QPRT converts quinolinate and PRPP toward nicotinic acid mononucleotide; the human enzyme structures resolve reactant quinolinate and product NaMN complexes.
Human quinolinate phosphoribosyltransferase / QPRT → Nicotinic acid mononucleotide source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/qprt2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 13–15 (0-based)", "start_char": 10597, "end_char": 15612, "file_sha256": "85fcc4a79a17f4f3846301f67698a444c3c9930829e167d86a96adbb72d830e6", "text_sha256": "8da78d25a53af6507018eece4ce553705dc505d0b169f678affad49ee21b10f6"}
experimental_model
Purified recombinant human QPRT crystallography, calorimetry and oligomer studies
exposure
Biochemical or structural assay; no dietary intervention
limitations
Structural and biochemical enzyme study; does not establish how much dietary tryptophan becomes NAD in a person.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
Quinolinate enters the same deamidated mononucleotide route used by nicotinic acid.
primary_references
[b3-pre-qprt2016] Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis. (2016). https://pubmed.ncbi.nlm.nih.gov/26805589/ DOI: 10.1038/srep19681
supporting_evidence_spans
[{"source_cache": "artifacts/niacin-precursors-sources/qprt2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 4–4 (0-based)", "start_char": 1453, "end_char": 3871, "file_sha256": "85fcc4a79a17f4f3846301f67698a444c3c9930829e167d86a96adbb72d830e6", "text_sha256": "be14ed97ccf53b635f2cb35969188ce42c84dd739db897a24cbf3e65d8a3e3d1"}]
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 537–549
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human QPRT crystallography, calorimetry and oligomer studies · source_derived_draft · unverified_draft
### b3-pre-qprt-namn Human QPRT converts quinolinate and PRPP toward nicotinic acid mononucleotide; the human enzyme structures resolve reactant quinolinate and product NaMN complexes. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Quinolinate enters the same deamidated mononucleotide route used by nicotinic acid. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human QPRT crystallography, calorimetry and oligomer studies limitations: Structural and biochemical enzyme study; does not establish how much dietary tryptophan becomes NAD in a person. exposure: Biochemical or structural assay; no dietary intervention evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/qprt2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 13–15 (0-based)", "start_char": 10597, "end_char": 15612, "file_sha256": "85fcc4a79a17f4f3846301f67698a444c3c9930829e167d86a96adbb72d830e6", "text_sha256": "8da78d25a53af6507018eece4ce553705dc505d0b169f678affad49ee21b10f6"} supporting_evidence_spans: [{"source_cache": "artifacts/niacin-precursors-sources/qprt2016.paragraphs.txt", "locator": "Normalized full-text paragraphs 4–4 (0-based)", "start_char": 1453, "end_char": 3871, "file_sha256": "85fcc4a79a17f4f3846301f67698a444c3c9930829e167d86a96adbb72d830e6", "text_sha256": "be14ed97ccf53b635f2cb35969188ce42c84dd739db897a24cbf3e65d8a3e3d1"}] [b3-pre-qprt2016] Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis. (2016). https://pubmed.ncbi.nlm.nih.gov/26805589/ DOI: 10.1038/srep19681
Complete structured claim and evidence
Purified human NADSYN1 catalyzed ATP-dependent NAD+ production from nicotinic acid adenine dinucleotide in glutamine-supported assays.
Human glutamine-dependent NAD synthetase / NADSYN1 → NAD+ source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"}
experimental_model
Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
The deamidated route finishes by making NAD+ through NADSYN1.
primary_references
[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 328–340
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft
### b3-pre-nadsyn-amidation Purified human NADSYN1 catalyzed ATP-dependent NAD+ production from nicotinic acid adenine dinucleotide in glutamine-supported assays. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The deamidated route finishes by making NAD+ through NADSYN1. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine supplies nitrogen for the final amidation of the nicotinic-acid/de novo NAD pathway. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 8–8 (0-based)", "start_char": 7090, "end_char": 8684, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "90cb4d2ce3001f2ecf18f1d751db36047726b71a75be94b073474f6f518c96cd"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4
Complete structured claim and evidence
Human NADSYN1 glutaminase activity was measured as glutamate production; NaAD plus ATP/Mg2+ increased that activity 31-fold over glutamine alone in the reported assay.
Human glutamine-dependent NAD synthetase / NADSYN1 → L-Glutamate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme.
evidence_span
{"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 10–10 (0-based)", "start_char": 8754, "end_char": 10450, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "32dd95b3bef542cb15f227e9dd3de1ed68b6b9c8f6cda41d34daf7b6fe387ce7"}
experimental_model
Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate
exposure
Biochemical or structural assay; no dietary intervention
limitations
Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
The two enzyme activities communicate while NAD is assembled.
primary_references
[b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 342–354
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate · source_derived_draft · unverified_draft
### b3-pre-nadsyn-glutaminase Human NADSYN1 glutaminase activity was measured as glutamate production; NaAD plus ATP/Mg2+ increased that activity 31-fold over glutamine alone in the reported assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two enzyme activities communicate while NAD is assembled. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human NADSYN1 steady-state kinetic assays and crystallography; bacterial comparison kept separate limitations: Purified-enzyme evidence does not establish dietary intake requirements or clinical outcomes. exposure: Biochemical or structural assay; no dietary intervention cross_nutrient: Glutamine nitrogen handling and magnesium-containing ATP chemistry couple in a niacin precursor enzyme. evidence_span: {"source_cache": "artifacts/niacin-precursors-sources/nadsyn2019.paragraphs.txt", "locator": "Normalized full-text paragraphs 10–10 (0-based)", "start_char": 8754, "end_char": 10450, "file_sha256": "36ad82ce734c8e0c44d01c7dc813b1641708738319b53a926e429155b1a602f4", "text_sha256": "32dd95b3bef542cb15f227e9dd3de1ed68b6b9c8f6cda41d34daf7b6fe387ce7"} [b3-pre-nadsyn2019] Different ways to transport ammonia in human and Mycobacterium tuberculosis NAD+ synthetases. (2020). https://pubmed.ncbi.nlm.nih.gov/31911602/ DOI: 10.1038/s41467-019-13845-4
Complete structured claim and evidence
Two patients with homozygous HAAO truncating variants p.D162* or p.W186* belonged to the reported congenital-malformation cohort with reduced circulating NAD.
Biallelic HAAO loss-of-function genotype → Circulating NAD content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Human 3-hydroxyanthranilate 3,4-dioxygenase / HAAO (affected_enzyme); L-Tryptophan (upstream_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme)
evidence_span
{"source_cache": "artifacts/niacin-clinical-sources/shi2017.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb", "start_char": 0, "end_char": 1874, "text_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb"}
experimental_model
Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments
exposure
Biallelic HAAO or KYNU loss-of-function variants
limitations
Rare inherited synthesis impairment is distinct from dietary shortage. Prevention with gestational niacin was demonstrated in mice, not as an established prenatal treatment in humans.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
An inherited break in the tryptophan pathway can leave NAD low even when the problem is not simply food intake.
primary_references
[nia-clin-shi2017] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. (2017). https://pubmed.ncbi.nlm.nih.gov/28792876/ DOI: 10.1056/nejmoa1616361
tissue_or_cell_type
Circulation and congenital organ development
trigger_kind
machinery_impairment Imported condition classification; unverified.
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1235–1247
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments · source_derived_draft · unverified_draft
### nia-clin-haao-human-low-nad Two patients with homozygous HAAO truncating variants p.D162* or p.W186* belonged to the reported congenital-malformation cohort with reduced circulating NAD. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: An inherited break in the tryptophan pathway can leave NAD low even when the problem is not simply food intake. organism: Homo sapiens tissue_or_cell_type: Circulation and congenital organ development experimental_model: Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments limitations: Rare inherited synthesis impairment is distinct from dietary shortage. Prevention with gestational niacin was demonstrated in mice, not as an established prenatal treatment in humans. exposure: Biallelic HAAO or KYNU loss-of-function variants cross_nutrient: Human 3-hydroxyanthranilate 3,4-dioxygenase / HAAO (affected_enzyme); L-Tryptophan (upstream_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/shi2017.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb", "start_char": 0, "end_char": 1874, "text_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb"} [nia-clin-shi2017] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. (2017). https://pubmed.ncbi.nlm.nih.gov/28792876/ DOI: 10.1056/nejmoa1616361
Complete structured claim and evidence
The cohort also included homozygous KYNU p.V57Efs*21 and compound-heterozygous p.Y156*/p.F349Kfs*4 patients with reduced circulating NAD and multiple malformations.
Biallelic KYNU loss-of-function genotype → Circulating NAD content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Human kynureninase / KYNU (affected_enzyme); L-Tryptophan (upstream_precursor); Malformations in congenital NAD deficiency disorder (observed_phenotype)
evidence_span
{"source_cache": "artifacts/niacin-clinical-sources/shi2017.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb", "start_char": 0, "end_char": 1874, "text_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb"}
experimental_model
Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments
exposure
Biallelic HAAO or KYNU loss-of-function variants
limitations
Rare inherited synthesis impairment is distinct from dietary shortage. Prevention with gestational niacin was demonstrated in mice, not as an established prenatal treatment in humans.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
KYNU is a second independent point where inherited failure can interrupt NAD production.
primary_references
[nia-clin-shi2017] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. (2017). https://pubmed.ncbi.nlm.nih.gov/28792876/ DOI: 10.1056/nejmoa1616361
tissue_or_cell_type
Circulation and congenital organ development
trigger_kind
machinery_impairment Imported condition classification; unverified.
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1249–1261
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments · source_derived_draft · unverified_draft
### nia-clin-kynu-human-low-nad The cohort also included homozygous KYNU p.V57Efs*21 and compound-heterozygous p.Y156*/p.F349Kfs*4 patients with reduced circulating NAD and multiple malformations. Condition category: machinery_impairment nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: KYNU is a second independent point where inherited failure can interrupt NAD production. organism: Homo sapiens tissue_or_cell_type: Circulation and congenital organ development experimental_model: Four patients from unrelated families; sequencing and circulating metabolites, with parallel enzyme and mouse experiments limitations: Rare inherited synthesis impairment is distinct from dietary shortage. Prevention with gestational niacin was demonstrated in mice, not as an established prenatal treatment in humans. exposure: Biallelic HAAO or KYNU loss-of-function variants cross_nutrient: Human kynureninase / KYNU (affected_enzyme); L-Tryptophan (upstream_precursor); Malformations in congenital NAD deficiency disorder (observed_phenotype) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/shi2017.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb", "start_char": 0, "end_char": 1874, "text_sha256": "2c5dcc72d338ac41bd47e4363a149abc503859e2760398fed030f02d5891e2bb"} [nia-clin-shi2017] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. (2017). https://pubmed.ncbi.nlm.nih.gov/28792876/ DOI: 10.1056/nejmoa1616361
Complete structured claim and evidence
Cheilosis and angular stomatitis occurred during the low-niacin/tryptophan regimen even with approximately 2 mg/day total riboflavin and supplemental pyridoxine; these lesions were not specific evidence of B2 deficiency.
Niacin (vitamin B3) → Niacin-related oral mucosal injury source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Riboflavin (vitamin B2) (supplied_co_nutrient); Pyridoxine (supplied_co_nutrient)
evidence_span
{"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "start_char": 15452, "end_char": 16019, "text_sha256": "66c68d7739e59c3e98f30fe0757f468a7952746f7dfe082138dfa6727fa54bf4"}
experimental_model
Historical metabolic-ward restriction; seven women, with three prolonged corn-diet cases developing pellagra
exposure
Corn diet about 4.7 mg niacin and 190 mg tryptophan/day; other B-vitamin supplements; 40–135 days depending on subject; subsequent niacinamide or DL-tryptophan
limitations
Very small nonrandomized historical experiment. Diets and exposure durations differed; signs were not universal. Nitrogen balance did not prove niacin sufficiency. This does not establish a modern intake threshold or demonstrate a corn toxin.
nutrient_topic
Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)
organism
Homo sapiens
plain_language
A sore mouth can arise from different nutrient problems. The appearance alone did not identify which vitamin was lacking.
primary_references
[nia-clin-goldsmith1952] Studies of niacin requirement in man. I. Experimental pellagra in subjects on corn diets low in niacin and tryptophan. (1952). https://pubmed.ncbi.nlm.nih.gov/14938430/ DOI: 10.1172/jci102638
supplementary_evidence_spans
[{"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "start_char": 8901, "end_char": 9290, "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "text_sha256": "59d1a659822aca95688b5e36bd07b41ea700bfbfdc92b40005acf11bd540b046", "locator": "Methods: supplied B-vitamin quantities"}, {"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "start_char": 31540, "end_char": 31811, "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "text_sha256": "ff226f4114a9dec08a00118aa9df933b8246dc89bcf362b2569c089b511d9d3e", "locator": "Discussion: riboflavin and pyridoxine supplements"}]
tissue_or_cell_type
Skin, oral and intestinal mucosa
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1205–1218
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward restriction; seven women, with three prolonged corn-diet cases developing pellagra · source_derived_draft · unverified_draft
### nia-clin-pellagra-riboflavin-context Cheilosis and angular stomatitis occurred during the low-niacin/tryptophan regimen even with approximately 2 mg/day total riboflavin and supplemental pyridoxine; these lesions were not specific evidence of B2 deficiency. Condition category: nutrient_deficiency nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A sore mouth can arise from different nutrient problems. The appearance alone did not identify which vitamin was lacking. organism: Homo sapiens tissue_or_cell_type: Skin, oral and intestinal mucosa experimental_model: Historical metabolic-ward restriction; seven women, with three prolonged corn-diet cases developing pellagra limitations: Very small nonrandomized historical experiment. Diets and exposure durations differed; signs were not universal. Nitrogen balance did not prove niacin sufficiency. This does not establish a modern intake threshold or demonstrate a corn toxin. exposure: Corn diet about 4.7 mg niacin and 190 mg tryptophan/day; other B-vitamin supplements; 40–135 days depending on subject; subsequent niacinamide or DL-tryptophan cross_nutrient: Riboflavin (vitamin B2) (supplied_co_nutrient); Pyridoxine (supplied_co_nutrient) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "start_char": 15452, "end_char": 16019, "text_sha256": "66c68d7739e59c3e98f30fe0757f468a7952746f7dfe082138dfa6727fa54bf4"} supplementary_evidence_spans: [{"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "start_char": 8901, "end_char": 9290, "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "text_sha256": "59d1a659822aca95688b5e36bd07b41ea700bfbfdc92b40005acf11bd540b046", "locator": "Methods: supplied B-vitamin quantities"}, {"source_cache": "artifacts/niacin-clinical-sources/goldsmith1952.txt", "start_char": 31540, "end_char": 31811, "file_sha256": "2d4004fb5985f80c8e44909506e1aa05b6eefd838f4c28102beac30fb3092bc5", "text_sha256": "ff226f4114a9dec08a00118aa9df933b8246dc89bcf362b2569c089b511d9d3e", "locator": "Discussion: riboflavin and pyridoxine supplements"}] [nia-clin-goldsmith1952] Studies of niacin requirement in man. I. Experimental pellagra in subjects on corn diets low in niacin and tryptophan. (1952). https://pubmed.ncbi.nlm.nih.gov/14938430/ DOI: 10.1172/jci102638
Complete structured claim and evidence
Purified human pineal TPH catalyzed tryptophan hydroxylation to 5-hydroxytryptophan.
Human tryptophan hydroxylase 1 / TPH1 → 5-Hydroxy-L-tryptophan source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/10525150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f", "start_char": 0, "end_char": 1489, "text_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f"}
experimental_model
Recombinant enzyme purification and catalysis
exposure
L-tryptophan with tetrahydrobiopterin; purified tetrameric enzyme
limitations
TPH1 and neuronal TPH2 are distinct. A cofactor-dependent reaction does not prove supplemental cofactor increases melatonin in a replete person.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human pineal TPH1 expressed in E. coli
plain_language
The amino acid tryptophan must pass through an enzyme-controlled first step.
primary_references
[melatonin-p10525150] Cloning and expression of recombinant human pineal tryptophan hydroxylase in Escherichia coli: purification and characterization of the cloned enzyme. (1999). https://pubmed.ncbi.nlm.nih.gov/10525150/ DOI: 10.1016/s0167-4838(99)00184-3
tissue_or_cell_type
Tryptophan hydroxylation
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 136–147
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme purification and catalysis · source_derived_draft · unverified_draft
### melatonin-tph1-hydroxylation Purified human pineal TPH catalyzed tryptophan hydroxylation to 5-hydroxytryptophan. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The amino acid tryptophan must pass through an enzyme-controlled first step. organism: Human pineal TPH1 expressed in E. coli tissue_or_cell_type: Tryptophan hydroxylation experimental_model: Recombinant enzyme purification and catalysis limitations: TPH1 and neuronal TPH2 are distinct. A cofactor-dependent reaction does not prove supplemental cofactor increases melatonin in a replete person. exposure: L-tryptophan with tetrahydrobiopterin; purified tetrameric enzyme evidence_span: {"source_cache": "artifacts/melatonin-research/10525150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f", "start_char": 0, "end_char": 1489, "text_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f"} [melatonin-p10525150] Cloning and expression of recombinant human pineal tryptophan hydroxylase in Escherichia coli: purification and characterization of the cloned enzyme. (1999). https://pubmed.ncbi.nlm.nih.gov/10525150/ DOI: 10.1016/s0167-4838(99)00184-3
Complete structured claim and evidence
The human TPH catalytic domain positioned tryptophan and a pterin analogue near its catalytic non-heme iron.
Human tryptophan hydroxylase 1 / TPH1 → Ferrous iron source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/11747434.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c98a1e028f9c3d7f749d37794a8e976c8c808e0ca9c5f08c394d9d29ae639e06", "start_char": 0, "end_char": 2063, "text_sha256": "c98a1e028f9c3d7f749d37794a8e976c8c808e0ca9c5f08c394d9d29ae639e06"}
experimental_model
NMR substrate/cofactor geometry and enzyme modeling
exposure
L-tryptophan and bound BH2 cofactor analogue
limitations
BH2 was a structural analogue in this experiment, not a demonstration that BH2 replaces physiological BH4. No clinical iron-deficiency threshold measured.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Recombinant human TPH1 catalytic domain
plain_language
The upstream hydroxylation machinery contains iron; giving more iron is not automatically a way to make more melatonin.
primary_references
[melatonin-p11747434] Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity. (2001). https://pubmed.ncbi.nlm.nih.gov/11747434/ DOI: 10.1021/bi015722x
tissue_or_cell_type
Non-heme iron active site
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 162–173
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · NMR substrate/cofactor geometry and enzyme modeling · source_derived_draft · unverified_draft
### melatonin-tph1-iron The human TPH catalytic domain positioned tryptophan and a pterin analogue near its catalytic non-heme iron. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The upstream hydroxylation machinery contains iron; giving more iron is not automatically a way to make more melatonin. organism: Recombinant human TPH1 catalytic domain tissue_or_cell_type: Non-heme iron active site experimental_model: NMR substrate/cofactor geometry and enzyme modeling limitations: BH2 was a structural analogue in this experiment, not a demonstration that BH2 replaces physiological BH4. No clinical iron-deficiency threshold measured. exposure: L-tryptophan and bound BH2 cofactor analogue evidence_span: {"source_cache": "artifacts/melatonin-research/11747434.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c98a1e028f9c3d7f749d37794a8e976c8c808e0ca9c5f08c394d9d29ae639e06", "start_char": 0, "end_char": 2063, "text_sha256": "c98a1e028f9c3d7f749d37794a8e976c8c808e0ca9c5f08c394d9d29ae639e06"} [melatonin-p11747434] Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity. (2001). https://pubmed.ncbi.nlm.nih.gov/11747434/ DOI: 10.1021/bi015722x
Complete structured claim and evidence
Human AANAT transferred an acetyl group from acetyl-CoA to serotonin, producing N-acetylserotonin.
Human arylalkylamine N-acetyltransferase / AANAT → N-Acetylserotonin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/10722724.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7fb8418b17e92c5b3fed5d9c08afdb32f28c922dfe94274d3bb02b7e12b2b8c8", "start_char": 0, "end_char": 1857, "text_sha256": "7fb8418b17e92c5b3fed5d9c08afdb32f28c922dfe94274d3bb02b7e12b2b8c8"}
experimental_model
Purified recombinant enzyme substrate-specificity study
exposure
Serotonin and radiolabeled acetyl-CoA; product HPLC
limitations
Biochemical mechanism, not evidence that dietary B5 or acetyl-CoA availability limits melatonin production in all humans.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human AANAT expressed in bacteria
plain_language
Serotonin is modified before it becomes melatonin.
primary_references
[melatonin-p10722724] Substrate specificity and inhibition studies of human serotonin N-acetyltransferase. (2000). https://pubmed.ncbi.nlm.nih.gov/10722724/ DOI: 10.1074/jbc.275.12.8794
tissue_or_cell_type
Serotonin acetylation
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 175–186
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme substrate-specificity study · source_derived_draft · unverified_draft
### melatonin-aanat-serotonin Human AANAT transferred an acetyl group from acetyl-CoA to serotonin, producing N-acetylserotonin. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Serotonin is modified before it becomes melatonin. organism: Human AANAT expressed in bacteria tissue_or_cell_type: Serotonin acetylation experimental_model: Purified recombinant enzyme substrate-specificity study limitations: Biochemical mechanism, not evidence that dietary B5 or acetyl-CoA availability limits melatonin production in all humans. exposure: Serotonin and radiolabeled acetyl-CoA; product HPLC evidence_span: {"source_cache": "artifacts/melatonin-research/10722724.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7fb8418b17e92c5b3fed5d9c08afdb32f28c922dfe94274d3bb02b7e12b2b8c8", "start_char": 0, "end_char": 1857, "text_sha256": "7fb8418b17e92c5b3fed5d9c08afdb32f28c922dfe94274d3bb02b7e12b2b8c8"} [melatonin-p10722724] Substrate specificity and inhibition studies of human serotonin N-acetyltransferase. (2000). https://pubmed.ncbi.nlm.nih.gov/10722724/ DOI: 10.1074/jbc.275.12.8794
Complete structured claim and evidence
Human ASMT catalyzes the terminal methylation step converting N-acetylserotonin to melatonin using SAM.
Human acetylserotonin O-methyltransferase / ASMT → Melatonin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"}
experimental_model
X-ray structure and radioenzymatic variant characterization
exposure
SAM-dependent methyltransferase structure and enzyme activity assays
limitations
Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human ASMT and 20 nonsynonymous variants
plain_language
A methyl group completes the molecule.
primary_references
[melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x
tissue_or_cell_type
Final melatonin synthesis step
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 201–212
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structure and radioenzymatic variant characterization · source_derived_draft · unverified_draft
### melatonin-asmt-methylation Human ASMT catalyzes the terminal methylation step converting N-acetylserotonin to melatonin using SAM. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A methyl group completes the molecule. organism: Human ASMT and 20 nonsynonymous variants tissue_or_cell_type: Final melatonin synthesis step experimental_model: X-ray structure and radioenzymatic variant characterization limitations: Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome. exposure: SAM-dependent methyltransferase structure and enzyme activity assays evidence_span: {"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"} [melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x
Complete structured claim and evidence
The N17K ASMT variant was among variants with reduced or abolished activity in the radioenzymatic screen.
Human ASMT p.Asn17Lys / N17K variant → Human ASMT catalytic activity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"}
experimental_model
X-ray structure and radioenzymatic variant characterization
exposure
SAM-dependent methyltransferase structure and enzyme activity assays
limitations
Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human ASMT and 20 nonsynonymous variants
plain_language
More precursor does not automatically repair an altered enzyme.
primary_references
[melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x
tissue_or_cell_type
Final melatonin synthesis step
trigger_kind
machinery_impairment Imported condition classification; unverified.
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 227–238
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structure and radioenzymatic variant characterization · source_derived_draft · unverified_draft
### melatonin-asmt-n17k The N17K ASMT variant was among variants with reduced or abolished activity in the radioenzymatic screen. Condition category: machinery_impairment nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: More precursor does not automatically repair an altered enzyme. organism: Human ASMT and 20 nonsynonymous variants tissue_or_cell_type: Final melatonin synthesis step experimental_model: X-ray structure and radioenzymatic variant characterization limitations: Reduced recombinant enzyme activity does not quantify pineal secretion or diagnose a sleep problem in an individual. Variant effects differ; no single universal melatonin-deficiency syndrome. exposure: SAM-dependent methyltransferase structure and enzyme activity assays evidence_span: {"source_cache": "artifacts/melatonin-research/22775292.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349", "start_char": 0, "end_char": 1205, "text_sha256": "6896e0a7e08f764e1ff8c370601b0477c594e4e1c945df52d0f564e9049a9349"} [melatonin-p22775292] Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. (2013). https://pubmed.ncbi.nlm.nih.gov/22775292/ DOI: 10.1111/j.1600-079x.2012.01020.x
Complete structured claim and evidence
HIOMT298 expression shifted the measured tryptophan metabolism from serotonin toward 5-MTP production.
Human HIOMT298 / ASMT 298-amino-acid splice isoform → Serotonin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/29794137.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "051e28814382bea96e610c4cc406e7bc1d4d705d245b43dea0bba61050ae341e", "start_char": 0, "end_char": 1575, "text_sha256": "051e28814382bea96e610c4cc406e7bc1d4d705d245b43dea0bba61050ae341e"}
experimental_model
Isoform expression, transfection and metabolic measurements
exposure
HIOMT298 expression versus pineal HIOMT345
limitations
The 298-aa isoform was studied for 5-MTP production. Do not assign its anti-tumor findings to melatonin or assume all ASMT isoforms have identical products.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human fibroblasts, A549 cancer cells and mouse xenografts
plain_language
A shared enzyme name does not mean every isoform feeds the melatonin branch.
primary_references
[melatonin-p29794137] Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression. (2018). https://pubmed.ncbi.nlm.nih.gov/29794137/ DOI: 10.1074/jbc.ra117.000597
tissue_or_cell_type
Alternative tryptophan metabolism
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 344–355
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isoform expression, transfection and metabolic measurements · source_derived_draft · unverified_draft
### melatonin-asmt-isoform-serotonin-switch HIOMT298 expression shifted the measured tryptophan metabolism from serotonin toward 5-MTP production. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shared enzyme name does not mean every isoform feeds the melatonin branch. organism: Human fibroblasts, A549 cancer cells and mouse xenografts tissue_or_cell_type: Alternative tryptophan metabolism experimental_model: Isoform expression, transfection and metabolic measurements limitations: The 298-aa isoform was studied for 5-MTP production. Do not assign its anti-tumor findings to melatonin or assume all ASMT isoforms have identical products. exposure: HIOMT298 expression versus pineal HIOMT345 evidence_span: {"source_cache": "artifacts/melatonin-research/29794137.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "051e28814382bea96e610c4cc406e7bc1d4d705d245b43dea0bba61050ae341e", "start_char": 0, "end_char": 1575, "text_sha256": "051e28814382bea96e610c4cc406e7bc1d4d705d245b43dea0bba61050ae341e"} [melatonin-p29794137] Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression. (2018). https://pubmed.ncbi.nlm.nih.gov/29794137/ DOI: 10.1074/jbc.ra117.000597
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.

Blocking a branch impairs muscle energy handling

Condition: machinery_impairment · Carbidopa inhibition in the mouse experiments.

Normal role: Muscle kynurenine transamination can support aspartate and malate–aspartate-shuttle metabolism.

Recorded consequence: Aspartate synthesis, respiration, exercise performance and force decline.

Scope: Mouse skeletal muscle

Transport support is missing

Condition: machinery_impairment · Mouse Ace2 deletion.

Normal role: Intestinal B0AT1 supports single-amino-acid uptake.

Recorded consequence: Gly-Trp bypassed uptake failure and nicotinamide rescued particular gut outcomes.

Scope: Mouse intestine and DSS colitis

Dietary tryptophan loss changes gut defense

Condition: nutrient_deficiency · Tryptophan-free mouse diet.

Normal role: Dietary supply supports antimicrobial-peptide regulation.

Recorded consequence: Antimicrobial peptides fall and induced-colitis susceptibility rises.

Scope: Mouse intestinal epithelium

Nicotinamide cannot bypass blocked mTOR signaling

Condition: machinery_impairment · Rapamycin exposure.

Normal role: mTOR contributes to intestinal antimicrobial-peptide expression.

Recorded consequence: Nicotinamide fails to restore the peptide response.

Scope: Mouse intestine

Local cancer-cell shortage alters translation

Condition: nutrient_deficiency · IFN-gamma/IDO1-associated depletion.

Normal role: WARS1 charges tryptophan onto tRNA.

Recorded consequence: Phenylalanine can replace tryptophan at some translated positions.

Scope: Human cancer-cell experiments

Missing hydroxylases separate brain and peripheral effects

Condition: machinery_impairment · Tph2 loss or Tph1/Tph2 double knockout.

Normal role: TPH isoforms support serotonin production in different compartments.

Recorded consequence: Brain serotonin falls with Tph2 loss; double loss also reduces peripheral serotonin.

Scope: Mouse genetic models

Acute depletion has population-dependent effects

Condition: nutrient_deficiency · Experimental tryptophan-free amino-acid drinks.

Normal role: Circulating tryptophan supplies downstream pathways.

Recorded consequence: Plasma falls; treatment context affects relapse, and another pilot shows memory effects without relapse.

Scope: Separate human research populations

Substrate cannot replace broken catalytic residues

Condition: machinery_impairment · Human IDO1 or mouse Afmid engineered active-site mutations.

Normal role: IDO1 and Afmid perform sequential reactions.

Recorded consequence: Activity is lost, sometimes despite retained substrate binding.

Scope: Separate human and mouse recombinant enzymes

Quinolinate accumulates while NAD falls

Condition: machinery_impairment · Mouse acute kidney injury or reduced Qprt gene dosage.

Normal role: QPRT uses quinolinate to support de novo NAD synthesis.

Recorded consequence: Quinolinate rises, renal NAD falls and vulnerability increases.

Scope: Mouse kidney

A urine ratio is not a direct enzyme assay

Condition: biomarker_context · High urinary quinolinate/tryptophan during high-risk hospitalization.

Normal role: Compartment-specific metabolites can indicate pathway disturbance.

Recorded consequence: The ratio predicts adverse outcomes; impaired QPRT is an interpretation informed by animal experiments.

Scope: Human clinical metabolomics

Replacing tryptophan does not reverse every interferon effect

Condition: nutrient_deficiency · IFN-gamma-induced depletion in two human cell lines.

Normal role: Local supply permits cell proliferation.

Recorded consequence: Repletion restores KB growth but not WiDr growth.

Scope: Human cancer-cell cultures

A stopped immune cell may need both nutrient and signal

Condition: nutrient_deficiency · Activation without tryptophan followed by arrest.

Normal role: TCR stimulation and tryptophan support entry into division.

Recorded consequence: T cells stop in mid-G1 and require renewed TCR signaling with repletion.

Scope: Human T-cell culture

Stress sensing and division arrest are not always the same dependency

Condition: machinery_impairment · Gcn2 deletion in differing T-cell experimental models.

Normal role: GCN2 mediates parts of the amino-acid stress response.

Recorded consequence: Studies disagree about suppression; CHOP induction and arrest can separate.

Scope: Mouse immune models

Local shortage changes growth and recycling signals

Condition: nutrient_deficiency · IDO-driven or medium-imposed deprivation.

Normal role: Tryptophan availability supports mTOR-associated signaling.

Recorded consequence: S6K phosphorylation falls and LC3-based autophagy readouts rise.

Scope: Human HeLa/MCF-7 experiments

Missing microbial enzymes change the available products

Condition: machinery_impairment · Disrupt fldC, fldH or acdA.

Normal role: C. sporogenes reductive aromatic metabolism produces indolepropionate.

Recorded consequence: Indolepropionate production is impaired.

Scope: Bacterial genetics with separate gnotobiotic outcomes

Receptor and inflammatory context determine a barrier response

Condition: machinery_impairment · Mouse Nr1i2 loss with or without Tlr4 loss.

Normal role: PXR contributes to epithelial barrier regulation.

Recorded consequence: Permeability increases after Nr1i2 loss and is corrected by additional Tlr4 deletion.

Scope: Mouse intestinal genetics

Tryptamine cannot produce this secretory response without HTR4

Condition: machinery_impairment · Htr4 knockout or receptor blockade.

Normal role: Tryptamine activates a colonic secretory response through HTR4.

Recorded consequence: The measured secretory response disappears.

Scope: Mouse colon/colonoids

The sources

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

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Phosphorus: metabolism, signaling and nutrient connections (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19)AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

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

Does kynurenic acid directly inhibit alpha7 nicotinic receptors?A 2001 neuronal study reported inhibition, whereas a 2012 rat/mouse slice study found no alpha7-current inhibition despite effective glutamatergic blockade and prolonged high exposure. This is an experimental disagreement, not a correction of draft wording.Read the recorded disagreement
Is GCN2 required for T-cell arrest during tryptophan limitation?The 2005 IDO-dendritic-cell study found GCN2-deficient T cells resistant to suppression; the 2016 genetic study found GCN2-deficient CD8 cells still unable to proliferate under amino-acid limitation and explicitly challenged the earlier model.Read the recorded disagreement

Open questions in this collection

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

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

Evidence, AI assistance and curation standards

L-Tryptophan

The mechanisms

Human LAT1 coexpressed with human SLC3A2/4F2hc in Xenopus oocytes transported large neutral amino acids; extracellular substrates exchanged intracellular leucine and glutamine.

Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium.

In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone.

Ace2 loss removed intestinal B0AT1 expression in mice; kidney B0AT1 regulation differed and depended on collectrin.

Gly-Trp feeding restored serum tryptophan and reduced DSS-colitis susceptibility in Ace2-deficient mice, bypassing loss of single-amino-acid uptake.

A tryptophan-free diet reduced small-intestinal antimicrobial peptide expression and increased chemically induced colitis susceptibility in wild-type mice.

Nicotinamide supplementation markedly alleviated colitis and diarrhea in Ace2-deficient mice.

Rapamycin reduced mouse intestinal antimicrobial peptides, and nicotinamide did not rescue that reduction.

Microbiota transfer from Ace2-mutant mice transmitted increased colitis susceptibility to germ-free wild-type recipients.

Human WARS1 recognizes tryptophan and its cognate tRNA; ATP-dependent activation precedes transfer to tRNA in protein-synthesis aminoacylation.

Under IFN-gamma/IDO1-associated tryptophan shortage, human cancer cells continued translation with WARS1-associated phenylalanine incorporation at tryptophan positions.

Tph2 knockout markedly reduced mouse brain serotonin while peripheral serotonin was not substantially reduced.

Combined Tph1/Tph2 knockout reduced peripheral as well as central serotonin in mice.

A tryptophan-free amino-acid drink lowered total and free plasma tryptophan by 70–80% after five hours in antidepressant responders.

During depletion, 8/15 fluoxetine responders relapsed versus 1/15 desipramine responders; significant depressive symptoms did not occur in control sessions.

Acute tryptophan depletion impaired delayed paragraph recall in a pilot of recently recovered menopausal women, without depressive relapse or significant mood worsening.

Human IDO1 uses heme-bound oxygen to cleave the tryptophan indole ring, incorporating both oxygen atoms during N-formylkynurenine formation.

Human IDO1 F226A, F227A and R231A mutants retained substrate binding but lacked catalytic activity.

Recombinant mouse Afmid hydrolyzed N-formyl-L-kynurenine with a Km of 0.18–0.19 mM, matching native mouse cytosolic enzyme.

S162A, D247A or H279A substitutions in mouse Afmid each removed more than 99% of measured enzyme activity.

Human KAT-II/AADAT is a PLP-dependent homodimer; the structure shows a PLP–Lys263 aldimine at its catalytic site.

Human KAT-II transaminates kynurenine to an intermediate that leads to kynurenic acid.

Recombinant human ACMSD activity increased with incorporated zinc; adding free metal to purified enzyme did not restore or increase activity.

Human ACMSD decarboxylates unstable ACMS, competing with its spontaneous conversion toward quinolinate in the NAD synthesis pathway.

ACMSD inhibition increased de novo NAD synthesis and SIRT1-related mitochondrial function in the mouse experiments.

Mouse acute kidney injury reduced renal QPRT and NAD while quinolinate accumulated.

Qprt-heterozygous mice had higher quinolinate, lower NAD and greater acute kidney injury susceptibility.

In critically ill humans, a higher urinary quinolinate/tryptophan ratio predicted acute kidney injury and adverse outcomes; reduced QPRT was a mechanistic interpretation informed by mouse work.

A phase-1 placebo-controlled oral nicotinamide study showed dose-related increases in circulating NAD metabolites and an exploratory association with less acute kidney injury.

Quinolinate at 75 micromolar opened NMDA channels in cultured rat hippocampal neurons in calcium-containing, magnesium-free recording solution.

Adding 30 micromolar magnesium reduced quinolinate-activated NMDA channel mean open time to about one-third at minus 100 mV.

Kynurenic acid inhibited alpha7 nicotinic responses in cultured rat hippocampal neurons after at least four minutes, with an IC50 near 7 micromolar.

Kynurenic acid did not inhibit choline-evoked alpha7 currents in rat hippocampal slice interneurons, contrasting with earlier reports.

Mouse hippocampal alpha7 currents remained insensitive to kynurenic acid, including slices prepared and stored in 1 mM for over 90 minutes, although glutamatergic currents were blocked.

Kynurenic-acid NMDA-blocking IC50 shifted from about 15 to 235 micromolar when 10 micromolar glycine was present.

IFN-gamma induced IDO activity and depleted almost all culture-medium tryptophan over two to three days in responsive human KB and WiDr cells.

Adding tryptophan reversed IFN-gamma-associated growth suppression in KB cells in a dose- and time-dependent manner.

Added tryptophan did not reverse IFN-gamma growth suppression in WiDr cells despite induced tryptophan catabolism.

CD40 ligand increased IFN-gamma-driven tryptophan catabolism in human monocyte-derived macrophages.

Human T cells activated without tryptophan arrested in mid-G1 while retaining early activation and some protein synthesis.

After tryptophan-sensitive arrest, human T cells required renewed T-cell-receptor signaling as well as tryptophan to resume division.

GCN2-deficient mouse T cells resisted suppression and anergy imposed by IDO-expressing dendritic cells in the 2005 study.

GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study.

GCN2 loss prevented induction of stress-target genes such as CHOP even though amino-acid-limited CD8 cells still arrested.

Donor mouse T cells lacking GCN2 still responded to IDO-mediated suppression in graft-versus-host disease experiments.

IFN-gamma/IDO-driven tryptophan depletion reduced S6K phosphorylation in human HeLa cells; tryptophan repletion restored the mTOR readout.

Tryptophan deprivation increased LC3-based autophagy readouts in human HeLa cells; tryptophan or D-1-methyltryptophan reversed those readouts.

Tryptophan add-back restored activating phosphorylation of ectopically expressed GST–PKC-theta after deprivation in human MCF-7 cells.

Human tumor-cell TDO-derived kynurenine supported AHR-dependent survival and motility in the study.

Incubation or storage increased kynurenine-solution AHR potency by 100–1000-fold; isolated trace condensation products accounted for potent activity.

Purified kynurenine-derived TEACOPs activated mouse AHR at low picomolar concentrations in the reported assays.

IL4I1 generated indole metabolites and kynurenic acid that activated AHR in the cancer study.

IDO1 inhibitors did not block IL4I1 in the study, leaving an alternative route to AHR activation.

The studied lactobacilli produced indole-3-aldehyde when using tryptophan as an energy source.

Microbial indole-3-aldehyde supported Ahr-dependent Il22 transcription in mice.

IL-22-dependent mucosal responses supported Candida colonization resistance and protection from inflammation in the mouse microbial-tryptophan study.

Disrupting fldC in C. sporogenes abolished indolepropionate accumulation in culture and altered aromatic-amino-acid metabolism.

C. sporogenes fldH disruption impaired the reductive metabolism of aromatic amino acids needed for indolepropionate production.

C. sporogenes acdA disruption impaired the reductive aromatic-amino-acid pathway leading to indolepropionate.

Gnotobiotic mice colonized with the fldC-mutant strain had reduced gut and circulating indolepropionate and increased intestinal permeability compared with wild-type colonization.

Indolepropionate activated mouse PXR with an EC50 near 0.55 micromolar in the reporter assay.

Indolepropionate alone weakly activated human PXR, with an EC50 near 120 micromolar; adding 1 mM indole enhanced activation.

Nr1i2-deficient mice had a barrier defect with increased TLR4-related signaling; additional Tlr4 deletion corrected the permeability phenotype.

Purified C. sporogenes CLOSPO_02083 catalyzed tryptophan decarboxylation to tryptamine as a PLP-dependent enzyme.

Purified R. gnavus RUMGNA_01526 robustly decarboxylated tryptophan despite only 26% sequence identity to the C. sporogenes enzyme.

Tryptamine increased epithelial ionic flux and colonoid fluid secretion through 5-HT4 receptors in mice.

Htr4 knockout or receptor antagonism removed the secretory response to tryptamine.

Colonizing germ-free mice with B. thetaiotaomicron engineered to produce tryptamine accelerated gastrointestinal transit.

Rat liver microsomal induction/inhibition experiments implicated CYP2E1 as the major enzyme oxidizing indole to indoxyl with NADPH support.

Recombinant human SULT1A1*2 converted indoxyl to indoxyl sulfate using PAPS; apparent indoxyl Km was 5.6 ± 1.8 micromolar.

Indoxyl sulfate entered human HK-2 proximal-tubule cells through organic-anion transport and induced Nrf2 activation consistent with intracellular oxidative stress.

The PGC-1alpha1–PPAR-alpha/delta program increased muscle kynurenine aminotransferases and conversion of kynurenine to kynurenic acid.

Muscle-specific PGC-1alpha1 transgenic mice resisted depression-like changes induced by chronic mild stress or kynurenine administration as peripheral kynurenine handling shifted.

Carbidopa inhibition of kynurenine aminotransferase activity impaired aspartate synthesis and mitochondrial respiration and reduced mouse exercise performance and muscle force.

Purified E. coli BW25113 TnaA converted L-tryptophan to indole in a PLP-containing assay; tryptophan Km was 0.19 ± 0.009 mM.

TnaA also converted 5-HTP to 5-hydroxyindole, with lower catalytic efficiency than for tryptophan.

5-Hydroxyindole stimulated rat colonic contraction, and 1 micromolar nifedipine inhibited the response.

Purified recombinant human NMNAT2 has adenylyltransferase activity toward nicotinic acid mononucleotide, supporting NaAD formation.

The cohort also included homozygous KYNU p.V57Efs21 and compound-heterozygous p.Y156/p.F349Kfs*4 patients with reduced circulating NAD and multiple malformations.