L-Tryptophan

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

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

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

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

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

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

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

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

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

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

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

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

evidence_span

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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

evidence_span

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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

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

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

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

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

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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

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

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

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

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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

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

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

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

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

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

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

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

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

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

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

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

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.

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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

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

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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

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

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

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

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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

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

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

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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

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

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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

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

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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

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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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

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

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

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

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

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

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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

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

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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

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

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

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

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

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

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

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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

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

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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

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

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

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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

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

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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

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

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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

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.

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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

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

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

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

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

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

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

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

evidence_access

Primary full text

experimental_model

Mouse circulating/tissue stable-isotope flux measurements.

limitations

Does not imply that all tissues lack de novo synthesis or that liver is the only contributor under every condition.

nutrient_topic

NAD+ collection; molecular form, preparation, species, exposure and manipulation remain explicit. · NAD+

plain_language

One organ can help supply another with recycled vitamin material.

primary_references

Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 188–194

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse circulating/tissue stable-isotope flux measurements. · source_derived_draft · unverified_draft

## nad-plus-liver-nam-export One organ can help supply another with recycled vitamin material. Mouse tracer experiments identified liver conversion of tryptophan to NAD followed by nicotinamide release to support other tissues. Model: Mouse circulating/tissue stable-isotope flux measurements. Limitations: Does not imply that all tissues lack de novo synthesis or that liver is the only contributor under every condition. Evidence access: Primary full text Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29685734/ · DOI 10.1016/j.cmet.2018.03.018

evidence_span

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experimental_model

Brain monoamine assays and metabolism inhibitors

exposure

Theanine administration; inhibitor-based interpretation

limitations

Do not generalize to human mood or claim serotonin always rises. Decreased synthesis/increased degradation were proposed from inhibitor experiments.

nutrient_topic

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

organism

Rats

plain_language

More precursor does not guarantee more downstream neurotransmitter.

primary_references

[theanine-p9614715] Theanine-induced reduction of brain serotonin concentration in rats. (1998). https://pubmed.ncbi.nlm.nih.gov/9614715/ DOI: 10.1271/bbb.62.816

tissue_or_cell_type

Brain tryptophan and serotonin metabolism

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 419–430

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Brain monoamine assays and metabolism inhibitors · source_derived_draft · unverified_draft

### theanine-tryptophan-pool Brain tryptophan increased or tended to increase despite lower serotonin in the rat study. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: More precursor does not guarantee more downstream neurotransmitter. organism: Rats tissue_or_cell_type: Brain tryptophan and serotonin metabolism experimental_model: Brain monoamine assays and metabolism inhibitors limitations: Do not generalize to human mood or claim serotonin always rises. Decreased synthesis/increased degradation were proposed from inhibitor experiments. exposure: Theanine administration; inhibitor-based interpretation evidence_span: {"source_cache": "artifacts/theanine-research/9614715.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ca01512b37779ba52ca0ebc23bcf73bb8c37df0756d8cf0c7d0a0de07e352a2", "start_char": 0, "end_char": 364, "text_sha256": "3ca01512b37779ba52ca0ebc23bcf73bb8c37df0756d8cf0c7d0a0de07e352a2"} [theanine-p9614715] Theanine-induced reduction of brain serotonin concentration in rats. (1998). https://pubmed.ncbi.nlm.nih.gov/9614715/ DOI: 10.1271/bbb.62.816

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments.

limitations

Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals.

nutrient_topic

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

plain_language

A liver hormone mediates part of the organism-level response to restricted supply.

primary_references

Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 346–352

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments. · source_derived_draft · unverified_draft

## l-threonine-fgf21-restriction A liver hormone mediates part of the organism-level response to restricted supply. Dietary threonine restriction produced systemic metabolic remodeling in mice that required liver-derived FGF21. Model: Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments. Limitations: Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals. Evidence access: Primary abstract Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z

cross_nutrient

Heme iron participates in a tryptophan-to-niacin upstream enzyme; the structure does not establish a dietary iron threshold.

evidence_span

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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

cross_nutrient

Tryptophan provides the carbon framework entering the de novo niacin pathway; downstream steps remain necessary.

evidence_span

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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

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

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

cross_nutrient

Niacin (vitamin B3) (repleted_nutrient); L-Tryptophan (measured_precursor); Oxidized nicotinamide adenine dinucleotide phosphate (co_measured_pool)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"}

experimental_model

Controlled metabolic-unit feeding; seven men, 80 days

exposure

6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine

limitations

Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

Extra leucine did not block niacin recovery under this tested diet.

primary_references

[nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

tissue_or_cell_type

Erythrocytes and plasma

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1135–1147

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled metabolic-unit feeding; seven men, 80 days · source_derived_draft · unverified_draft

### nia-clin-leucine-repletion Adding 7.8 g/day leucine during repletion did not change end-period erythrocyte NAD or NADP or plasma tryptophan in this study. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra leucine did not block niacin recovery under this tested diet. organism: Homo sapiens tissue_or_cell_type: Erythrocytes and plasma experimental_model: Controlled metabolic-unit feeding; seven men, 80 days limitations: Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials. exposure: 6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine cross_nutrient: Niacin (vitamin B3) (repleted_nutrient); L-Tryptophan (measured_precursor); Oxidized nicotinamide adenine dinucleotide phosphate (co_measured_pool) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"} [nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

L-Tryptophan (measured_precursor); N1-methylnicotinamide (measured_metabolite)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/bouma2016.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "1c1db5a8c0880ceda2066e1fcf23020ab293689782b99402d9913ff326917497", "start_char": 0, "end_char": 1869, "text_sha256": "1c1db5a8c0880ceda2066e1fcf23020ab293689782b99402d9913ff326917497"}

experimental_model

Retrospective serotonin-producing NET cohort; 42 baseline and 34 paired samples; 133 healthy urine references

exposure

Patients selected for low tryptophan and/or pellagra-associated symptoms; prescribed oral niacin mean 144 mg/day

limitations

No randomized comparator or direct tracer measurement of tryptophan diversion. Biomarker normalization does not establish symptom cure. Indexed abstract does not unambiguously specify the administered chemical form; retain niacin rather than guessing nicotinamide.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

In some serotonin-producing tumor patients, low tryptophan was accompanied by a low niacin marker.

primary_references

[nia-clin-bouma2016] Niacin (Vitamin B3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor. (2016). https://pubmed.ncbi.nlm.nih.gov/26335390/ DOI: 10.1159/000440621

tissue_or_cell_type

Plasma and urine

trigger_kind

biomarker_context Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1263–1275

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retrospective serotonin-producing NET cohort; 42 baseline and 34 paired samples; 133 healthy urine references · source_derived_draft · unverified_draft

### nia-clin-net-low-marker In the selected NET cohort, mean plasma tryptophan was 31.8 micromol/L and 45% had urinary N1-methylnicotinamide below the study reference range. Condition category: biomarker_context nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: In some serotonin-producing tumor patients, low tryptophan was accompanied by a low niacin marker. organism: Homo sapiens tissue_or_cell_type: Plasma and urine experimental_model: Retrospective serotonin-producing NET cohort; 42 baseline and 34 paired samples; 133 healthy urine references limitations: No randomized comparator or direct tracer measurement of tryptophan diversion. Biomarker normalization does not establish symptom cure. Indexed abstract does not unambiguously specify the administered chemical form; retain niacin rather than guessing nicotinamide. exposure: Patients selected for low tryptophan and/or pellagra-associated symptoms; prescribed oral niacin mean 144 mg/day cross_nutrient: L-Tryptophan (measured_precursor); N1-methylnicotinamide (measured_metabolite) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/bouma2016.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "1c1db5a8c0880ceda2066e1fcf23020ab293689782b99402d9913ff326917497", "start_char": 0, "end_char": 1869, "text_sha256": "1c1db5a8c0880ceda2066e1fcf23020ab293689782b99402d9913ff326917497"} [nia-clin-bouma2016] Niacin (Vitamin B3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor. (2016). https://pubmed.ncbi.nlm.nih.gov/26335390/ DOI: 10.1159/000440621

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

L-Tryptophan (co_restricted_precursor)

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": 13468, "end_char": 15488, "text_sha256": "78476c492b7ccdbe08740a06623f5a4856394c368e22b1bfdcdde2bc345e9a36"}

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

Long enough shortage injured skin and mucosal tissues, but people did not develop the same signs in the same order.

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

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 1191–1203

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-lesions The three prolonged corn-diet subjects developed initial pellagra signs between days 50 and 60; lesions differed between individuals, and typical hand dermatitis developed later in two. Condition category: nutrient_deficiency nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long enough shortage injured skin and mucosal tissues, but people did not develop the same signs in the same order. 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: L-Tryptophan (co_restricted_precursor) 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": 13468, "end_char": 15488, "text_sha256": "78476c492b7ccdbe08740a06623f5a4856394c368e22b1bfdcdde2bc345e9a36"} [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

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

L-Tryptophan (alternative_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"}

experimental_model

Controlled metabolic-unit feeding; seven men, 80 days

exposure

6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine

limitations

Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

With too little niacin and tryptophan, red blood cells lost much of their NAD supply; restoring intake raised it.

primary_references

[nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

tissue_or_cell_type

Erythrocytes and plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1107–1119

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled metabolic-unit feeding; seven men, 80 days · source_derived_draft · unverified_draft

### nia-clin-restriction-nad At both low niacin-equivalent intakes, erythrocyte NAD fell by about 70% in the seven-man feeding study and increased during adequate-intake repletion. Condition category: nutrient_deficiency nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: With too little niacin and tryptophan, red blood cells lost much of their NAD supply; restoring intake raised it. organism: Homo sapiens tissue_or_cell_type: Erythrocytes and plasma experimental_model: Controlled metabolic-unit feeding; seven men, 80 days limitations: Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials. exposure: 6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine cross_nutrient: L-Tryptophan (alternative_precursor); Nicotinamide adenine dinucleotide, oxidized (measured_coenzyme) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"} [nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Same ten-person 3 g comparison.

limitations

The ratio is not a measured change in brain serotonin or dopamine.

nutrient_topic

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

plain_language

Transport competition depends partly on the mixture reaching blood.

primary_references

Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same ten-person 3 g comparison. · source_derived_draft · unverified_draft

## aspartame-formulation-ratio Transport competition depends partly on the mixture reaching blood. Solution versus capsules produced a higher plasma phenylalanine-to-other-LNAA ratio, 0.36 versus 0.23. Model: Same ten-person 3 g comparison. Limitations: The ratio is not a measured change in brain serotonin or dopamine. Evidence access: Primary abstract Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7