Nutrient chapter

L-Phenylalanine

Context-specific entity; species, compartment and exposure are stated on each claim.

62 recorded mechanisms · 10 availability situations · 10 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

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

PAH catalyzes phenylalanine hydroxylation to tyrosine using BH4, molecular oxygen and non-heme ferrous iron.
Human phenylalanine hydroxylase / PAH → L-Tyrosine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; reaction background distinguished from new structural experiments
experimental_model
Human PAH structural study; established reaction described in the full-text introduction.
limitations
This record describes the established reaction, not a new dietary intervention or a human iron-deficiency threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Making tyrosine requires a working enzyme and its chemical helpers.
primary_references
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 14–20
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PAH structural study; established reaction described in the full-text introduction. · source_derived_draft · unverified_draft
## l-phenylalanine-pah-conversion Making tyrosine requires a working enzyme and its chemical helpers. PAH catalyzes phenylalanine hydroxylation to tyrosine using BH4, molecular oxygen and non-heme ferrous iron. Model: Human PAH structural study; established reaction described in the full-text introduction. Limitations: This record describes the established reaction, not a new dietary intervention or a human iron-deficiency threshold. Evidence access: Primary full text; reaction background distinguished from new structural experiments Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
Complete structured claim and evidence
Phenylalanine bound at the interface of two ACT regulatory domains and stabilized the human PAH regulatory-domain dimer.
L-Phenylalanine → Human phenylalanine hydroxylase / PAH source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine.
limitations
An isolated domain at experimental concentrations does not establish an oral-dose activation threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Phenylalanine helps switch on the machinery that processes it.
primary_references
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 22–28
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine. · source_derived_draft · unverified_draft
## l-phenylalanine-pah-allostery Phenylalanine helps switch on the machinery that processes it. Phenylalanine bound at the interface of two ACT regulatory domains and stabilized the human PAH regulatory-domain dimer. Model: Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine. Limitations: An isolated domain at experimental concentrations does not establish an oral-dose activation threshold. Evidence access: Primary full text Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
Complete structured claim and evidence
The disease-associated E76A regulatory-domain mutant showed reduced phenylalanine binding, dimerization and stability.
Human phenylalanine hydroxylase / PAH → Human PAH E76A regulatory-domain response source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Purified human PAH regulatory-domain E76A comparison.
limitations
Domain behavior does not quantify whole-body phenylalanine clearance for every PAH variant.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A PAH variant can damage the substrate-sensing switch.
primary_references
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 30–36
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human PAH regulatory-domain E76A comparison. · source_derived_draft · unverified_draft
## l-phenylalanine-pah-variant A PAH variant can damage the substrate-sensing switch. The disease-associated E76A regulatory-domain mutant showed reduced phenylalanine binding, dimerization and stability. Model: Purified human PAH regulatory-domain E76A comparison. Limitations: Domain behavior does not quantify whole-body phenylalanine clearance for every PAH variant. Evidence access: Primary full text Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
Complete structured claim and evidence
Recombinant human GFRP enabled phenylalanine-dependent stimulation of recombinant human GCH1.
L-Phenylalanine → GCH1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human proteins; primary abstract.
limitations
GCH1 controls an early BH4-biosynthesis step; this is not proof that supplemental phenylalanine raises BH4 in every tissue.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The substrate can signal for more of the cofactor-making machinery to work.
primary_references
Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 38–44
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human proteins; primary abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-gch1-feedforward The substrate can signal for more of the cofactor-making machinery to work. Recombinant human GFRP enabled phenylalanine-dependent stimulation of recombinant human GCH1. Model: Recombinant human proteins; primary abstract. Limitations: GCH1 controls an early BH4-biosynthesis step; this is not proof that supplemental phenylalanine raises BH4 in every tissue. Evidence access: Primary abstract Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
Complete structured claim and evidence
BH4 and phenylalanine favored inhibited and activated human GCH1-GFRP complexes, respectively; ligand-dependent conformational changes stabilized binding.
Tetrahydrobiopterin / BH4 → Human GTP cyclohydrolase 1 feedback regulatory protein / GCHFR source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human purified proteins, crystallography and binding/kinetic studies.
limitations
Cofactor synthesis has additional steps; structural regulation does not establish a clinical depletion or supplementation effect.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Cofactor production has both a demand signal and a feedback brake.
primary_references
Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33387654/ · DOI 10.1016/j.jsb.2020.107691
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 46–52
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human purified proteins, crystallography and binding/kinetic studies. · source_derived_draft · unverified_draft
## l-phenylalanine-gch1-feedback Cofactor production has both a demand signal and a feedback brake. BH4 and phenylalanine favored inhibited and activated human GCH1-GFRP complexes, respectively; ligand-dependent conformational changes stabilized binding. Model: Human purified proteins, crystallography and binding/kinetic studies. Limitations: Cofactor synthesis has additional steps; structural regulation does not establish a clinical depletion or supplementation effect. Evidence access: Primary abstract Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33387654/ · DOI 10.1016/j.jsb.2020.107691
Complete structured claim and evidence
LPS at 1 microgram/mL reduced GFRP expression in human THP-1 cells; with interferon-gamma plus LPS, pteridine production became phenylalanine-independent.
Human GTP cyclohydrolase 1 feedback regulatory protein / GCHFR → THP-1 pteridine response under LPS and interferon-gamma source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human THP-1 cells; interferon-gamma alone compared with interferon-gamma plus LPS.
limitations
Pteridine output is not synonymous with bioavailable BH4; no clinical inflammatory threshold is defined.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Inflammatory stimulation changed how this cell model responded to phenylalanine.
primary_references
Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 54–60
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human THP-1 cells; interferon-gamma alone compared with interferon-gamma plus LPS. · source_derived_draft · unverified_draft
## l-phenylalanine-inflammation-feedback Inflammatory stimulation changed how this cell model responded to phenylalanine. LPS at 1 microgram/mL reduced GFRP expression in human THP-1 cells; with interferon-gamma plus LPS, pteridine production became phenylalanine-independent. Model: Human THP-1 cells; interferon-gamma alone compared with interferon-gamma plus LPS. Limitations: Pteridine output is not synonymous with bioavailable BH4; no clinical inflammatory threshold is defined. Evidence access: Primary abstract Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
Complete structured claim and evidence
PCBD1 has a pterin-carbinolamine dehydratase role in BH4 regeneration; biallelic defects are associated with transient neonatal hyperphenylalaninemia and primapterinuria.
Human pterin-4-alpha-carbinolamine dehydratase / PCBD1 → Tetrahydrobiopterin / BH4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human PCBD1 mutation study; established biochemical role and disease background.
limitations
The renal study does not directly measure whole-body BH4 recycling flux. The transcriptional role below is separately recorded.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
One cofactor-recycling protein has another important job in the kidney.
primary_references
Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 62–68
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PCBD1 mutation study; established biochemical role and disease background. · source_derived_draft · unverified_draft
## l-phenylalanine-pcbd-recycling-role One cofactor-recycling protein has another important job in the kidney. PCBD1 has a pterin-carbinolamine dehydratase role in BH4 regeneration; biallelic defects are associated with transient neonatal hyperphenylalaninemia and primapterinuria. Model: Human PCBD1 mutation study; established biochemical role and disease background. Limitations: The renal study does not directly measure whole-body BH4 recycling flux. The transcriptional role below is separately recorded. Evidence access: Primary abstract Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
Complete structured claim and evidence
A catalytically characterized recombinant human dihydropteridine reductase was crystallized in complex with NADH at 2.5-angstrom resolution.
Human quinoid dihydropteridine reductase / QDPR → NADH source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human QDPR expressed in E. coli; enzyme purification, kinetic characterization and structure.
limitations
This binary structure alone does not show that niacin supplementation changes phenylalanine clearance.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The cofactor-recycling network includes an NADH-binding enzyme.
primary_references
The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8262916/
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 70–76
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human QDPR expressed in E. coli; enzyme purification, kinetic characterization and structure. · source_derived_draft · unverified_draft
## l-phenylalanine-qdpr-nadh The cofactor-recycling network includes an NADH-binding enzyme. A catalytically characterized recombinant human dihydropteridine reductase was crystallized in complex with NADH at 2.5-angstrom resolution. Model: Human QDPR expressed in E. coli; enzyme purification, kinetic characterization and structure. Limitations: This binary structure alone does not show that niacin supplementation changes phenylalanine clearance. Evidence access: Primary abstract The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8262916/
Complete structured claim and evidence
Overexpressed wild-type PCBD1 bound HNF1B and increased FXYD2 promoter activity in a human kidney cell line.
Human pterin-4-alpha-carbinolamine dehydratase / PCBD1 → Human sodium/potassium ATPase regulatory subunit / FXYD2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human kidney-cell overexpression and promoter assay.
limitations
Promoter activity is not a direct measurement of magnesium flux or proof that phenylalanine intake regulates magnesium.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A protein used in phenylalanine metabolism also helps control a kidney transport regulator.
primary_references
Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 78–84
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human kidney-cell overexpression and promoter assay. · source_derived_draft · unverified_draft
## l-phenylalanine-pcbd-transcription A protein used in phenylalanine metabolism also helps control a kidney transport regulator. Overexpressed wild-type PCBD1 bound HNF1B and increased FXYD2 promoter activity in a human kidney cell line. Model: Human kidney-cell overexpression and promoter assay. Limitations: Promoter activity is not a direct measurement of magnesium flux or proof that phenylalanine intake regulates magnesium. Evidence access: Primary abstract Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
Complete structured claim and evidence
Five of seven tested PCBD1 mutations caused proteolytic instability and reduced FXYD2 promoter activity.
Human pterin-4-alpha-carbinolamine dehydratase / PCBD1 → Human sodium/potassium ATPase regulatory subunit / FXYD2 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human PCBD1 variant expression and promoter assays.
limitations
Variant effects are not uniform and do not establish dietary phenylalanine deficiency.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Some mutations damage the protein and weaken its kidney-related transcriptional function.
primary_references
Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 86–92
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PCBD1 variant expression and promoter assays. · source_derived_draft · unverified_draft
## l-phenylalanine-pcbd-mutants Some mutations damage the protein and weaken its kidney-related transcriptional function. Five of seven tested PCBD1 mutations caused proteolytic instability and reduced FXYD2 promoter activity. Model: Human PCBD1 variant expression and promoter assays. Limitations: Variant effects are not uniform and do not establish dietary phenylalanine deficiency. Evidence access: Primary abstract Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
Complete structured claim and evidence
Two of three adults with homozygous PCBD1 mutations had hypomagnesemia with renal magnesium loss.
Human pterin-4-alpha-carbinolamine dehydratase / PCBD1 → Urinary magnesium excretion source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Small human case series, three adults with homozygous PCBD1 mutations.
limitations
Two also had MODY-like diabetes regardless of magnesium status; neither finding establishes that phenylalanine supplements cause or correct the disorder.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A genetic defect can connect abnormal phenylalanine handling with magnesium wasting.
primary_references
Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 94–100
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small human case series, three adults with homozygous PCBD1 mutations. · source_derived_draft · unverified_draft
## l-phenylalanine-pcbd-magnesium A genetic defect can connect abnormal phenylalanine handling with magnesium wasting. Two of three adults with homozygous PCBD1 mutations had hypomagnesemia with renal magnesium loss. Model: Small human case series, three adults with homozygous PCBD1 mutations. Limitations: Two also had MODY-like diabetes regardless of magnesium status; neither finding establishes that phenylalanine supplements cause or correct the disorder. Evidence access: Primary abstract Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24204001/ · DOI 10.1681/ASN.2013040337
Complete structured claim and evidence
DNAJC12 interacted with aromatic amino-acid hydroxylases, including PAH, tyrosine hydroxylase and tryptophan hydroxylases.
Human chaperone DNAJC12 → Human phenylalanine hydroxylase / PAH source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human DNAJC12 deficiency study with functional interaction experiments.
limitations
Interaction does not imply identical effects in all tissues or rescue by extra substrate.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A shared chaperone supports several amino-acid processing enzymes.
primary_references
Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 102–108
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human DNAJC12 deficiency study with functional interaction experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-dnaj-chaperone A shared chaperone supports several amino-acid processing enzymes. DNAJC12 interacted with aromatic amino-acid hydroxylases, including PAH, tyrosine hydroxylase and tryptophan hydroxylases. Model: Human DNAJC12 deficiency study with functional interaction experiments. Limitations: Interaction does not imply identical effects in all tissues or rescue by extra substrate. Evidence access: Primary abstract Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
Complete structured claim and evidence
Biallelic DNAJC12 variants in six patients from four families accompanied hyperphenylalaninemia and neurotransmitter abnormalities; functional studies found reduced PAH activity.
Human chaperone DNAJC12 → Human phenylalanine hydroxylase / PAH source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human genetic case series and functional experiments.
limitations
Early combined BH4/neurotransmitter-precursor treatment was not a controlled test of phenylalanine supplementation.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Phenylalanine can accumulate because its supporting machinery is defective.
primary_references
Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 110–116
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human genetic case series and functional experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-dnaj-failure Phenylalanine can accumulate because its supporting machinery is defective. Biallelic DNAJC12 variants in six patients from four families accompanied hyperphenylalaninemia and neurotransmitter abnormalities; functional studies found reduced PAH activity. Model: Human genetic case series and functional experiments. Limitations: Early combined BH4/neurotransmitter-precursor treatment was not a controlled test of phenylalanine supplementation. Evidence access: Primary abstract Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
Complete structured claim and evidence
Human tyrosine hydroxylase catalyzes BH4-dependent tyrosine hydroxylation to L-DOPA, a downstream step in dopamine biosynthesis.
Human tyrosine hydroxylase → L-3,4-Dihydroxyphenylalanine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human TH variant study; established enzyme reaction described in the abstract.
limitations
This is a downstream connection, not evidence that oral phenylalanine predictably raises brain dopamine.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Producing tyrosine is only the first part of the route toward dopamine.
primary_references
Tyrosine hydroxylase variants influence protein expression, cellular localization, stability, enzymatic activity and the physical interaction between tyrosine hydroxylase and GTP cyclohydrolase 1. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38084654/ · DOI 10.1002/jimd.12690
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 118–124
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human TH variant study; established enzyme reaction described in the abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-tyrosine-next-step Producing tyrosine is only the first part of the route toward dopamine. Human tyrosine hydroxylase catalyzes BH4-dependent tyrosine hydroxylation to L-DOPA, a downstream step in dopamine biosynthesis. Model: Human TH variant study; established enzyme reaction described in the abstract. Limitations: This is a downstream connection, not evidence that oral phenylalanine predictably raises brain dopamine. Evidence access: Primary abstract Tyrosine hydroxylase variants influence protein expression, cellular localization, stability, enzymatic activity and the physical interaction between tyrosine hydroxylase and GTP cyclohydrolase 1. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38084654/ · DOI 10.1002/jimd.12690
Complete structured claim and evidence
Human cytosolic phenylalanyl-tRNA synthetase activates phenylalanine and attaches it to tRNA(Phe), with editing that discriminates against mischarged aromatic amino acids.
Human cytosolic FARSA/FARSB phenylalanyl-tRNA synthetase → Human cytosolic tRNA(Phe) source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human phenylalanyl-tRNA synthetase biochemical comparison.
limitations
This aminoacylation function is distinct from conversion of phenylalanine to tyrosine.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Protein construction needs a molecular loading and proofreading system.
primary_references
Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 126–132
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human phenylalanyl-tRNA synthetase biochemical comparison. · source_derived_draft · unverified_draft
## l-phenylalanine-cytosolic-charging Protein construction needs a molecular loading and proofreading system. Human cytosolic phenylalanyl-tRNA synthetase activates phenylalanine and attaches it to tRNA(Phe), with editing that discriminates against mischarged aromatic amino acids. Model: Human phenylalanyl-tRNA synthetase biochemical comparison. Limitations: This aminoacylation function is distinct from conversion of phenylalanine to tyrosine. Evidence access: Primary abstract Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008
Complete structured claim and evidence
Human cytosolic and mitochondrial phenylalanyl-tRNA synthetases could mischarge L-DOPA in biochemical assays; cytosolic editing hydrolyzed L-DOPA- and tyrosine-mischarged tRNA, whereas the mitochondrial system discriminated less effectively.
Human cytosolic FARSA/FARSB phenylalanyl-tRNA synthetase → L-3,4-Dihydroxyphenylalanine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
In-vitro human cytosolic and mitochondrial synthetase assays.
limitations
Assay mischarging does not establish clinical proteotoxicity from a usual phenylalanine intake.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Similar-looking molecules can challenge protein-building accuracy.
primary_references
Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 134–140
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · In-vitro human cytosolic and mitochondrial synthetase assays. · source_derived_draft · unverified_draft
## l-phenylalanine-charging-fidelity Similar-looking molecules can challenge protein-building accuracy. Human cytosolic and mitochondrial phenylalanyl-tRNA synthetases could mischarge L-DOPA in biochemical assays; cytosolic editing hydrolyzed L-DOPA- and tyrosine-mischarged tRNA, whereas the mitochondrial system discriminated less effectively. Model: In-vitro human cytosolic and mitochondrial synthetase assays. Limitations: Assay mischarging does not establish clinical proteotoxicity from a usual phenylalanine intake. Evidence access: Primary abstract Bacterial and eukaryotic phenylalanyl-tRNA synthetases catalyze misaminoacylation of tRNA(Phe) with 3,4-dihydroxy-L-phenylalanine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/22035791/ · DOI 10.1016/j.chembiol.2011.08.008
Complete structured claim and evidence
Cardiac Fars2 deficiency impaired mitochondrial tRNA(Phe) aminoacylation and mitochondrial protein synthesis in mice.
Mouse mitochondrial phenylalanyl-tRNA synthetase / Fars2 → Mouse mitochondrial tRNA(Phe) charging source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Heart-specific Fars2-deficient mice and mitochondrial translation assays.
limitations
Genetic enzyme loss is not the same as inadequate dietary phenylalanine; human variant binding predictions were not direct kinetic measurements.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Mitochondria need their own phenylalanine-loading enzyme.
primary_references
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 142–148
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Heart-specific Fars2-deficient mice and mitochondrial translation assays. · source_derived_draft · unverified_draft
## l-phenylalanine-mitochondrial-charging Mitochondria need their own phenylalanine-loading enzyme. Cardiac Fars2 deficiency impaired mitochondrial tRNA(Phe) aminoacylation and mitochondrial protein synthesis in mice. Model: Heart-specific Fars2-deficient mice and mitochondrial translation assays. Limitations: Genetic enzyme loss is not the same as inadequate dietary phenylalanine; human variant binding predictions were not direct kinetic measurements. Evidence access: Primary full text FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
Complete structured claim and evidence
Heart-specific Fars2 loss produced hypertrophy, ventricular dilation and progressive cardiac failure with mitochondrial dysfunction.
Mouse mitochondrial phenylalanyl-tRNA synthetase / Fars2 → Cardiac function in Fars2-deficient mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Conditional mouse cardiac Fars2 knockout; separate R415L model also studied.
limitations
No evidence here that phenylalanine supplements rescue the genetic defect.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Failure at the protein-loading step can affect an organ that needs substantial energy.
primary_references
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 150–156
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Conditional mouse cardiac Fars2 knockout; separate R415L model also studied. · source_derived_draft · unverified_draft
## l-phenylalanine-mitochondrial-heart Failure at the protein-loading step can affect an organ that needs substantial energy. Heart-specific Fars2 loss produced hypertrophy, ventricular dilation and progressive cardiac failure with mitochondrial dysfunction. Model: Conditional mouse cardiac Fars2 knockout; separate R415L model also studied. Limitations: No evidence here that phenylalanine supplements rescue the genetic defect. Evidence access: Primary full text FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
Complete structured claim and evidence
Fars2 knockdown in neonatal rat ventricular myocytes lowered ATP and mitochondrial membrane potential, increased ROS, and reduced the NAD+/NADH ratio.
Rat mitochondrial phenylalanyl-tRNA synthetase / Fars2 → Rat cardiomyocyte mitochondrial energy and redox state source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Neonatal rat ventricular myocyte knockdown assays.
limitations
These are related cellular readouts, not proof of human niacin or phenylalanine deficiency.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The downstream effects include both energy production and redox balance.
primary_references
FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 158–164
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Neonatal rat ventricular myocyte knockdown assays. · source_derived_draft · unverified_draft
## l-phenylalanine-mitochondrial-energy The downstream effects include both energy production and redox balance. Fars2 knockdown in neonatal rat ventricular myocytes lowered ATP and mitochondrial membrane potential, increased ROS, and reduced the NAD+/NADH ratio. Model: Neonatal rat ventricular myocyte knockdown assays. Limitations: These are related cellular readouts, not proof of human niacin or phenylalanine deficiency. Evidence access: Primary full text FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38362779/ · DOI 10.1161/CIRCULATIONAHA.123.064489
Complete structured claim and evidence
B0AT1/SLC6A19 transports neutral amino acids including phenylalanine during intestinal absorption and renal reuptake.
Human neutral amino acid transporter B0AT1 / SLC6A19 → L-Phenylalanine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human B0AT1 structural and transport study; established physiological role described in abstract.
limitations
Transporter identity does not specify a universal saturation threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The gut and kidney transport machinery helps determine phenylalanine availability.
primary_references
Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
transport_effect
raises Recorded as acting during intestinal absorption and renal reuptake, both of which are inward.
transport_pool
the enterocyte and tubule cell interior Recorded as acting during intestinal absorption and renal reuptake, both of which are inward.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 166–172
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human B0AT1 structural and transport study; established physiological role described in abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-renal-transporter The gut and kidney transport machinery helps determine phenylalanine availability. B0AT1/SLC6A19 transports neutral amino acids including phenylalanine during intestinal absorption and renal reuptake. Model: Human B0AT1 structural and transport study; established physiological role described in abstract. Limitations: Transporter identity does not specify a universal saturation threshold. Evidence access: Primary abstract Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
Complete structured claim and evidence
A designed inhibitor occupied an allosteric B0AT1 pocket about 17 angstroms from the substrate site, stabilized an outward-occluded state and blocked transport with submicromolar IC50.
Experimental B0AT1 inhibitor from the 2026 structure-guided study → Human neutral amino acid transporter B0AT1 / SLC6A19 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human transporter cryo-EM and human/mouse transport inhibition assays.
limitations
Compound identity is not resolved in the accessed abstract; this is experimental pharmacology, not a supplement recommendation.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Transport can be blocked at a site away from where the amino acid binds.
primary_references
Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 174–180
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter cryo-EM and human/mouse transport inhibition assays. · source_derived_draft · unverified_draft
## l-phenylalanine-renal-inhibition Transport can be blocked at a site away from where the amino acid binds. A designed inhibitor occupied an allosteric B0AT1 pocket about 17 angstroms from the substrate site, stabilized an outward-occluded state and blocked transport with submicromolar IC50. Model: Human transporter cryo-EM and human/mouse transport inhibition assays. Limitations: Compound identity is not resolved in the accessed abstract; this is experimental pharmacology, not a supplement recommendation. Evidence access: Primary abstract Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
Complete structured claim and evidence
Oral experimental B0AT1 inhibition increased urinary phenylalanine and lowered plasma phenylalanine in PKU-model mice.
Experimental B0AT1 inhibitor from the 2026 structure-guided study → Mouse urinary phenylalanine excretion source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
PKU-model mice; oral dosing, dose not specified in accessed abstract.
limitations
Human efficacy and effects on other neutral amino acids are not established here.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A transporter intervention can lower blood levels by increasing urinary loss.
primary_references
Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 182–188
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · PKU-model mice; oral dosing, dose not specified in accessed abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-renal-excretion A transporter intervention can lower blood levels by increasing urinary loss. Oral experimental B0AT1 inhibition increased urinary phenylalanine and lowered plasma phenylalanine in PKU-model mice. Model: PKU-model mice; oral dosing, dose not specified in accessed abstract. Limitations: Human efficacy and effects on other neutral amino acids are not established here. Evidence access: Primary abstract Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
Complete structured claim and evidence
After 100 mg/kg oral phenylalanine in six healthy men, plasma phenylalanine rose about elevenfold and brain uptake of the artificial large-neutral-amino-acid tracer carbon-11 ACHC fell from 0.036 to 0.019 mL/g/min.
L-Phenylalanine → Human brain influx of carbon-11 ACHC tracer source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human PET loading study in six men.
limitations
ACHC is a transport tracer; each individual natural amino acid was not directly measured. This is not a normal-meal threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A large phenylalanine load can compete with other molecules for brain entry.
primary_references
Inhibition of neutral amino acid transport across the human blood-brain barrier by phenylalanine. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7861158/ · DOI 10.1046/j.1471-4159.1995.64031252.x
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 190–196
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PET loading study in six men. · source_derived_draft · unverified_draft
## l-phenylalanine-brain-competition A large phenylalanine load can compete with other molecules for brain entry. After 100 mg/kg oral phenylalanine in six healthy men, plasma phenylalanine rose about elevenfold and brain uptake of the artificial large-neutral-amino-acid tracer carbon-11 ACHC fell from 0.036 to 0.019 mL/g/min. Model: Human PET loading study in six men. Limitations: ACHC is a transport tracer; each individual natural amino acid was not directly measured. This is not a normal-meal threshold. Evidence access: Primary abstract Inhibition of neutral amino acid transport across the human blood-brain barrier by phenylalanine. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7861158/ · DOI 10.1046/j.1471-4159.1995.64031252.x
Complete structured claim and evidence
In ten PKU patients, 300 mg/kg/day tyrosine transiently raised calculated brain tyrosine influx from 27% to 90% of normal, but it remained below 70% for half the sampled period.
L-Tyrosine → Calculated tyrosine brain influx in PKU source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Forty-eight-hour human study with tyrosine on day two and calculated transport estimates.
limitations
Brain influx was modeled, not directly measured; high phenylalanine and other competing amino acids remain part of the model.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A blood rise after supplementation need not provide steady predicted brain delivery.
primary_references
Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11562623/ · DOI 10.1067/mpd.2001.117576
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 198–204
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Forty-eight-hour human study with tyrosine on day two and calculated transport estimates. · source_derived_draft · unverified_draft
## l-phenylalanine-tyrosine-brain-estimate A blood rise after supplementation need not provide steady predicted brain delivery. In ten PKU patients, 300 mg/kg/day tyrosine transiently raised calculated brain tyrosine influx from 27% to 90% of normal, but it remained below 70% for half the sampled period. Model: Forty-eight-hour human study with tyrosine on day two and calculated transport estimates. Limitations: Brain influx was modeled, not directly measured; high phenylalanine and other competing amino acids remain part of the model. Evidence access: Primary abstract Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11562623/ · DOI 10.1067/mpd.2001.117576
Complete structured claim and evidence
In a 16-person PKU crossover study, LNAA supplementation produced limited executive-function benefits and lowered plasma phenylalanine mainly when participants were not taking their usual medical product.
Study-specific large neutral amino acid supplementation in PKU → Executive-function outcomes in the small PKU LNAA trial source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Four two-week crossover phases involving LNAA/placebo with or without medical product.
limitations
Small, short study; not a replacement recommendation for established PKU management.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A mixture can change outcomes, but the existing diet affects its added value.
primary_references
The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17368065/ · DOI 10.1016/j.ymgme.2007.02.002
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 206–212
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four two-week crossover phases involving LNAA/placebo with or without medical product. · source_derived_draft · unverified_draft
## l-phenylalanine-lnaa-clinical-boundary A mixture can change outcomes, but the existing diet affects its added value. In a 16-person PKU crossover study, LNAA supplementation produced limited executive-function benefits and lowered plasma phenylalanine mainly when participants were not taking their usual medical product. Model: Four two-week crossover phases involving LNAA/placebo with or without medical product. Limitations: Small, short study; not a replacement recommendation for established PKU management. Evidence access: Primary abstract The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17368065/ · DOI 10.1016/j.ymgme.2007.02.002
Complete structured claim and evidence
In ten adults with PKU, LNAA supplementation increased melatonin measures and urinary dopamine while phenylalanine itself did not significantly change.
Study-specific large neutral amino acid supplementation in PKU → Melatonin and urinary dopamine markers during PKU LNAA supplementation source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Three three-week crossover periods; serum/urine melatonin, urinary dopamine and plasma amino-acid ratios.
limitations
Urinary dopamine and melatonin are surrogate readouts, not a direct demonstration of restored brain neurotransmitter concentrations.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A downstream marker can improve even when phenylalanine concentration stays similar.
primary_references
Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23164313/ · DOI 10.1016/j.jpeds.2012.10.015
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 214–220
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Three three-week crossover periods; serum/urine melatonin, urinary dopamine and plasma amino-acid ratios. · source_derived_draft · unverified_draft
## l-phenylalanine-lnaa-monoamine-markers A downstream marker can improve even when phenylalanine concentration stays similar. In ten adults with PKU, LNAA supplementation increased melatonin measures and urinary dopamine while phenylalanine itself did not significantly change. Model: Three three-week crossover periods; serum/urine melatonin, urinary dopamine and plasma amino-acid ratios. Limitations: Urinary dopamine and melatonin are surrogate readouts, not a direct demonstration of restored brain neurotransmitter concentrations. Evidence access: Primary full text Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23164313/ · DOI 10.1016/j.jpeds.2012.10.015
Complete structured claim and evidence
In an 89-participant six-week PKU trial, sapropterin 10 mg/kg/day lowered mean phenylalanine by 236 micromol/L versus a 3 micromol/L rise with placebo; 44% versus 9% had at least a 30% reduction.
Sapropterin, pharmaceutical tetrahydrobiopterin → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Randomized human PKU study enriched through prior responsiveness assessment.
limitations
Not all PAH defects respond; trial dose is historical evidence, not individualized guidance.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Providing the pharmaceutical cofactor helped some patients, with substantial response variation.
primary_references
Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17693179/ · DOI 10.1016/S0140-6736(07)61234-3
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 222–228
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized human PKU study enriched through prior responsiveness assessment. · source_derived_draft · unverified_draft
## l-phenylalanine-sapropterin-response Providing the pharmaceutical cofactor helped some patients, with substantial response variation. In an 89-participant six-week PKU trial, sapropterin 10 mg/kg/day lowered mean phenylalanine by 236 micromol/L versus a 3 micromol/L rise with placebo; 44% versus 9% had at least a 30% reduction. Model: Randomized human PKU study enriched through prior responsiveness assessment. Limitations: Not all PAH defects respond; trial dose is historical evidence, not individualized guidance. Evidence access: Primary abstract Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17693179/ · DOI 10.1016/S0140-6736(07)61234-3
Complete structured claim and evidence
In 46 preselected sapropterin-responsive children, 20 mg/kg/day allowed more supplemental dietary phenylalanine while maintaining study blood targets: 20.9 versus 2.9 mg/kg/day with placebo.
Sapropterin, pharmaceutical tetrahydrobiopterin → Dietary phenylalanine tolerance in responsive PKU children source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Ten-week randomized trial after responder selection.
limitations
Selected pediatric responders cannot represent all PKU patients.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
When processing capacity improves, a responsive patient may tolerate more dietary phenylalanine.
primary_references
Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19261295/ · DOI 10.1016/j.jpeds.2008.11.040
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 230–236
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ten-week randomized trial after responder selection. · source_derived_draft · unverified_draft
## l-phenylalanine-sapropterin-tolerance When processing capacity improves, a responsive patient may tolerate more dietary phenylalanine. In 46 preselected sapropterin-responsive children, 20 mg/kg/day allowed more supplemental dietary phenylalanine while maintaining study blood targets: 20.9 versus 2.9 mg/kg/day with placebo. Model: Ten-week randomized trial after responder selection. Limitations: Selected pediatric responders cannot represent all PKU patients. Evidence access: Primary abstract Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19261295/ · DOI 10.1016/j.jpeds.2008.11.040
Complete structured claim and evidence
Pegvaliase supplies a PEGylated microbial phenylalanine ammonia lyase pathway that converts phenylalanine to trans-cinnamate and ammonia rather than tyrosine.
Pegvaliase, PEGylated Anabaena variabilis phenylalanine ammonia lyase → trans-Cinnamate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Enzyme mechanism described in the primary PRISM clinical report.
limitations
Lowering phenylalanine through this bypass does not restore the PAH-to-tyrosine reaction.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A drug can remove the accumulating substrate through a different chemical route.
primary_references
Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29653686/ · DOI 10.1016/j.ymgme.2018.03.006
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 238–244
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Enzyme mechanism described in the primary PRISM clinical report. · source_derived_draft · unverified_draft
## l-phenylalanine-pal-bypass A drug can remove the accumulating substrate through a different chemical route. Pegvaliase supplies a PEGylated microbial phenylalanine ammonia lyase pathway that converts phenylalanine to trans-cinnamate and ammonia rather than tyrosine. Model: Enzyme mechanism described in the primary PRISM clinical report. Limitations: Lowering phenylalanine through this bypass does not restore the PAH-to-tyrosine reaction. Evidence access: Primary abstract Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29653686/ · DOI 10.1016/j.ymgme.2018.03.006
Complete structured claim and evidence
PRISM studies in 261 adults with PAH deficiency found substantial phenylalanine reductions during induction, titration and maintenance pegvaliase treatment.
Pegvaliase, PEGylated Anabaena variabilis phenylalanine ammonia lyase → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Adult phase-3 clinical program with long-term titrated exposure.
limitations
Immune-mediated adverse events matter: 17 events in 12 participants met acute systemic hypersensitivity/anaphylaxis criteria. This is not dietary enzyme use.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The bypass can lower blood phenylalanine, but has its own treatment risks.
primary_references
Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29653686/ · DOI 10.1016/j.ymgme.2018.03.006
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 246–252
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Adult phase-3 clinical program with long-term titrated exposure. · source_derived_draft · unverified_draft
## l-phenylalanine-pal-clinical The bypass can lower blood phenylalanine, but has its own treatment risks. PRISM studies in 261 adults with PAH deficiency found substantial phenylalanine reductions during induction, titration and maintenance pegvaliase treatment. Model: Adult phase-3 clinical program with long-term titrated exposure. Limitations: Immune-mediated adverse events matter: 17 events in 12 participants met acute systemic hypersensitivity/anaphylaxis criteria. This is not dietary enzyme use. Evidence access: Primary abstract Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). · 2018 · https://pubmed.ncbi.nlm.nih.gov/29653686/ · DOI 10.1016/j.ymgme.2018.03.006
Complete structured claim and evidence
An infant treated for tyrosinemia type I developed growth failure, anorexia, lethargy and hypotonia with low phenylalanine and tyrosine during restriction; adding both amino acids reversed these manifestations without reversing cirrhosis.
L-Phenylalanine → Infant illness during combined phenylalanine and tyrosine restriction source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Single historical infant case with combined phenylalanine/tyrosine restriction and repletion.
limitations
Cannot attribute every manifestation to isolated phenylalanine deficiency or generalize a dose threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Over-restricting these building blocks can create a new shortage problem.
primary_references
Phenylalanine-tyrosine deficiency syndrome as a complication of the management of hereditary tyrosinemia. · 1977 · https://pubmed.ncbi.nlm.nih.gov/835507/ · DOI 10.1093/ajcn/30.2.209
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 254–260
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single historical infant case with combined phenylalanine/tyrosine restriction and repletion. · source_derived_draft · unverified_draft
## l-phenylalanine-combined-shortage Over-restricting these building blocks can create a new shortage problem. An infant treated for tyrosinemia type I developed growth failure, anorexia, lethargy and hypotonia with low phenylalanine and tyrosine during restriction; adding both amino acids reversed these manifestations without reversing cirrhosis. Model: Single historical infant case with combined phenylalanine/tyrosine restriction and repletion. Limitations: Cannot attribute every manifestation to isolated phenylalanine deficiency or generalize a dose threshold. Evidence access: Primary abstract Phenylalanine-tyrosine deficiency syndrome as a complication of the management of hereditary tyrosinemia. · 1977 · https://pubmed.ncbi.nlm.nih.gov/835507/ · DOI 10.1093/ajcn/30.2.209
Complete structured claim and evidence
With excess tyrosine supplied, indicator-amino-acid oxidation in twelve older adults across 66 studies estimated mean phenylalanine requirement at 9.03 mg/kg/day and its upper 95% confidence limit at 15.9 mg/kg/day.
L-Tyrosine → Human dietary phenylalanine requirement estimate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human tracer feeding study with phenylalanine intakes 7.2–40 mg/kg/day and excess tyrosine.
limitations
This conditional estimate is not a universal intake target or evidence that tyrosine replaces phenylalanine in proteins.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Supplying tyrosine changes how much phenylalanine must be reserved for making it.
primary_references
The Phenylalanine Requirement of Elderly Men and Women Measured by Direct 13C Carbon Oxidation Method Is Similar to That of Young Adults. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31271193/ · DOI 10.1093/jn/nxz137
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 262–268
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human tracer feeding study with phenylalanine intakes 7.2–40 mg/kg/day and excess tyrosine. · source_derived_draft · unverified_draft
## l-phenylalanine-tyrosine-sparing Supplying tyrosine changes how much phenylalanine must be reserved for making it. With excess tyrosine supplied, indicator-amino-acid oxidation in twelve older adults across 66 studies estimated mean phenylalanine requirement at 9.03 mg/kg/day and its upper 95% confidence limit at 15.9 mg/kg/day. Model: Human tracer feeding study with phenylalanine intakes 7.2–40 mg/kg/day and excess tyrosine. Limitations: This conditional estimate is not a universal intake target or evidence that tyrosine replaces phenylalanine in proteins. Evidence access: Primary abstract The Phenylalanine Requirement of Elderly Men and Women Measured by Direct 13C Carbon Oxidation Method Is Similar to That of Young Adults. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31271193/ · DOI 10.1093/jn/nxz137
Complete structured claim and evidence
A tracer study in healthy Indian adults consuming no tyrosine estimated mean phenylalanine requirement at about 38 mg/kg/day.
L-Phenylalanine → Human dietary phenylalanine requirement estimate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human indicator amino-acid oxidation/balance feeding study without dietary tyrosine.
limitations
Population and protocol differ from the older-adult excess-tyrosine study; different estimates are not treated as a scientific contradiction.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
When tyrosine is absent, phenylalanine must cover an additional metabolic demand.
primary_references
The daily phenylalanine requirement of healthy Indian adults. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16762944/ · DOI 10.1093/ajcn/83.6.1331
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 270–276
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human indicator amino-acid oxidation/balance feeding study without dietary tyrosine. · source_derived_draft · unverified_draft
## l-phenylalanine-no-tyrosine-requirement When tyrosine is absent, phenylalanine must cover an additional metabolic demand. A tracer study in healthy Indian adults consuming no tyrosine estimated mean phenylalanine requirement at about 38 mg/kg/day. Model: Human indicator amino-acid oxidation/balance feeding study without dietary tyrosine. Limitations: Population and protocol differ from the older-adult excess-tyrosine study; different estimates are not treated as a scientific contradiction. Evidence access: Primary abstract The daily phenylalanine requirement of healthy Indian adults. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16762944/ · DOI 10.1093/ajcn/83.6.1331
Complete structured claim and evidence
L-phenylalanine stimulated CaSR-dependent calcium signaling and CCK release in primary mouse duodenal I cells; CCK responses were greater at 2.5 than at 1.26 mM extracellular calcium.
L-Phenylalanine → Mouse primary intestinal I-cell CCK secretion source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Primary mouse I cells; stereoselective L- versus D-phenylalanine responses.
limitations
Cell assay responses do not establish that calcium supplements enhance satiety in humans.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Gut amino-acid sensing can depend on both the amino acid and calcium.
primary_references
The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 278–284
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary mouse I cells; stereoselective L- versus D-phenylalanine responses. · source_derived_draft · unverified_draft
## l-phenylalanine-casr-cck Gut amino-acid sensing can depend on both the amino acid and calcium. L-phenylalanine stimulated CaSR-dependent calcium signaling and CCK release in primary mouse duodenal I cells; CCK responses were greater at 2.5 than at 1.26 mM extracellular calcium. Model: Primary mouse I cells; stereoselective L- versus D-phenylalanine responses. Limitations: Cell assay responses do not establish that calcium supplements enhance satiety in humans. Evidence access: Primary abstract The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010
Complete structured claim and evidence
CaSR knockout abolished the phenylalanine-evoked calcium response in primary mouse I cells and prevented the normal stimulatory CCK response; responses to KCl and tryptone were preserved.
Mouse calcium-sensing receptor / Casr → Mouse primary intestinal I-cell CCK secretion source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
CaSR-null compared with wild-type primary mouse intestinal I cells.
limitations
This is receptor failure, not phenylalanine or calcium dietary deficiency.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Removing one sensor disables that route without disabling every secretion trigger.
primary_references
The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 286–292
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · CaSR-null compared with wild-type primary mouse intestinal I cells. · source_derived_draft · unverified_draft
## l-phenylalanine-casr-loss Removing one sensor disables that route without disabling every secretion trigger. CaSR knockout abolished the phenylalanine-evoked calcium response in primary mouse I cells and prevented the normal stimulatory CCK response; responses to KCl and tryptone were preserved. Model: CaSR-null compared with wild-type primary mouse intestinal I cells. Limitations: This is receptor failure, not phenylalanine or calcium dietary deficiency. Evidence access: Primary abstract The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010
Complete structured claim and evidence
Phenylalanine activated transfected human and mouse GPR142 IP1 signaling with EC50 values around 3.5 and 2.8 mM, respectively.
L-Phenylalanine → Human GPR142 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human or mouse receptor expressed in HEK293 cells.
limitations
Millimolar cell-assay potency does not prove that GPR142 mediates every whole-animal phenylalanine response.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A second amino-acid receptor can respond to phenylalanine.
primary_references
GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27322810/ · DOI 10.1371/journal.pone.0157298
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 294–300
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human or mouse receptor expressed in HEK293 cells. · source_derived_draft · unverified_draft
## l-phenylalanine-gpr142-sensing A second amino-acid receptor can respond to phenylalanine. Phenylalanine activated transfected human and mouse GPR142 IP1 signaling with EC50 values around 3.5 and 2.8 mM, respectively. Model: Human or mouse receptor expressed in HEK293 cells. Limitations: Millimolar cell-assay potency does not prove that GPR142 mediates every whole-animal phenylalanine response. Evidence access: Primary full text GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27322810/ · DOI 10.1371/journal.pone.0157298
Complete structured claim and evidence
Phenylalanine-associated glucose-tolerance improvement persisted in Gpr142-knockout mice, and its modest islet insulin response was not significantly different between knockout and wild-type mice.
Mouse Gpr142 → Mouse glucose-tolerance response to phenylalanine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse receptor-knockout whole-animal and islet experiments.
limitations
This differs from the study tryptophan result; it does not negate GPR142 signaling in a different cell model.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A receptor that responds in a dish may not be essential for the overall response.
primary_references
GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27322810/ · DOI 10.1371/journal.pone.0157298
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 302–308
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse receptor-knockout whole-animal and islet experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-gpr142-dispensability A receptor that responds in a dish may not be essential for the overall response. Phenylalanine-associated glucose-tolerance improvement persisted in Gpr142-knockout mice, and its modest islet insulin response was not significantly different between knockout and wild-type mice. Model: Mouse receptor-knockout whole-animal and islet experiments. Limitations: This differs from the study tryptophan result; it does not negate GPR142 signaling in a different cell model. Evidence access: Primary full text GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27322810/ · DOI 10.1371/journal.pone.0157298
Complete structured claim and evidence
In STC-1 enteroendocrine cells, phenylalanine stimulated a GPR142/Gq-linked calcium response contributing to GLP-1 release.
L-Phenylalanine → Mouse Gpr142 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse STC-1 cells, live-cell signaling and pharmacologic experiments.
limitations
Exposure details beyond the accessed abstract are unresolved; this is not direct human gut evidence.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A gut-cell model used a receptor-to-calcium pathway to release a hormone.
primary_references
Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 310–316
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse STC-1 cells, live-cell signaling and pharmacologic experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-stc-gpr142 A gut-cell model used a receptor-to-calcium pathway to release a hormone. In STC-1 enteroendocrine cells, phenylalanine stimulated a GPR142/Gq-linked calcium response contributing to GLP-1 release. Model: Mouse STC-1 cells, live-cell signaling and pharmacologic experiments. Limitations: Exposure details beyond the accessed abstract are unresolved; this is not direct human gut evidence. Evidence access: Primary abstract Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043
Complete structured claim and evidence
Sodium-dependent phenylalanine uptake contributed to depolarization and GLP-1 secretion in STC-1 cells.
L-Phenylalanine → STC-1 phenylalanine-evoked membrane depolarization source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse STC-1 cell transport, membrane-potential and secretion assays.
limitations
The accessed abstract does not identify a specific transporter isoform; B0AT1 is not assigned by inference.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Amino-acid transport can supply an electrical signal as well as a nutrient.
primary_references
Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 318–324
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse STC-1 cell transport, membrane-potential and secretion assays. · source_derived_draft · unverified_draft
## l-phenylalanine-stc-sodium Amino-acid transport can supply an electrical signal as well as a nutrient. Sodium-dependent phenylalanine uptake contributed to depolarization and GLP-1 secretion in STC-1 cells. Model: Mouse STC-1 cell transport, membrane-potential and secretion assays. Limitations: The accessed abstract does not identify a specific transporter isoform; B0AT1 is not assigned by inference. Evidence access: Primary abstract Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043
Complete structured claim and evidence
In ten healthy men, intraduodenal phenylalanine at 0.15 or 0.45 kcal/min for 90 minutes increased plasma CCK.
L-Phenylalanine → Human plasma cholecystokinin response source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Randomized crossover intraduodenal infusion study.
limitations
This route and exposure differ from eating mixed protein; measured hormones do not identify the responsible receptor.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Directly delivering phenylalanine to the small intestine changed a human gut-hormone signal.
primary_references
Effects of Intraduodenal Infusions of L-phenylalanine and L-glutamine on Antropyloroduodenal Motility and Plasma Cholecystokinin in Healthy Men. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26130636/ · DOI 10.5056/jnm14143
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 326–332
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized crossover intraduodenal infusion study. · source_derived_draft · unverified_draft
## l-phenylalanine-human-gut-hormone Directly delivering phenylalanine to the small intestine changed a human gut-hormone signal. In ten healthy men, intraduodenal phenylalanine at 0.15 or 0.45 kcal/min for 90 minutes increased plasma CCK. Model: Randomized crossover intraduodenal infusion study. Limitations: This route and exposure differ from eating mixed protein; measured hormones do not identify the responsible receptor. Evidence access: Primary full text Effects of Intraduodenal Infusions of L-phenylalanine and L-glutamine on Antropyloroduodenal Motility and Plasma Cholecystokinin in Healthy Men. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26130636/ · DOI 10.5056/jnm14143
Complete structured claim and evidence
The higher intraduodenal phenylalanine load suppressed antral and increased phasic pyloric pressures; duodenal pressures and tonic pyloric pressure were not significantly changed.
L-Phenylalanine → Human antropyloric motility during phenylalanine infusion source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Ten healthy men; 0.45 kcal/min intraduodenal infusion for 90 minutes.
limitations
Gastric emptying was inferred from motor effects rather than directly measured in this experiment.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The stomach-outlet motor response was selective, not a shutdown of all gut movement.
primary_references
Effects of Intraduodenal Infusions of L-phenylalanine and L-glutamine on Antropyloroduodenal Motility and Plasma Cholecystokinin in Healthy Men. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26130636/ · DOI 10.5056/jnm14143
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 334–340
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ten healthy men; 0.45 kcal/min intraduodenal infusion for 90 minutes. · source_derived_draft · unverified_draft
## l-phenylalanine-human-gut-motor The stomach-outlet motor response was selective, not a shutdown of all gut movement. The higher intraduodenal phenylalanine load suppressed antral and increased phasic pyloric pressures; duodenal pressures and tonic pyloric pressure were not significantly changed. Model: Ten healthy men; 0.45 kcal/min intraduodenal infusion for 90 minutes. Limitations: Gastric emptying was inferred from motor effects rather than directly measured in this experiment. Evidence access: Primary full text Effects of Intraduodenal Infusions of L-phenylalanine and L-glutamine on Antropyloroduodenal Motility and Plasma Cholecystokinin in Healthy Men. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26130636/ · DOI 10.5056/jnm14143
Complete structured claim and evidence
Clostridium sporogenes porA disruption reduced the oxidative conversion of phenylalanine-derived carbon to phenylacetate; labeled phenylalanine tracing supported the pathway through phenylpyruvate.
Clostridium sporogenes PorA → Phenylacetic acid / phenylacetate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Defined bacterial cultures and stable-isotope experiments; 100 micromolar labeled phenylalanine over 24 hours.
limitations
Bacterial flux is strain- and environment-dependent; no human dietary conversion fraction is established.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Some gut bacteria send phenylalanine into a different metabolic route.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 342–348
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Defined bacterial cultures and stable-isotope experiments; 100 micromolar labeled phenylalanine over 24 hours. · source_derived_draft · unverified_draft
## l-phenylalanine-microbial-oxidation Some gut bacteria send phenylalanine into a different metabolic route. Clostridium sporogenes porA disruption reduced the oxidative conversion of phenylalanine-derived carbon to phenylacetate; labeled phenylalanine tracing supported the pathway through phenylpyruvate. Model: Defined bacterial cultures and stable-isotope experiments; 100 micromolar labeled phenylalanine over 24 hours. Limitations: Bacterial flux is strain- and environment-dependent; no human dietary conversion fraction is established. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
The C. sporogenes FldH-dependent reductive aromatic-amino-acid branch competed with the PorA-associated oxidative branch; gene perturbations changed phenylacetate versus phenylpropionate output.
Clostridium sporogenes FldH → 3-Phenylpropionic acid / phenylpropionate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
C. sporogenes mutant culture and metabolite measurements.
limitations
A branch in one organism is not a fixed whole-microbiome fate map.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Which microbial enzymes are present can change which metabolite is produced.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 350–356
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · C. sporogenes mutant culture and metabolite measurements. · source_derived_draft · unverified_draft
## l-phenylalanine-microbial-branch Which microbial enzymes are present can change which metabolite is produced. The C. sporogenes FldH-dependent reductive aromatic-amino-acid branch competed with the PorA-associated oxidative branch; gene perturbations changed phenylacetate versus phenylpropionate output. Model: C. sporogenes mutant culture and metabolite measurements. Limitations: A branch in one organism is not a fixed whole-microbiome fate map. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
Host conjugation of microbially derived phenylacetate with glutamine produces PAGln, the predominant human conjugate in the study; glycine conjugation produces PAGly, predominant in mice.
Phenylacetic acid / phenylacetate → Phenylacetylglutamine / PAGln source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human/mouse metabolomics study; established conjugation route described in primary full text.
limitations
This is not a purified conjugating-enzyme kinetic experiment and does not show clinically meaningful glutamine or glycine depletion.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Host amino acids help turn a bacterial product into circulating metabolites.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human/mouse metabolomics study; established conjugation route described in primary full text. · source_derived_draft · unverified_draft
## l-phenylalanine-host-conjugation Host amino acids help turn a bacterial product into circulating metabolites. Host conjugation of microbially derived phenylacetate with glutamine produces PAGln, the predominant human conjugate in the study; glycine conjugation produces PAGly, predominant in mice. Model: Human/mouse metabolomics study; established conjugation route described in primary full text. Limitations: This is not a purified conjugating-enzyme kinetic experiment and does not show clinically meaningful glutamine or glycine depletion. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
Seven days of broad-spectrum antibiotics in fifteen subjects markedly reduced circulating PAGln, with recovery after microbial repopulation.
Phenylacetylglutamine / PAGln → Human PAGln response to microbiota suppression source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human antibiotic suppression and post-antibiotic recovery sampling at least three weeks later.
limitations
Antibiotics affect many microbes and metabolites; this does not isolate one bacterial enzyme or recommend antimicrobial use.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The human circulating metabolite depends in part on gut microbial activity.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 366–372
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human antibiotic suppression and post-antibiotic recovery sampling at least three weeks later. · source_derived_draft · unverified_draft
## l-phenylalanine-microbial-human-dependence The human circulating metabolite depends in part on gut microbial activity. Seven days of broad-spectrum antibiotics in fifteen subjects markedly reduced circulating PAGln, with recovery after microbial repopulation. Model: Human antibiotic suppression and post-antibiotic recovery sampling at least three weeks later. Limitations: Antibiotics affect many microbes and metabolites; this does not isolate one bacterial enzyme or recommend antimicrobial use. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
PAGln at 100 micromolar for 30 minutes enhanced agonist-induced human platelet responses, including calcium signaling.
Phenylacetylglutamine / PAGln → Human platelet agonist responsiveness during PAGln exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Isolated human platelets; agonist-challenge experiments.
limitations
Metabolite exposure is not phenylalanine exposure; this does not establish that dietary phenylalanine causes thrombosis.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A downstream microbial-host metabolite can alter platelet responsiveness in an assay.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 374–380
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human platelets; agonist-challenge experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-pagln-platelets A downstream microbial-host metabolite can alter platelet responsiveness in an assay. PAGln at 100 micromolar for 30 minutes enhanced agonist-induced human platelet responses, including calcium signaling. Model: Isolated human platelets; agonist-challenge experiments. Limitations: Metabolite exposure is not phenylalanine exposure; this does not establish that dietary phenylalanine causes thrombosis. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
Knockdown and overexpression experiments implicated ADRA2A, ADRA2B and ADRB2 in PAGln-associated signaling, supporting an adrenergic-receptor-dependent route.
Phenylacetylglutamine / PAGln → PAGln adrenergic-receptor-associated signaling source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human MEG-01 receptor knockdown and HEK293 receptor-expression experiments, with pharmacologic comparisons.
limitations
Functional dependence is not proof of a single orthosteric binding mode or a clinical drug interaction.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The platelet-related signal connects to receptors used by other physiological pathways.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 382–388
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human MEG-01 receptor knockdown and HEK293 receptor-expression experiments, with pharmacologic comparisons. · source_derived_draft · unverified_draft
## l-phenylalanine-pagln-adrenergic The platelet-related signal connects to receptors used by other physiological pathways. Knockdown and overexpression experiments implicated ADRA2A, ADRA2B and ADRB2 in PAGln-associated signaling, supporting an adrenergic-receptor-dependent route. Model: Human MEG-01 receptor knockdown and HEK293 receptor-expression experiments, with pharmacologic comparisons. Limitations: Functional dependence is not proof of a single orthosteric binding mode or a clinical drug interaction. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
Circulating PAGln was associated with cardiovascular disease and subsequent major adverse cardiovascular events in discovery and validation cohorts of 1162 and 4000 subjects.
Phenylacetylglutamine / PAGln → Cardiovascular events associated with circulating PAGln source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human clinical cohorts; three-year event follow-up.
limitations
Residual confounding and renal clearance matter; no randomized dietary phenylalanine intervention establishes causation.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A blood association identifies a research signal, not the cause by itself.
primary_references
A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 390–396
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human clinical cohorts; three-year event follow-up. · source_derived_draft · unverified_draft
## l-phenylalanine-pagln-outcomes A blood association identifies a research signal, not the cause by itself. Circulating PAGln was associated with cardiovascular disease and subsequent major adverse cardiovascular events in discovery and validation cohorts of 1162 and 4000 subjects. Model: Human clinical cohorts; three-year event follow-up. Limitations: Residual confounding and renal clearance matter; no randomized dietary phenylalanine intervention establishes causation. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016
Complete structured claim and evidence
Lac-Phe rose after exercise in human cohorts of 36 and 8 participants; in the modality comparison, changes tracked lactate and were greatest after sprint exercise.
N-Lactoyl-phenylalanine / Lac-Phe → Human exercise-associated circulating Lac-Phe source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human metabolomics and endurance/sprint/resistance comparisons.
limitations
A biomarker rise is not evidence that taking phenylalanine reproduces exercise benefits.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Phenylalanine can join lactate in a metabolite that rises after exercise.
primary_references
An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 398–404
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human metabolomics and endurance/sprint/resistance comparisons. · source_derived_draft · unverified_draft
## l-phenylalanine-lacphe-exercise Phenylalanine can join lactate in a metabolite that rises after exercise. Lac-Phe rose after exercise in human cohorts of 36 and 8 participants; in the modality comparison, changes tracked lactate and were greatest after sprint exercise. Model: Human metabolomics and endurance/sprint/resistance comparisons. Limitations: A biomarker rise is not evidence that taking phenylalanine reproduces exercise benefits. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
Complete structured claim and evidence
Injected Lac-Phe at 50 mg/kg reduced food intake in diet-induced obese mice; daily injection for ten days reduced intake, adiposity and weight.
N-Lactoyl-phenylalanine / Lac-Phe → Mouse food intake during Lac-Phe administration source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Intraperitoneal pharmacological dosing in diet-induced obese mice.
limitations
Oral dosing did not reproduce the effect; lean mice did not respond even up to 150 mg/kg. Lactate and phenylalanine separately did not reproduce it.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The combined metabolite changed feeding in a specific mouse model.
primary_references
An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 406–412
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Intraperitoneal pharmacological dosing in diet-induced obese mice. · source_derived_draft · unverified_draft
## l-phenylalanine-lacphe-obese-mice The combined metabolite changed feeding in a specific mouse model. Injected Lac-Phe at 50 mg/kg reduced food intake in diet-induced obese mice; daily injection for ten days reduced intake, adiposity and weight. Model: Intraperitoneal pharmacological dosing in diet-induced obese mice. Limitations: Oral dosing did not reproduce the effect; lean mice did not respond even up to 150 mg/kg. Lactate and phenylalanine separately did not reproduce it. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
Complete structured claim and evidence
Global Cndp2 knockout markedly reduced circulating Lac-Phe and attenuated the food-intake and weight response to chronic exercise on a high-fat diet.
Mouse cytosolic nonspecific dipeptidase / Cndp2 → Mouse exercise-associated Lac-Phe and feeding regulation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding.
limitations
Cndp2 has other substrates; the phenotype was conditional on exercise and diet and did not establish a human deficiency syndrome.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Removing a production enzyme weakened one part of the exercise response.
primary_references
An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 414–420
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding. · source_derived_draft · unverified_draft
## l-phenylalanine-lacphe-genetic Removing a production enzyme weakened one part of the exercise response. Global Cndp2 knockout markedly reduced circulating Lac-Phe and attenuated the food-intake and weight response to chronic exercise on a high-fat diet. Model: Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding. Limitations: Cndp2 has other substrates; the phenotype was conditional on exercise and diet and did not establish a human deficiency syndrome. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
Complete structured claim and evidence
Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium.
Human TAT1 / SLC16A10 → L-Tryptophan source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cloned transporter; expression strongest in kidney and intestine.
limitations
The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Tryptophan also has an aromatic-amino-acid transport route.
primary_references
The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
transport_effect
raises An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
transport_pool
the expressing cell An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 50–56
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cloned transporter; expression strongest in kidney and intestine. · source_derived_draft · unverified_draft
## tryptophan-tat1-transport Tryptophan also has an aromatic-amino-acid transport route. Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium. Model: Human cloned transporter; expression strongest in kidney and intestine. Limitations: The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome. Evidence access: Primary abstract The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
Complete structured claim and evidence
Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient.
Human L-type amino acid transporter 2 / LAT2 / SLC7A8 → L-Methionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human transporter in Xenopus oocytes; tracer influx and efflux.
limitations
Does not show that ordinary mixed meals deplete methionine.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Transport depends on substrates on both sides of the membrane.
primary_references
Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 28–34
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter in Xenopus oocytes; tracer influx and efflux. · source_derived_draft · unverified_draft
## methionine-lat2-exchange Transport depends on substrates on both sides of the membrane. Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient. Model: Human transporter in Xenopus oocytes; tracer influx and efflux. Limitations: Does not show that ordinary mixed meals deplete methionine. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
Complete structured claim and evidence
In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone.
L-Leucine → Rat brain tryptophan content source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Overnight-fasted rats receiving defined meals with different amino-acid mixtures.
limitations
Not a validated universal human threshold or proof that protein-rich meals worsen mood.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
A higher blood level need not mean more tryptophan reaches the brain.
primary_references
Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 58–64
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Overnight-fasted rats receiving defined meals with different amino-acid mixtures. · source_derived_draft · unverified_draft
## tryptophan-brain-competition A higher blood level need not mean more tryptophan reaches the brain. In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone. Model: Overnight-fasted rats receiving defined meals with different amino-acid mixtures. Limitations: Not a validated universal human threshold or proof that protein-rich meals worsen mood. Evidence access: Primary abstract Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759
Complete structured claim and evidence
Under IFN-gamma/IDO1-associated tryptophan shortage, human cancer cells continued translation with WARS1-associated phenylalanine incorporation at tryptophan positions.
Human cytosolic tryptophanyl-tRNA synthetase / WARS1 → Human cancer-cell tryptophan-to-phenylalanine translational substitution source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract; primary correction full text reviewed
experimental_model
Human cancer-cell depletion, molecular assays and tumor proteomics.
limitations
Not a DNA mutation or a universal consequence of a low-tryptophan meal. Tumor proteomic filtering was clarified in a correction. Correction record: The 2022 author correction adds omitted funding acknowledgements and clarifies that the maximum-sample peptide filter was used in the intra-tumour analysis (Fig. 3f) but not for W>F substitutants in the tumour-specific analysis (Fig. 3a). Authors report similar biological conclusions with both strategies. This is a publication correction, not an opposing mechanism claim. https://www.nature.com/articles/s41586-022-05097-y
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Severe local shortage can change what a cancer cell puts into a protein.
primary_references
Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35264796/ · DOI 10.1038/s41586-022-04499-2
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 122–128
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell depletion, molecular assays and tumor proteomics. · source_derived_draft · unverified_draft
## tryptophan-w-to-f-shortage Severe local shortage can change what a cancer cell puts into a protein. Under IFN-gamma/IDO1-associated tryptophan shortage, human cancer cells continued translation with WARS1-associated phenylalanine incorporation at tryptophan positions. Model: Human cancer-cell depletion, molecular assays and tumor proteomics. Limitations: Not a DNA mutation or a universal consequence of a low-tryptophan meal. Tumor proteomic filtering was clarified in a correction. Correction record: The 2022 author correction adds omitted funding acknowledgements and clarifies that the maximum-sample peptide filter was used in the intra-tumour analysis (Fig. 3f) but not for W>F substitutants in the tumour-specific analysis (Fig. 3a). Authors report similar biological conclusions with both strategies. This is a publication correction, not an opposing mechanism claim. https://www.nature.com/articles/s41586-022-05097-y Evidence access: Primary abstract; primary correction full text reviewed Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35264796/ · DOI 10.1038/s41586-022-04499-2
Complete structured claim and evidence
Deleting CNDP2 in human RT4 bladder epithelial cells reduced Lac-Phe production; extracellular lactate stimulated production in the control cells.
Human cytosolic nonspecific dipeptidase / CNDP2 → N-Lactoyl-phenylalanine / Lac-Phe source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text Figure 2 and CRISPR methods
experimental_model
Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2.
limitations
This is a shared-enzyme connection, not proof that carnosine changes appetite.
nutrient_topic
Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine
plain_language
The peptide-processing enzyme also participates in another metabolic pathway.
primary_references
An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 172–178
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2. · source_derived_draft · unverified_draft
## carnosine-cndp2-lacphe The peptide-processing enzyme also participates in another metabolic pathway. Deleting CNDP2 in human RT4 bladder epithelial cells reduced Lac-Phe production; extracellular lactate stimulated production in the control cells. Model: Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2. Limitations: This is a shared-enzyme connection, not proof that carnosine changes appetite. Evidence access: Primary abstract and PMC full-text Figure 2 and CRISPR methods An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5
Complete structured claim and evidence
Expressed human DDC decarboxylated L-DOPA; added PLP enhanced the measured activity.
Human aromatic L-amino acid decarboxylase / DDC → Dopamine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human DDC expressed in monkey COS cells; enzyme assays
exposure
PLP addition to transfected COS-cell enzyme incubations.
limitations
An expression-system response is not proof that supplements increase brain monoamines.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Human DDC expressed in monkey COS cells
plain_language
B6 cofactor supports this monoamine-producing step.
primary_references
[sumi-1990-ddc] Characterization of recombinant human aromatic L-amino acid decarboxylase expressed in COS cells (1990). https://doi.org/10.1111/j.1471-4159.1990.tb04601.x DOI: 10.1111/j.1471-4159.1990.tb04601.x
tissue_or_cell_type
COS-cell expression system
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 999–1009
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DDC expressed in monkey COS cells; enzyme assays · source_derived_draft · unverified_draft
### b6-neuro-ddc-dopamine Expressed human DDC decarboxylated L-DOPA; added PLP enhanced the measured activity. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6 cofactor supports this monoamine-producing step. organism: Human DDC expressed in monkey COS cells tissue_or_cell_type: COS-cell expression system experimental_model: Human DDC expressed in monkey COS cells; enzyme assays limitations: An expression-system response is not proof that supplements increase brain monoamines. exposure: PLP addition to transfected COS-cell enzyme incubations. [sumi-1990-ddc] Characterization of recombinant human aromatic L-amino acid decarboxylase expressed in COS cells (1990). https://doi.org/10.1111/j.1471-4159.1990.tb04601.x DOI: 10.1111/j.1471-4159.1990.tb04601.x
Complete structured claim and evidence
Human DBH is the copper-enzyme step converting dopamine to norepinephrine; the study resolved its catalytic-core architecture.
Human dopamine beta-hydroxylase / DBH → Norepinephrine source_derived_draftungraded
Experimental context and source evidence
evidence_span
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experimental_model
Human DBH X-ray crystallography
exposure
Crystal structure at 2.9 angstrom resolution
limitations
Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake.
nutrient_topic
Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper
organism
Human protein
plain_language
Copper is part of the enzyme that converts one neurotransmitter into another.
primary_references
[copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980
tissue_or_cell_type
Purified dimeric enzyme
Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1079–1090
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DBH X-ray crystallography · source_derived_draft · unverified_draft
### copper-dbh-neurotransmitter-step Human DBH is the copper-enzyme step converting dopamine to norepinephrine; the study resolved its catalytic-core architecture. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Copper is part of the enzyme that converts one neurotransmitter into another. organism: Human protein tissue_or_cell_type: Purified dimeric enzyme experimental_model: Human DBH X-ray crystallography limitations: Open and closed conformations were observed; the proposed catalytic alternation and fully occupied binuclear states require further evidence. Do not equate a structural model with proof of psychiatric effects from copper intake. exposure: Crystal structure at 2.9 angstrom resolution evidence_span: {"source_cache": "artifacts/copper-research/27152332.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09", "start_char": 0, "end_char": 1325, "text_sha256": "984a9036d5157e29cdef55d42201887d3ff43cf533185148ba4e3f5c143ced09"} [copper-p27152332] The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. (2016). https://pubmed.ncbi.nlm.nih.gov/27152332/ DOI: 10.1126/sciadv.1500980
Complete structured claim and evidence
Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy.
L-Ascorbate → Ascorbate-reduced bovine dopamine beta-hydroxylase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS
exposure
Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH.
limitations
Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme.
primary_references
[scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
tissue_or_cell_type
Adrenal-medullary enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 793–805
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS · source_derived_draft · unverified_draft
### vc-enzyme-dbh-copper-reduction Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme. organism: Bos taurus tissue_or_cell_type: Adrenal-medullary enzyme preparation experimental_model: Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS limitations: Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH. [scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
Complete structured claim and evidence
Biochemical experiments identified QDPR activity that repairs oxidatively damaged tetrahydrofolate.
Human quinoid dihydropteridine reductase / QDPR → Oxidative degradation of reduced folates source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Shared QDPR machinery connects biopterin and folate redox maintenance.
experimental_model
Biochemical enzyme experiments
exposure
Assay conditions described in the linked primary study.
limitations
Repair capacity is finite; no human dietary requirement was determined.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
An enzyme also used in biopterin metabolism helps preserve reduced folate.
primary_references
[zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041
tissue_or_cell_type
Cell-free and cancer-cell experiments
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1230–1241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical enzyme experiments · source_derived_draft · unverified_draft
### qdpr-folate-repair Biochemical experiments identified QDPR activity that repairs oxidatively damaged tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme also used in biopterin metabolism helps preserve reduced folate. organism: Homo sapiens tissue_or_cell_type: Cell-free and cancer-cell experiments experimental_model: Biochemical enzyme experiments limitations: Repair capacity is finite; no human dietary requirement was determined. exposure: Assay conditions described in the linked primary study. cross_nutrient: Shared QDPR machinery connects biopterin and folate redox maintenance. [zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041
Complete structured claim and evidence
Purified human eNOS showed an absolute BH4 requirement for the measured catalytic reaction.
Tetrahydrobiopterin / BH4 → Human eNOS catalytic activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"}
experimental_model
Purified recombinant enzyme activity and cofactor analysis
exposure
Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements
limitations
Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people.
nutrient_topic
Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline
organism
Human NOS3 expressed in yeast
plain_language
Supplying substrate does not replace the required pterin cofactor.
primary_references
[citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658
tissue_or_cell_type
Endothelial NOS enzyme preparation
Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 515–526
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme activity and cofactor analysis · source_derived_draft · unverified_draft
### citrulline-nos-bh4 Purified human eNOS showed an absolute BH4 requirement for the measured catalytic reaction. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying substrate does not replace the required pterin cofactor. organism: Human NOS3 expressed in yeast tissue_or_cell_type: Endothelial NOS enzyme preparation experimental_model: Purified recombinant enzyme activity and cofactor analysis limitations: Biochemical cofactor findings do not show that extra dietary cofactors increase NO in healthy people. exposure: Arginine substrate; BH4, FAD, FMN, heme, iron and zinc measurements evidence_span: {"source_cache": "artifacts/citrulline-research/10608822.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd", "start_char": 0, "end_char": 2100, "text_sha256": "1600b193cc63f30b204285729710bb81f34bc2918a8ca7f97aa97bc4acd998fd"} [citrulline-p10608822] Characterization of recombinant human endothelial nitric-oxide synthase purified from the yeast Pichia pastoris. (1999). https://pubmed.ncbi.nlm.nih.gov/10608822/ DOI: 10.1074/jbc.274.53.37658
Complete structured claim and evidence
Human pineal TPH activity was measured with BH4, and a transient 4alpha-hydroxytetrahydrobiopterin intermediate was detected.
Tetrahydrobiopterin / BH4 → Human tryptophan hydroxylase 1 / TPH1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/melatonin-research/10525150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f", "start_char": 0, "end_char": 1489, "text_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f"}
experimental_model
Recombinant enzyme purification and catalysis
exposure
L-tryptophan with tetrahydrobiopterin; purified tetrameric enzyme
limitations
TPH1 and neuronal TPH2 are distinct. A cofactor-dependent reaction does not prove supplemental cofactor increases melatonin in a replete person.
nutrient_topic
Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin
organism
Human pineal TPH1 expressed in E. coli
plain_language
The pterin cofactor participates chemically; it is not interchangeable with folate.
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 149–160
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-bh4 Human pineal TPH activity was measured with BH4, and a transient 4alpha-hydroxytetrahydrobiopterin intermediate was detected. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The pterin cofactor participates chemically; it is not interchangeable with folate. organism: Human pineal TPH1 expressed in E. coli tissue_or_cell_type: Tryptophan hydroxylation experimental_model: Recombinant enzyme purification and catalysis limitations: TPH1 and neuronal TPH2 are distinct. A cofactor-dependent reaction does not prove supplemental cofactor increases melatonin in a replete person. exposure: L-tryptophan with tetrahydrobiopterin; purified tetrameric enzyme evidence_span: {"source_cache": "artifacts/melatonin-research/10525150.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f", "start_char": 0, "end_char": 1489, "text_sha256": "032acfb7b1818f5282f5457e093a7e371895bbdc95f058c8958766fc57f9118f"} [melatonin-p10525150] Cloning and expression of recombinant human pineal tryptophan hydroxylase in Escherichia coli: purification and characterization of the cloned enzyme. (1999). https://pubmed.ncbi.nlm.nih.gov/10525150/ DOI: 10.1016/s0167-4838(99)00184-3
Complete structured claim and evidence

Availability and dependencies

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

A substrate-sensing switch can fail

Condition: machinery_impairment · PAH E76A regulatory-domain variant.