Component

Human phenylalanine hydroxylase / PAH

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

10 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. 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

  2. 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

  3. Stable-isotope studies in 12 healthy adults demonstrated renal phenylalanine-to-tyrosine conversion and net renal tyrosine release.

    Human phenylalanine hydroxylase / PAH → Human renal phenylalanine-to-tyrosine conversion source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary abstract
    experimental_model
    Arterial/renal-vein tracer sampling; comparison with a separate 12-person splanchnic study.
    limitations
    The organ flux measurement is direct; the assignment to PAH is the established reaction, not selective PAH perturbation in this study.
    nutrient_topic
    L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine
    plain_language
    The kidney contributes to precursor production as well as filtration.
    primary_references
    The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10655515/ · DOI 10.1073/pnas.97.3.1242

    L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 20–26

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Arterial/renal-vein tracer sampling; comparison with a separate 12-person splanchnic study. · source_derived_draft · unverified_draft

    ## l-tyrosine-renal-production The kidney contributes to precursor production as well as filtration. Stable-isotope studies in 12 healthy adults demonstrated renal phenylalanine-to-tyrosine conversion and net renal tyrosine release. Model: Arterial/renal-vein tracer sampling; comparison with a separate 12-person splanchnic study. Limitations: The organ flux measurement is direct; the assignment to PAH is the established reaction, not selective PAH perturbation in this study. Evidence access: Primary abstract The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10655515/ · DOI 10.1073/pnas.97.3.1242
    Complete structured claim and evidence

What acts on it

  1. 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

  2. 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

  3. 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

Where it participates (unsigned role)

  1. 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

  2. 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

  3. 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

  4. After 34 mg/kg, twelve female PKU heterozygotes had higher peak phenylalanine than ten noncarrier females, 15.1 versus 8.95 micromol/dL.

    Aspartame → Human plasma phenylalanine concentration source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_access
    Primary abstract
    experimental_model
    Human carrier comparison, also including twelve noncarrier men.
    limitations
    Heterozygotes do not represent patients with biallelic PAH deficiency; the damaged male-baseline sentence in indexed abstract is not reconstructed.
    nutrient_topic
    Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
    plain_language
    Reduced metabolic reserve can change the response to a precursor source.
    primary_references
    Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7268794/ · DOI 10.1016/0300-483x(81)90108-6
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 146–152

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human carrier comparison, also including twelve noncarrier men. · source_derived_draft · unverified_draft

    ## aspartame-pku-carrier-kinetics Reduced metabolic reserve can change the response to a precursor source. After 34 mg/kg, twelve female PKU heterozygotes had higher peak phenylalanine than ten noncarrier females, 15.1 versus 8.95 micromol/dL. Model: Human carrier comparison, also including twelve noncarrier men. Limitations: Heterozygotes do not represent patients with biallelic PAH deficiency; the damaged male-baseline sentence in indexed abstract is not reconstructed. Evidence access: Primary abstract Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7268794/ · DOI 10.1016/0300-483x(81)90108-6
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

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