Skip to content

pah.md

Latest commit

 

History

History
81 lines (64 loc) · 3.7 KB

pah.md

File metadata and controls

81 lines (64 loc) · 3.7 KB
Raw

Atlas — PAH (Phenylalanine hydroxylase)

UniProt: P00439 Gene symbol: PAH Protein: Phenylalanine-4-hydroxylase Organism: Homo sapiens (taxonomy ID 9606) Disease (MONDO): MONDO:0009861 — phenylketonuria; see also MONDO:0017739 (mild hyperphenylalaninemia). OMIM: 612349 (PAH gene), 261600 (PKU), 261630 (HPABH4A). Disease class: rare-disease metabolic enzyme deficiency; aromatic-amino-acid hydroxylase family.

Question this atlas entry answers

A metabolic-disease genetics team interprets a PAH variant in a newborn-screening positive. They need: which structural domain is affected (regulatory N-term, catalytic, tetramerisation), co-factor / metal-binding sites (BH4, iron), and whether the variant is responsive to BH4 supplementation (sapropterin / Kuvan).

Tool sequence

# Tool Question
1 uniprot_get_entry("P00439") Function (Phe → Tyr hydroxylation), 452 aa, three domains.
2 uniprot_features_at_position("P00439", <pos>) Which domain houses the variant?
3 uniprot_get_active_sites("P00439") Iron-binding residues (His-285, His-290, Glu-330) + BH4-binding region.
4 uniprot_get_alphafold_confidence("P00439") High pLDDT across the catalytic domain.
5 uniprot_resolve_pdb("P00439") Many PDB structures; tetrameric and monomeric forms.
6 uniprot_resolve_clinvar("P00439", size=10) Variants by clinical significance.
7 uniprot_get_disease_associations("P00439") PKU, HPA, HPABH4A.

Expected response shape

  • Step 3: at least three Metal-binding annotations for iron (the active-site iron is co-ordinated by two histidines and a glutamate); BH4 binding site annotations.
  • Step 5: structures include the catalytic domain alone, tetrameric assembly, and the regulatory ACT-domain in complex with phenylalanine.
  • Step 7: at least PKU (MIM:261600) and one HPA-related entry.

Therapeutic axis (interpretation)

  • Diet: phenylalanine-restricted diet (cornerstone since 1950s).
  • BH4 supplementation: sapropterin (Kuvan) for BH4-responsive variants — typically those that destabilise the dimer/tetramer but retain catalytic activity. Predicting BH4-responsiveness from a variant requires structural reasoning, which the position-aware feature tool supports.
  • Enzyme replacement: pegvaliase (Palynziq) — pegylated phenylalanine ammonia lyase from Anabaena, an alternative Phe-degrading enzyme. Not a PAH-targeted therapy.
  • Gene therapy: in clinical trial.
  • ChEMBL bridge: sapropterin (BH4 cofactor analogue).

Provenance fields

Standard envelope on every response.

Cross-references in scope

Resource Returned via
PDB Many structures; tetramer, monomer, ACT-domain–Phe complex.
AlphaFold DB AF-P00439-F1.
ChEMBL Sapropterin and analogues.
ClinVar Hundreds of PAH variants with PKU/HPA classifications.
OMIM 261600 (PKU), 261630 (HPABH4A), 264070 (HPA mild).

Adjacent ontologies

Ontology Identifier
MONDO MONDO:0009861 (PKU), MONDO:0017739 (mild HPA)
HPO HP:0002148 (hyperphenylalaninemia), HP:0001249 (intellectual disability), HP:0000718 (aggressive behavior), HP:0002375 (hypotonia)
Orphanet ORPHA:716 (PKU)

Why PAH

PAH demonstrates the enzyme drug-target workflow: surface the co-factor binding (BH4) and metal-binding (iron) residues via the biomedical-features family of tools, then connect to therapeutic matchmaking (BH4-responsive vs not). It also exercises the mature-protein active-site annotations on a small, well-resolved metabolic enzyme.