id: E8NH57
gene_symbol: Hn
taxon:
  id: NCBITaxon:7227
  label: Drosophila melanogaster
status: COMPLETE
description: The native Hn-PD product lacks conserved substrate/cofactor architecture required for pteridine-dependent
  hydroxylase activity. The activity prediction is refuted; aromatic-amino-acid-process participation
  remains unresolved.
source_documents:
- genes/DROME/Hn/Hn-protnlm-source.json
- genes/DROME/Hn/Hn-bioinformatics/RESULTS.md
- genes/DROME/Hn/Hn-flybase.txt
predictions:
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-09-08
  source_reference_id: file:DROME/Hn/Hn-protnlm-source.json
  predicted_term:
    id: GO:0009072
    label: aromatic amino acid metabolic process
  predicted_term_type: GO_BP
  review:
    assessment: UNC
    confidence_score: 1
    summary: The native 178-residue Hn-PD isoform lacks substrate/cofactor architecture required for conventional
      hydroxylase chemistry, as established by mapping human PAH structural sites through full-length
      Hn. This refutes intrinsic hydroxylase activity but does not exclude a noncatalytic or regulatory
      contribution to aromatic amino acid metabolism. No evidence establishes such a process contribution
      by PD, so the broad process prediction remains UNC.
    supported_by:
    - reference_id: file:DROME/Hn/Hn-bioinformatics/RESULTS.md
      supporting_text: Iron-ligand positions His284, His289 and Glu329 map to target His10, His15 and
        Glu55.
    - reference_id: file:DROME/Hn/Hn-flybase.txt
      supporting_text: Hn-PD FBpp0306708 20.1 178 4.34 E8NH57 NP_001261543 AGB94238
    - &id001
      reference_id: file:DROME/Hn/Hn-bioinformatics/RESULTS.md
      supporting_text: The human substrate-responsive loop 131–155 (PMID:12126628), pterin-binding loop
        245–250 and cofactor-stacking Phe254 (PMID:10694386) are absent in PD.
- source_method: ProtNLM2
  source_version: UniProt API snapshot 2026-09-08
  source_reference_id: file:DROME/Hn/Hn-protnlm-source.json
  predicted_term:
    id: GO:0016714
    label: oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular
      oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen
  predicted_term_type: GO_MF
  review:
    assessment: NPI
    error_type: DOMAIN_ARCHITECTURE_MISMATCH
    confidence_score: 0
    summary: The exact native PD isoform lacks the PAH substrate-responsive loop, pterin-binding loop
      and cofactor-stacking Phe site, established by human-to-full-length-Hn mapping and their absence
      from PD. Primary structural and mutagenesis studies identify these as reaction-center features;
      only 149 of 307 aligned catalytic-domain residues remain. The three iron ligands and Glu cofactor
      contact are retained, but cannot supply the missing substrate/cofactor architecture. This refutes
      transfer of conventional pteridine-dependent hydroxylase chemistry, despite overlap with an existing
      electronic annotation. The conclusion concerns intrinsic catalysis, not all possible process participation
      or a supposed error in the native transcript sequence.
    supported_by:
    - *id001
    - reference_id: PMID:10694386
      supporting_text: 'Site-specific mutations of Glu286 (E286A and E286Q), Phe254 (F254A and

        F254L), and Tyr325 (Y325F) have confirmed the important contribution of Glu286

        and Phe254 to the normal positioning of the pterin cofactor and catalytic

        activity of hPheOH.'
    - reference_id: PMID:12126628
      supporting_text: 'The largest

        change occurs in the loop region comprising residues 131-155'
references:
- id: file:DROME/Hn/Hn-bioinformatics/RESULTS.md
  title: RESULTS.md
  findings: []
- id: file:DROME/Hn/Hn-flybase.txt
  title: Hn-flybase.txt
  findings: []
- id: PMID:10694386
  title: Crystal structure and site-specific mutagenesis of pterin-bound human phenylalanine hydroxylase.
  findings: []
- id: PMID:12126628
  title: Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase
    with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis
    and substrate activation.
  findings: []