ProtNLM2 External predictions
View prediction review YAML · Hn-protnlm-predictions-review.yaml · Review status: COMPLETE
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
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08 · file:DROME/Hn/Hn-protnlm-source.json
Review rationale: 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.
Supporting Evidence:
- file:DROME/Hn/Hn-bioinformatics/RESULTS.md: "Iron-ligand positions His284, His289 and Glu329 map to target His10, His15 and Glu55."
- file:DROME/Hn/Hn-flybase.txt: "Hn-PD FBpp0306708 20.1 178 4.34 E8NH57 NP_001261543 AGB94238"
- file:DROME/Hn/Hn-bioinformatics/RESULTS.md: "The human substrate-responsive loop 131–155 (PMID:12126628), pterin-binding loop 245–250 and cofactor-stacking Phe254 (PMID:10694386) are absent in PD."
GO:0016714 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 GO_MF
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08 · file:DROME/Hn/Hn-protnlm-source.json
DOMAIN ARCHITECTURE MISMATCH
Review rationale: 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.
Supporting Evidence:
- file:DROME/Hn/Hn-bioinformatics/RESULTS.md: "The human substrate-responsive loop 131–155 (PMID:12126628), pterin-binding loop 245–250 and cofactor-stacking Phe254 (PMID:10694386) are absent in PD."
- PMID:10694386: "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."
- PMID:12126628: "The largest change occurs in the loop region comprising residues 131-155"