cyp26a1 (Danio rerio) review notes

Batch 05 curation notes

• Core interpretation: cyp26a1 encodes cytochrome P450 26A1, an endoplasmic-reticulum retinoic-acid hydroxylase that catabolizes all-trans retinoic acid and thereby shapes retinoic-acid signaling during zebrafish development. Developmental patterning annotations are treated as downstream consequences of this core retinoic-acid metabolic activity.
• Key UniProt support: Catalyzes the hydroxylation of carbon hydrogen bonds of atRA primarily at C-4.
• Existing GOA annotations were reviewed against this core role; broad, inferred, or downstream phenotype annotations were kept as non-core unless they overstate the direct function.

Re-review 2026-09-29

Full re-review of the templated batch-05 review against the cached literature (13 PMIDs) and the refreshed UniProt/GOA records. All 44 GOA rows now carry substantive, row-specific review blocks; the 6 rows appended as PENDING after the GOA refresh (blood vessel development IMP/morpholino, vasculature development IGI, monooxygenase activity IBA, two rhombomere 4 morphogenesis IGI rows, atrial cardiac muscle cell development IGI) were resolved consistently with the existing rows for the same term/paper.

What changed and why:

• Core activity. GO:0062182 all-trans retinoic acid 4-hydrolase activity (EXP/IEA-Rhea), GO:0008401 retinoic acid 4-hydroxylase activity (IDA/IEA-ARBA), GO:0034653 retinoic acid catabolic process (IBA/IEA/IMP) and GO:0042573 retinoic acid metabolic process (IDA x2, IMP) are ACCEPT. The anchor evidence is the original zebrafish cloning paper [PMID:8939936 "In COS-1 cells transfected with the P450RAI cDNA, all-trans-RA is rapidly metabolized to more polar metabolites." and "We have identified 4-oxo-RA and 4-OH-RA as major metabolic products of this enzyme."] together with the UniProt catalytic-activity line (RHEA:51492) and the in vivo genetics PMID:19416885.
• GO:0042573 IDA from PMID:16455818 (a Cyp26D1 paper) is ACCEPT, not treated as paralog mis-attribution: the cached abstract itself states cyp26a1 was assayed in the same study PMID:16455818.
• GO:0042574 retinal metabolic process IMP (PMID:17164423): re-adjudicated from a previous REMOVE (which had a boilerplate reason) to MARK_AS_OVER_ANNOTATED. REMOVE was not defensible under the "do not overrule curators" rule - the cached copy of PMID:17164423 is flagged full-text but contains only the abstract and introduction, so the ZFIN curator's basis cannot be checked. The over-annotation argument rests on accessible evidence: zebrafish CYP26 enzymes do not turn over retinal PMID:16455818, the paper itself assigns retinal oxidation to Aldh1a2 PMID:17164423, and a QuickGO comparator check (2026-09-29) shows GO:0042574 is carried in human/mouse/zebrafish only by enzymes and carriers that make or consume retinal (RDH10/11/13, DHRS4, dhrs9, rdh1, ALDH1A3, BCO1/2, RPE65, ABCA4) and by no CYP26 other than this zebrafish row. No replacement proposed because GO:0042573 is already annotated from the same paper.
• Generic P450 IEA/IBA terms (GO:0004497 monooxygenase activity IEA+IBA, GO:0016705, GO:0005506 iron ion binding, GO:0020037 heme binding) are KEEP_AS_NON_CORE: correct (UniProt cofactor heme, axial ligand at residue 438) but uninformative relative to GO:0062182/GO:0008401, which already exist in the set, so no MODIFY is proposed. The IBA GO:0004497 row derives from the pan-P450 node PTN000669383; node placement is not disputed.
• GO:0005789 endoplasmic reticulum membrane (IEA-SubCell, ISS from human O43174) ACCEPT, supported by the UniProt SUBCELLULAR LOCATION line rather than the FUNCTION line.
• All 27 ZFIN developmental IMP/IGI/IDA rows (hindbrain, rhombomere 4, forebrain A/P, brain morphogenesis, MHB, somitogenesis, heart, atrial cardiomyocyte, outflow tract, vasculature, blood vessel, pancreas, pronephros A/P, mesodermal-endodermal signalling, RAR signalling pathway, cellular response to vitamin A, CNS development IBA) are KEEP_AS_NON_CORE under the participation test: Cyp26a1 performs one step, RA destruction, and each phenotype follows from altered ligand concentration, often cell non-autonomously PMID:24667328 and often only on co-depletion of paralogs [PMID:23990796 "In either the RARαb1 or Cyp26a1 deficient embryos alone, we never observed absence of the MHB or defects in tail elongation"; PMID:17164423 "cyp26a1 mutants in the fish and mouse exhibit relatively subtle hindbrain patterning defects inconsistent with a global role for cyp26a1 in hindbrain patterning"]. None removed.
• NEW: GO:0048387 negative regulation of retinoic acid receptor signaling pathway (IMP, PMID:27406002). Participation: Cyp26a1 itself catalyses the ligand-destroying step. Comparator check (QuickGO, 2026-09-29): the term is held by human CYP26A1 (TAS), CYP26B1 (TAS), CYP26C1 (NAS), mouse Cyp26b1 (IMP) and Dhrs3 (IMP), and zebrafish cyp26b1 (IDA) - so zebrafish cyp26a1 is the anomalous absence PMID:27406002.
• References: every PMID carries a reference_review; titles verified against the cached publications by validation. Description rewritten as standalone biology; core_functions has one entry (GO:0062182 in GO:0005789, directly involved in GO:0034653 and GO:0048387).
• Validation: zero errors; one residual warning (deep-research file not cited - deliberately, since primary literature is cached for every claim).