Calcitriol Biosynthesis from Calciol — Obsoletion & Replacement

SCOPING OBSOLETION

Species: human, mouse, rat

Genes: CYP27B1, CYP2R1, CYP24A1, CYP27A1, CYP3A4

Warnings (1)

Calcitriol Biosynthesis from Calciol — Obsoletion & Replacement

Overview

A GO obsoletion proposal will obsolete the biological-process term
GO:0036378 calcitriol biosynthetic process from calciol and replace it
with the sibling term GO:1901755 vitamin D3 biosynthetic process. The
upstream rationale is that the two enzymatic steps captured by GO:0036378
(25-hydroxylation in liver + 1α-hydroxylation in kidney) are the only two
enzymatic steps in the broader MetaCyc vitamin D3 biosynthesis pathway
(MetaCyc:PWY-6076), so the narrower term is redundant once GO:1901755 is
re-defined to have calcitriol (CHEBI:17823, the active hormone) as its
has_primary_output rather than calciol. With that re-definition,
GO:1901755 subsumes the content of GO:0036378 exactly, and a clean
replaced_by is appropriate.

This is a small, well-scoped curation hygiene job: 24 experimental
annotations on 5 cytochrome P450 genes, none of which currently has an
*-ai-review.yaml here. Both groups listed upstream (BHF-UCL, UniProt)
have already marked their portions done in the tracking spreadsheet.

Upstream tickets

Obsoletion plan (per upstream)

Obsoleted term ID Replacement
calcitriol biosynthetic process from calciol (BP) GO:0036378 GO:1901755 vitamin D3 biosynthetic process (re-defined to output calcitriol)

Term metadata confirmed in OLS on 2026-06-20:

Affected experimental / curated annotations (24)

Retrieved from the QuickGO annotation API on 2026-06-20
(goId=GO:0036378, manual / experimental evidence codes only). Matches the
upstream group counts after accounting for ZFIN, MGI and RGD assertions that
the upstream tally rolls into "other groups":

# Source Accession Symbol Organism Evidence Reference
1 BHF-UCL UniProtKB:O15528 CYP27B1 Human IDA PMID:15795327
2 BHF-UCL UniProtKB:O15528 CYP27B1 Human IDA PMID:16549446
3 BHF-UCL UniProtKB:O15528 CYP27B1 Human IDA PMID:17023519
4 BHF-UCL UniProtKB:O15528 CYP27B1 Human IDA PMID:9415400
5 BHF-UCL UniProtKB:P08684 CYP3A4 Human IDA PMID:15546903
6 BHF-UCL UniProtKB:O35084 Cyp27b1 Mouse IDA PMID:9295274
7 BHF-UCL UniProtKB:O35132 Cyp27b1 Rat IDA PMID:9333115
8 UniProt UniProtKB:O15528 CYP27B1 Human EXP PMID:10518789
9 UniProt UniProtKB:O15528 CYP27B1 Human EXP PMID:10566658
10 UniProt UniProtKB:O15528 CYP27B1 Human EXP PMID:12050193
11 UniProt UniProtKB:O15528 CYP27B1 Human EXP PMID:9486994
12 UniProt UniProtKB:O15528 CYP27B1 Human IDA PMID:22862690
13 UniProt UniProtKB:O35084 Cyp27b1 Mouse EXP PMID:10092858
14 UniProt UniProtKB:O35084 Cyp27b1 Mouse IDA PMID:15972816
15 UniProt UniProtKB:Q02318 CYP27A1 Human IDA PMID:15465040
16 UniProt UniProtKB:Q6VVX0 CYP2R1 Human EXP PMID:12867411
17 UniProt UniProtKB:Q6VVX0 CYP2R1 Human IDA PMID:15465040
18 UniProt UniProtKB:Q6VVX0 CYP2R1 Human IDA PMID:18511070
19 UniProt UniProtKB:Q07973 CYP24A1 Human IDA PMID:25727742
20 UniProt UniProtKB:Q09128 Cyp24a1 Rat IDA PMID:25727742
21 MGI UniProtKB:Q6VVW9 Cyp2r1 Mouse IDA PMID:12867411
22 RGD UniProtKB:O35132 Cyp27b1 Rat IDA PMID:9371776
23 RGD UniProtKB:P17178 Cyp27a1 Rat IDA PMID:2175615
24 ZFIN UniProtKB:A0A097HUX0 cyp27b1 Zebrafish IDA PMID:25290078

On top of these 24 curated records, GO:0036378 currently has ~2,048 total
annotations (QuickGO, 2026-06-20). The non-experimental tail is small for
this term (the first 100 results contained only one IBA + IDA + ~98 IEA),
which is consistent with a tightly-scoped catalytic BP rather than a
broadly-propagated complex/localization term.

Why a clean replaced_by is appropriate here

Unlike GO:0030943 mitochondrion targeting sequence binding
([[MITOCHONDRION_TARGETING_SEQUENCE_BINDING_OBSOLETION]]), where the affected
annotations span biologically distinct mechanism classes, all 24 affected
annotations are on enzymes catalyzing one of the two hydroxylation steps in
the vitamin D3 → calcitriol pathway, and the re-defined GO:1901755
(has_primary_output = calcitriol) literally subsumes the old GO:0036378
content. The four annotated CYP roles are:

Impact on this repo

None of the five affected genes currently has an *-ai-review.yaml under
genes/ (verified 2026-06-20 across genes/human/, genes/mouse/,
genes/rat/, genes/zebrafish/). There are also no other reviews here that
cite GO:0036378 (grep -r "GO:0036378" genes/ returned no hits). So this
obsoletion does not invalidate any existing AI Gene Review content.

That said, vitamin D biosynthesis is a small, well-characterized,
high-textbook-coverage pathway, and CYP27B1 in particular is medically
important (loss-of-function causes vitamin D-dependent rickets type 1A). It
is a natural candidate for a small, focused gene-family review project, with
this obsoletion as a clean entry point.

Scope

Candidate genes for initial review

Listed in priority order. The first three would directly exercise the
re-defined GO:1901755 once the obsoletion lands.

  1. CYP27B1 (human, O15528) — 1α-hydroxylase; the canonical
    "vitamin D activation" enzyme; 9 of the 24 affected annotations. Highest
    priority and best positive control.
  2. CYP2R1 (human, Q6VVX0) — principal hepatic 25-hydroxylase; 3 of the
    24 annotations. The other half of the activation route.
  3. CYP27A1 (human, Q02318) — secondary 25-hydroxylase / sterol
    27-hydroxylase; pleiotropic (also acts on bile-acid precursors).
  4. CYP3A4 (human, P08684) — drug-metabolizing CYP; vitamin D
    25-hydroxylation is a minor, non-core activity. Good test case for
    MARK_AS_OVER_ANNOTATED vs. KEEP_AS_NON_CORE.
  5. CYP24A1 (human, Q07973) — 24-hydroxylase / vitamin D inactivator. The
    edge case: decide whether GO:1901755 is the right successor or whether
    a catabolic vitamin D term should be used instead. Coordinate with the
    upstream ontology ticket.

The rodent orthologs (Cyp27b1 mouse/rat, Cyp2r1 mouse, Cyp24a1 rat,
Cyp27a1 rat, cyp27b1 zebrafish) are not initial-priority for individual
review here — the human reviews will pull their orthologs in via IBA, and
curators in MGI/RGD/ZFIN have already marked or can mirror the upstream
remapping.

Proposed approach

  1. Wait for the upstream replaced_by to land. The first two ontology
    proposals (xref + has_primary_output) are marked done; the obsoletion
  2. replaced_by step is still pending in go-ontology#32077. Once it
    merges, all 24 annotations migrate automatically.
  3. Open a CYP27B1 review first (just fetch-gene human CYP27B1) as the
    highest-value, lowest-risk case. Use it to validate that the re-defined
    GO:1901755 is the right molecular_function / involved_in BP for the
    1α-hydroxylation step.
  4. Add CYP2R1 and CYP27A1 next; these establish the 25-hydroxylase
    half of the pathway and will also need a vitamin D metabolic / sterol
    hydroxylase     MF.
  5. Handle CYP3A4 and CYP24A1 as edge cases. For CYP3A4, the vitamin D
    25-hydroxylation is a non-core, low-affinity activity and may warrant
    KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED rather than ACCEPT. For
    CYP24A1, the right successor is plausibly a catabolic vitamin D term,
    not GO:1901755; flag this back to the upstream tracker if confirmed.
  6. No InterPro2GO / UniRule / UniProt-Keyword cleanup needed. The
    upstream issue explicitly notes "No Mappings" for GO:0036378. The
    downstream-mapping triage that the larger obsoletion projects need
    (e.g. [[NLS_BINDING_OBSOLETION]], [[VESICLE_DOCKING_OBSOLETION]]) does not
    apply here.

Priority

Low–Medium. Only 24 curated annotations on a five-gene set with no current
reviews here, no mapping fallout, and both upstream curator groups already
marking their work done. The value of opening this is twofold: (a) a clean
test of the replaced_by flow on a small, well-defined pathway; and (b) a
natural anchor for a focused vitamin D / cytochrome P450 mini-review of
CYP27B1 (medically important; vitamin D-dependent rickets type 1A) and its
hydroxylase partners. Skip if higher-priority obsoletions are still open.

Status