UniProtKB: P05093 (CP17A_HUMAN). HGNC:2593. Human, NCBITaxon:9606.
Name: Steroid 17-alpha-hydroxylase/17,20 lyase; Cytochrome P450c17; Cytochrome P450 17A1.
EC 1.14.14.19 (17alpha-hydroxylase) and EC 1.14.14.32 (17,20-lyase / 17-alpha-hydroxyprogesterone aldolase).
CYP17A1 is a microsomal (ER-membrane) heme-thiolate cytochrome P450 monooxygenase that
sits at the branch point of steroidogenesis, determining whether pregnane precursors are
routed toward glucocorticoids (cortisol) or toward androgens/estrogens. It is a single,
bifunctional enzyme carrying two catalytic activities on one polypeptide:
17-alpha-hydroxylase (EC 1.14.14.19): hydroxylates C21 steroids —
pregnenolone -> 17alpha-hydroxypregnenolone, progesterone -> 17alpha-hydroxyprogesterone.
These 17-OH intermediates are precursors of cortisol (adrenal glucocorticoid pathway).
PMID:9452426
17,20-lyase (EC 1.14.14.32): cleaves the C17-C20 bond of the 17-OH intermediates ->
DHEA (from 17OH-pregnenolone) and androstenedione (from 17OH-progesterone), the committed
step toward androgens/estrogens.
PMID:9452426
The lyase reaction is cytochrome b5- and POR-dependent: cytochrome b5 acts as an
allosteric effector that raises the Vmax of the lyase (not the hydroxylase) reaction, without
direct electron transfer. PMID:9452426
[file quote P05093 "The 17,20-lyase activity is stimulated by cytochrome b5, which acts as an allosteric effector increasing the Vmax of the lyase activity"]
Mechanism: monooxygenase using molecular O2, one atom inserted into substrate, second reduced
to water; two electrons from NADPH via cytochrome P450 reductase (POR).
[file quote P05093 "two electrons provided by NADPH via cytochrome P450 reductase"]
Minor/additional activities (UniProt): 16-alpha-hydroxylase activity relevant to estriol
synthesis (PMID:25301938, PMID:27339894); mouse ortholog characterized similarly (PMID:36640554).
ER membrane / microsome membrane. [file quote P05093 "Endoplasmic reticulum membrane"]
NAS/TAS legacy annotations (GO:0005783 endoplasmic reticulum; GO:0005789 ER membrane) all
consistent. UniProt SUBCELLULAR LOCATION cites PubMed:2808364.
Combined 17alpha-hydroxylase/17,20-lyase deficiency = Adrenal hyperplasia 5 (AH5, MIM:202110),
a form of congenital adrenal hyperplasia: hypertension + sexual-development defects.
PMID:24140098
Isolated 17,20-lyase deficiency also occurs (46,XY DSD); true isolated lyase deficiency can
also be caused by CYB5A mutation. [PMID:9326943; PMID:22170710]
Multiple X-ray structures (DeVore & Scott 2012 PMID:22266943 with abiraterone/TOK-001;
Petrunak 2014 PMID:25301938 with substrates). Heme-iron axial Cys442; substrate binding
via Asn202. Abiraterone (prostate cancer drug) is a CYP17A1 inhibitor.
Core MF: GO:0004508 steroid 17-alpha-monooxygenase activity (no dedicated 17,20-lyase MF term
exists in GO; GO:0004508 is the canonical CYP17A1 MF, well supported by IDA/EXP/IMP + IBA).
Core BP: androgen biosynthesis (GO:0006702), glucocorticoid/cortisol biosynthesis
(GO:0006704 / GO:0034651). Core CC: GO:0005789 ER membrane. Secondary MF: heme binding
(GO:0020037), iron ion binding (GO:0005506).
Over-annotated / generic IEA MF terms (monooxygenase, steroid hydroxylase, oxidoreductase
16705/16712) are not wrong but are ancestors of the specific GO:0004508; keep as non-core.
GO:0019825 oxygen binding (legacy TAS from PINC/ProtInc, cited to PMID:2808364 which does not
mention oxygen binding) is an over-annotation for a P450 — mark as over-annotated.
Generic ARBA IEA BP terms (primary alcohol metabolic, olefinic compound metabolic) are
mechanistically-derived over-general terms — keep as non-core / over-annotated.
All seeded annotation fields outside review were preserved exactly. Every row was reassessed; broad true claims were refined and cofactor activities retained. No NEW process annotations were added. just deep-research-falcon human CYP17A1 --fallback perplexity-lite ran concurrently with publication caching. Falcon authentication failed, then Perplexity returned HTTP401 insufficient quota. Manual primary research substitutes for unavailable provider output; no provider-labelled report was fabricated.
PMID25301938 structural/biochemical evidence supports human Delta5 lyase preference:17OH-pregnenolone→DHEA is efficient, while17OH-progesterone→androstenedione is poor rather than absent. PMID40340376(full text) directly measures second-electron transfer and product formation using b5 or POR. The dominant b5 effect on multiple-turnover kinetics is increased coupling; older9452426 yeast-microsome results cannot justify a universal allosteric-only/no-electron-transfer assertion.
QuickGO definition GO0004508 is only17alpha hydroxylation(RHEA65760). Queries for17,20-lyase, hydroxyprogesterone deacetylase andEC1.14.14.32 found no specific matching GO term. Proposed steroid17,20-lyase MF therefore covers oxidative C17-C20 cleavage, C19 steroid+acetate products; EC1.14.14.32 and RHEA50244/14753 are in the curated UniProt reactions. The oxidative reaction is not assigned to a nonoxidative lyase class just from its common name.
PMID19403566 supports tissue-specific rat adrenal repression versus testes; PMID7588219 demonstrates fetal mouse adrenal expression/activity(E12.5–14.5), lost by late gestation/adulthood. The boundary is normal adult adrenal output, not absence of the gene or gonadal activity. Mouse-focused36640554 includes human comparison and is not rejected from its title.
GO-CAM67b1629100003765 gives CYP17A1 hydroxylase/cortisol roles; it does not supply lyase evidence. Cached Reactome193070/193099 describe lyase despite GO4508 attachment and name acetaldehyde instead of the acetate supported by primary chemistry/Rhea. These limitations are assessed explicitly. Reactome194002 incorrectly attributes pregnenolone→17OH-progesterone entirely to HSD3B; the CYP17 step is required.
Verified GO ancestry live on 2026-10-25 via https://www.ebi.ac.uk/QuickGO/services/ontology/go/terms/GO:0034651/paths/GO:0034308?relations=is_a,part_of . The response contains two paths, both entirely is_a: GO:0034651 → GO:0034650 → GO:0034308, and GO:0034651 → GO:0034309 → GO:0034308. Thus cortisol biosynthesis is a descendant of primary alcohol metabolism; the existing MODIFY is a specialization, not a lateral replacement. Added the explicit chains to the reason and shortened the summary to distinguish the claim from its justification. No actions or replacement terms changed.
The supported root endoplasmic reticulum annotations are retained as ACCEPT, separately from unchanged subcompartment claims. This supersedes earlier journal wording that refined the root location or treated its breadth as non-core. Original annotation payloads, unrelated review decisions and core functions are preserved. Source-specific rationales distinguish curated location/inference, original experimental annotations and source access limits; no new assay or target-table inspection is claimed.