id: P05093
gene_symbol: CYP17A1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CYP17A1 (cytochrome P450c17; steroid 17-alpha-hydroxylase/17,20 lyase) is a microsomal,
  endoplasmic-reticulum-membrane heme-thiolate cytochrome P450 monooxygenase that sits at the
  central branch point of steroidogenesis. It is a single bifunctional enzyme with two
  catalytic activities on one polypeptide: (1) 17-alpha-hydroxylase (EC 1.14.14.19), which
  hydroxylates the C21 steroids pregnenolone and progesterone to their 17-alpha-hydroxy
  derivatives (precursors of the glucocorticoid cortisol), and (2) 17,20-lyase (EC 1.14.14.32),
  which cleaves the C17-C20 bond of the 17-alpha-hydroxy intermediates to generate the C19
  androgen precursors dehydroepiandrosterone (from 17-alpha-hydroxypregnenolone) and
  androstenedione (from 17-alpha-hydroxyprogesterone), the committed step toward androgens and
  estrogens. The relative use of the hydroxylase-only versus hydroxylase-plus-lyase route
  determines whether steroid flux is directed to cortisol or to sex steroids. Catalysis is a
  cytochrome-P450 monooxygenase reaction using molecular oxygen, with two electrons supplied by
  NADPH via cytochrome P450 reductase (POR); the 17,20-lyase activity additionally requires
  cytochrome b5, which acts as an allosteric effector that increases the lyase Vmax without
  direct electron transfer. The enzyme is predominantly expressed in the adrenal cortex and
  gonads. Loss-of-function of CYP17A1 causes combined 17-alpha-hydroxylase/17,20-lyase
  deficiency (a form of congenital adrenal hyperplasia, MIM:202110), presenting with
  hypertension and defective sexual development; isolated 17,20-lyase deficiency (46,XY
  disorder of sex development) also occurs. CYP17A1 is a validated drug target: the inhibitor
  abiraterone blocks androgen synthesis in castration-resistant prostate cancer.
existing_annotations:
- term:
    id: GO:0042446
    label: hormone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 catalyzes committed steps in the biosynthesis of steroid hormones (glucocorticoids
      and sex steroids), so hormone biosynthetic process is correct. It is a broad grouping term;
      the specific glucocorticoid/cortisol and androgen biosynthetic process annotations are more
      informative for the core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate phylogenetic annotation but too general to represent the core function on its own;
      the specific downstream biosynthesis terms (androgen, glucocorticoid, cortisol) are the
      core BP annotations.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        controlling the levels of mineralocorticoids influencing
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Steroid 17-alpha-monooxygenase activity is the canonical, phylogenetically conserved
      molecular function of CYP17A1 and is the term most directly capturing its core catalytic
      role. This IBA is well corroborated by multiple experimental annotations (IDA/EXP/IMP).
    action: ACCEPT
    reason: >-
      This is the core molecular function of the enzyme, supported by the PANTHER family and by
      direct experimental evidence (structures, kinetics, and mutant characterization).
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        P450c17 is the single enzyme that
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0042448
    label: progesterone metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 metabolizes progesterone (17-alpha-hydroxylation of progesterone to
      17-alpha-hydroxyprogesterone, and further lyase cleavage), so progesterone metabolic
      process is a correct, if general, annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Substrate-level metabolic term is accurate but not the primary biological role; the
      steroid-hormone biosynthetic processes are the core BP annotations.
    supported_by:
    - reference_id: PMID:36640554
      supporting_text: >-
        progesterone and pregnenolone
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Monooxygenase activity is a correct but very general parent of the specific steroid
      17-alpha-monooxygenase activity (GO:0004508) that CYP17A1 enables.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This InterPro-derived term is an ancestor of the specific MF GO:0004508 that is already
      annotated with experimental evidence; it is redundant/over-general for the core function.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (UniProt/RHEA/EC) assignment of the correct core molecular function
      steroid 17-alpha-monooxygenase activity, consistent with EC 1.14.14.19/1.14.14.32.
    action: ACCEPT
    reason: >-
      Correct core MF, redundant with the experimentally supported GO:0004508 annotations.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      CYP17A1 is a heme-thiolate P450 whose heme iron (axial Cys442) is essential for catalysis;
      iron ion binding is correct as a supporting molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate cofactor/metal-binding annotation but supportive (part of the heme active site)
      rather than the enzyme's defining catalytic function.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        bind the haem iron
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      CYP17A1 is a microsomal P450 localized to the endoplasmic reticulum membrane, consistent
      with UniProt subcellular location and multiple Reactome annotations.
    action: ACCEPT
    reason: >-
      Correct core cellular location for this microsomal steroidogenic P450.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Steroid metabolic process is correct but a broad grouping term; the specific steroid
      hormone biosynthetic processes are more informative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but over-general parent of the specific androgen/glucocorticoid biosynthetic
      processes that constitute the core function.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        catalyses the biosynthesis of androgens in humans
- term:
    id: GO:0008395
    label: steroid hydroxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Steroid hydroxylase activity correctly describes the 17-alpha-hydroxylase reaction but is a
      parent of the more specific GO:0004508 steroid 17-alpha-monooxygenase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general parent of the specific, experimentally supported core MF GO:0004508.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0016705
    label: oxidoreductase activity, acting on paired donors, with incorporation or
      reduction of molecular oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct high-level oxidoreductase/monooxygenase parent term for a cytochrome P450, but
      much more general than the specific GO:0004508.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      InterPro-derived ancestor of the specific core MF; retained by the ontology for the P450
      fold but over-general for the gene's function.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        two electrons provided
- term:
    id: GO:0016712
    label: oxidoreductase activity, acting on paired donors, with incorporation or
      reduction of molecular oxygen, reduced flavin or flavoprotein as one donor,
      and incorporation of one atom of oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Describes the P450/POR (flavoprotein donor) monooxygenase mechanism; correct mechanistically
      but a general parent of the specific steroid 17-alpha-monooxygenase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Mechanistic ancestor term (reduced flavoprotein donor, one oxygen atom incorporated);
      over-general relative to the specific core MF GO:0004508.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        two electrons provided
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      CYP17A1 is a heme-thiolate cytochrome P450; heme binding is a correct, essential supporting
      molecular function (heme is the catalytic prosthetic group).
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate cofactor-binding function that supports, but does not define, the enzyme's
      catalytic activity; retained as a secondary (non-core) molecular function.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        bind the haem iron
- term:
    id: GO:0034308
    label: primary alcohol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      This ARBA electronic term derives from the enzyme's hydroxylation chemistry (introducing
      hydroxyl groups). It does not correspond to a recognized biological role of CYP17A1;
      steroid 17-alpha-hydroxyl products are not usefully described as "primary alcohol
      metabolism".
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Chemistry-derived over-annotation; not a biologically meaningful process term for this
      steroidogenic enzyme. The relevant BP is steroid hormone biosynthesis.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0042445
    label: hormone metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Correct but broad grouping term; CYP17A1 participates in steroid hormone metabolism. The
      specific biosynthesis terms are more informative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate general parent of the specific hormone biosynthetic processes.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        controlling the levels of mineralocorticoids influencing
- term:
    id: GO:0120254
    label: olefinic compound metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      This ARBA electronic term derives from the fact that steroid substrates contain carbon-carbon
      double bonds; it is a chemistry-based over-general grouping that does not describe a
      biologically meaningful role of CYP17A1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Chemistry-derived over-annotation with no biological specificity for this enzyme; the
      meaningful process is steroid hormone biosynthesis.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in corticoid and
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193048
  qualifier: involved_in
  review:
    summary: >-
      Via its 17,20-lyase activity, CYP17A1 catalyzes the committed step that generates C19
      androgen precursors (DHEA, androstenedione), so androgen biosynthetic process is a correct
      core biological process.
    action: ACCEPT
    reason: >-
      Core biological process; CYP17A1 is the gatekeeper of the androgen branch of steroidogenesis.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        catalyses the biosynthesis of androgens in humans
    - reference_id: PMID:9452426
      supporting_text: >-
        the 17,20-lyase activity that cleaves the C17-C20 bond to produce C19 sex steroids
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194002
  qualifier: involved_in
  review:
    summary: >-
      The 17-alpha-hydroxylase activity of CYP17A1 produces 17-alpha-hydroxyprogesterone, the
      precursor required for cortisol (glucocorticoid) synthesis, so glucocorticoid biosynthetic
      process is a correct core biological process.
    action: ACCEPT
    reason: >-
      Core biological process; CYP17A1 17-alpha-hydroxylation is required for the glucocorticoid
      (cortisol) branch of adrenal steroidogenesis.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        glucocorticoids involved in immune and stress responses
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-derived electronic annotation to the same glucocorticoid biosynthetic process
      supported by the Reactome TAS annotation; correct core biological process.
    action: ACCEPT
    reason: >-
      Correct core BP, consistent with the UniProt PATHWAY (glucocorticoid biosynthesis) and the
      Reactome TAS annotation.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Steroid biosynthesis; glucocorticoid biosynthesis.
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193068
  qualifier: enables
  review:
    summary: >-
      Reactome reaction "CYP17A1 17-hydroxylates PREG" annotates the core steroid
      17-alpha-monooxygenase activity.
    action: ACCEPT
    reason: >-
      Correct core MF; Reactome curated the 17-alpha-hydroxylation of pregnenolone.
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        P450c17 is the single enzyme that
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193070
  qualifier: enables
  review:
    summary: >-
      Reactome reaction "CYP17A1 cleaves 17aHPREG to DHA" annotates the core steroid
      17-alpha-monooxygenase/lyase activity (DHEA production).
    action: ACCEPT
    reason: >-
      Correct core MF; captures the 17,20-lyase cleavage step producing DHEA.
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        the 17,20-lyase activity that cleaves the C17-C20 bond to produce C19 sex steroids
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193072
  qualifier: enables
  review:
    summary: >-
      Reactome reaction "CYP17A1 17-hydroxylates P4 to 17aHPROG" annotates the core steroid
      17-alpha-monooxygenase activity (progesterone hydroxylation).
    action: ACCEPT
    reason: >-
      Correct core MF; 17-alpha-hydroxylation of progesterone.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        both hydroxylase substrates pregnenolone and
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193099
  qualifier: enables
  review:
    summary: >-
      Reactome reaction "CYP17A1 cleaves 17aHPROG to ANDST" annotates the core steroid
      17-alpha-monooxygenase/lyase activity (androstenedione production).
    action: ACCEPT
    reason: >-
      Correct core MF; captures the 17,20-lyase cleavage step producing androstenedione.
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        the 17,20-lyase activity that cleaves the C17-C20 bond to produce C19 sex steroids
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5601843
  qualifier: enables
  review:
    summary: >-
      Reactome reaction (defective CYP17A1 does not 17-hydroxylate PREG) annotates the core
      steroid 17-alpha-monooxygenase activity in the context of loss-of-function disease.
    action: ACCEPT
    reason: >-
      Correct core MF, curated in the AH5 disease context.
    supported_by:
    - reference_id: PMID:24140098
      supporting_text: >-
        loss-of-function mutations in CYP17A1
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035954
  qualifier: enables
  review:
    summary: >-
      Reactome reaction (defective CYP17A1 does not 17-hydroxylate P4) annotates the core
      steroid 17-alpha-monooxygenase activity in the loss-of-function disease context.
    action: ACCEPT
    reason: >-
      Correct core MF, curated in the AH5 disease context.
    supported_by:
    - reference_id: PMID:24140098
      supporting_text: >-
        loss-of-function mutations in CYP17A1
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035956
  qualifier: enables
  review:
    summary: >-
      Reactome reaction (defective CYP17A1 does not cleave 17aHPROG) annotates the core
      steroid 17-alpha-monooxygenase/lyase activity in the loss-of-function disease context.
    action: ACCEPT
    reason: >-
      Correct core MF, curated in the AH5 disease context.
    supported_by:
    - reference_id: PMID:24140098
      supporting_text: >-
        loss-of-function mutations in CYP17A1
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:9452426
  qualifier: enables
  review:
    summary: >-
      Auchus et al. functionally characterized human P450c17 17-alpha-hydroxylase and 17,20-lyase
      activities in reconstituted yeast microsomes; direct experimental evidence for the core MF.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        P450c17 is the single enzyme that
- term:
    id: GO:0034651
    label: cortisol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:9452426
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 17-alpha-hydroxylation of 21-carbon steroids produces the 17-OH intermediates
      required for cortisol synthesis; this IDA annotates the specific cortisol biosynthetic
      process, the most precise glucocorticoid-branch BP term.
    action: ACCEPT
    reason: >-
      Correct, specific core biological process; the 17-alpha-hydroxylase step is obligatory for
      cortisol biosynthesis.
    supported_by:
    - reference_id: PMID:9452426
      supporting_text: >-
        17alpha-hydroxylation of 21-carbon steroids
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: EXP
  original_reference_id: PMID:25301938
  qualifier: enables
  review:
    summary: >-
      Petrunak et al. determined substrate-bound CYP17A1 structures and characterized its
      hydroxylase/lyase catalysis; experimental support for the core MF.
    action: ACCEPT
    reason: >-
      Experimental (EXP) support for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        both hydroxylase substrates pregnenolone and
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: EXP
  original_reference_id: PMID:27339894
  qualifier: enables
  review:
    summary: >-
      Yoshimoto et al. mechanistically characterized the 17-alpha,20-lyase and hydroxylation
      reactions of human P450 17A1; experimental support for the core MF.
    action: ACCEPT
    reason: >-
      Experimental (EXP) support for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:27339894
      supporting_text: >-
        17α,20-lyase reactions of human P450 17A1
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:36640554
  qualifier: enables
  review:
    summary: >-
      Lee et al. purified and characterized CYP17A1 (mouse ortholog) hydroxylation and lyase
      reactions with progesterone and pregnenolone; direct evidence for the conserved core MF.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the core steroid 17-alpha-monooxygenase activity; UniProt
      cites this paper as experimental evidence for the human enzyme's activities.
    supported_by:
    - reference_id: PMID:36640554
      supporting_text: >-
        catalyzes 17α-hydroxylation and 17,20-lyase
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IMP
  original_reference_id: PMID:24140098
  qualifier: enables
  review:
    summary: >-
      Kim et al. characterized loss-of-function CYP17A1 mutations that impair 17-alpha-hydroxylase/
      17,20-lyase activity in patients with 17-hydroxylase/17,20-lyase deficiency; mutant-phenotype
      (IMP) support for the core MF.
    action: ACCEPT
    reason: >-
      Mutant-based experimental support (IMP) for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:24140098
      supporting_text: >-
        loss-of-function mutations in CYP17A1
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5601843
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the endoplasmic reticulum membrane, consistent
      with the microsomal P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035954
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the endoplasmic reticulum membrane, consistent
      with the microsomal P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035956
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the endoplasmic reticulum membrane, consistent
      with the microsomal P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IMP
  original_reference_id: PMID:22170710
  qualifier: enables
  review:
    summary: >-
      Idkowiak et al. described a CYB5A missense mutation causing true isolated 17,20-lyase
      deficiency, demonstrating that the CYP17A1-catalyzed lyase activity depends on cytochrome
      b5; supports the core CYP17A1 monooxygenase/lyase function via its partner-dependent
      regulation. Note the mutation studied is in CYB5A (b5), not CYP17A1, but the paper directly
      addresses CYP17A1 lyase function.
    action: ACCEPT
    reason: >-
      Experimental (IMP) annotation retained; the paper establishes b5-dependence of CYP17A1
      17,20-lyase activity. The full text (available) characterizes CYP17A1 lyase function; per
      curation policy, the curator's experimental annotation is respected.
    supported_by:
    - reference_id: PMID:22170710
      supporting_text: >-
        severely reduced 17,20 lyase activity
    - reference_id: PMID:22170710
      supporting_text: >-
        bifunctional enzyme cytochrome P450 (CYP) enzyme
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:22266943
  qualifier: enables
  review:
    summary: >-
      DeVore & Scott solved CYP17A1 crystal structures and characterized its dual hydroxylase/
      lyase catalysis; direct experimental support for the core MF.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        catalyses the biosynthesis of androgens in humans
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:22266943
  qualifier: involved_in
  review:
    summary: >-
      Steroid metabolic process is a correct but broad grouping; the specific androgen/
      glucocorticoid biosynthetic processes are more informative for the core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but over-general parent of the specific steroid hormone biosynthetic processes.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        catalyses the biosynthesis of androgens in humans
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:22266943
  qualifier: enables
  review:
    summary: >-
      Crystal structures show CYP17A1 binds heme (inhibitors coordinate the heme iron), directly
      demonstrating heme binding; essential supporting cofactor function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported cofactor-binding function; supportive of, but not the defining
      catalytic role of, the enzyme. Retained as secondary molecular function.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        bind the haem iron
- term:
    id: GO:0042446
    label: hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22266943
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 biosynthesizes steroid hormones (androgens, glucocorticoid precursors); correct but
      general BP term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate general parent of the specific androgen/glucocorticoid biosynthetic processes.
    supported_by:
    - reference_id: PMID:22266943
      supporting_text: >-
        catalyses the biosynthesis of androgens in humans
- term:
    id: GO:0042448
    label: progesterone metabolic process
  evidence_type: IDA
  original_reference_id: PMID:22266943
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 hydroxylates progesterone (17-alpha-hydroxylation) and further cleaves the product;
      progesterone metabolic process is correct at substrate level.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate substrate-level metabolic term; the steroid hormone biosynthetic processes are the
      core BP annotations.
    supported_by:
    - reference_id: PMID:25301938
      supporting_text: >-
        both hydroxylase substrates pregnenolone and
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193068
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the ER membrane, consistent with the microsomal
      P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193070
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the ER membrane, consistent with the microsomal
      P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193072
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the ER membrane, consistent with the microsomal
      P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193099
  qualifier: located_in
  review:
    summary: >-
      Reactome localizes the CYP17A1 reaction to the ER membrane, consistent with the microsomal
      P450 subcellular location.
    action: ACCEPT
    reason: >-
      Correct core cellular location.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: NAS
  original_reference_id: PMID:9326943
  qualifier: located_in
  review:
    summary: >-
      Endoplasmic reticulum is a correct (if less specific) location for this microsomal P450;
      the ER membrane term (GO:0005789) is more precise.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less-specific parent of the ER membrane location; retained as non-core in favor
      of the more precise GO:0005789.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        Microsome membrane
- term:
    id: GO:0019825
    label: oxygen binding
  evidence_type: TAS
  original_reference_id: PMID:2808364
  qualifier: enables
  review:
    summary: >-
      Oxygen binding is a legacy (ProtInc/PINC) annotation. Although CYP17A1 uses molecular oxygen
      as a co-substrate in its monooxygenase mechanism, "oxygen binding" (typically used for
      reversible O2 carriers such as hemoglobin/myoglobin) is not an informative molecular
      function for a P450 monooxygenase, and the cited reference (PubMed:2808364, on the F53
      deletion causing combined deficiency) does not address oxygen binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Legacy, uninformative MF for a P450; the O2 co-substrate chemistry is already captured by
      the monooxygenase/oxidoreductase terms. Not a genuine reversible-oxygen-binding activity.
    supported_by:
    - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
      supporting_text: >-
        two electrons provided
- term:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: PMID:1347802
  qualifier: enables
  review:
    summary: >-
      Krohn et al. identified the Addison's-disease autoantigen by molecular cloning as steroid
      17-alpha-hydroxylase (CYP17A1); supports the core MF assignment.
    action: ACCEPT
    reason: >-
      Author-stated (TAS) support for the core steroid 17-alpha-monooxygenase activity.
    supported_by:
    - reference_id: PMID:1347802
      supporting_text: >-
        steroid 17 alpha-hydroxylase
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:3500022
  qualifier: involved_in
  review:
    summary: >-
      Picado-Leonard & Miller describe P450c17 as a single cytochrome P450 mediating both
      17-alpha-hydroxylase and 17,20-lyase activities in steroid hormone biosynthesis; steroid
      biosynthetic process is correct but a broad parent of the specific biosynthesis terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but over-general parent of the specific androgen/glucocorticoid biosynthetic
      processes.
    supported_by:
    - reference_id: PMID:3500022
      supporting_text: >-
        single cytochrome P450 enzyme mediating both 17 alpha-hydroxylase
- term:
    id: GO:0007548
    label: sex differentiation
  evidence_type: TAS
  original_reference_id: PMID:9326943
  qualifier: involved_in
  review:
    summary: >-
      CYP17A1 17,20-lyase activity is required for fetal testicular androgen (testosterone
      precursor) production, and its deficiency causes disorders of sexual development; sex
      differentiation is an accurate but downstream/systemic process rather than the enzyme's
      direct molecular role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate downstream physiological consequence of androgen biosynthesis; not the enzyme's
      direct core molecular/biological function, so retained as non-core.
    supported_by:
    - reference_id: PMID:9326943
      supporting_text: >-
        male sexual differentiation requires production of fetal testicular
core_functions:
- description: >-
    Steroid 17-alpha-hydroxylase activity (EC 1.14.14.19): as a microsomal cytochrome P450
    monooxygenase, CYP17A1 hydroxylates the C21 steroids pregnenolone and progesterone at C17 to
    yield 17-alpha-hydroxypregnenolone and 17-alpha-hydroxyprogesterone, the obligatory
    precursors for cortisol (glucocorticoid) biosynthesis, using O2 and electrons from NADPH via
    cytochrome P450 reductase.
  molecular_function:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  directly_involved_in:
  - id: GO:0034651
    label: cortisol biosynthetic process
  - id: GO:0006704
    label: glucocorticoid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:9452426
    supporting_text: >-
      17alpha-hydroxylation of 21-carbon steroids
  - reference_id: PMID:25301938
    supporting_text: >-
      both hydroxylase substrates pregnenolone and
  - reference_id: file:human/CYP17A1/CYP17A1-uniprot.txt
    supporting_text: >-
      A cytochrome P450 monooxygenase involved in corticoid and
- description: >-
    Steroid 17,20-lyase activity (EC 1.14.14.32): CYP17A1 cleaves the C17-C20 bond of the
    17-alpha-hydroxy intermediates (17-alpha-hydroxypregnenolone -> dehydroepiandrosterone;
    17-alpha-hydroxyprogesterone -> androstenedione), the committed step generating C19 androgen
    precursors. This second oxidative activity resides on the same polypeptide as the hydroxylase
    and requires cytochrome b5 as an allosteric effector (with POR as the electron donor),
    determining the flux of steroidogenesis toward androgens and estrogens.
  molecular_function:
    id: GO:0004508
    label: steroid 17-alpha-monooxygenase activity
  directly_involved_in:
  - id: GO:0006702
    label: androgen biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:9452426
    supporting_text: >-
      the 17,20-lyase activity that cleaves the C17-C20 bond to produce C19 sex steroids
  - reference_id: PMID:9452426
    supporting_text: >-
      coexpression of human b5 with P450c17 also
  - reference_id: PMID:22266943
    supporting_text: >-
      catalyses the biosynthesis of androgens in humans
- description: >-
    Heme binding: CYP17A1 is a heme-thiolate cytochrome P450 whose heme prosthetic group
    (iron axially coordinated by Cys442) is essential for its monooxygenase/lyase catalysis;
    heme/iron binding is the supporting cofactor function underpinning both catalytic activities.
  molecular_function:
    id: GO:0020037
    label: heme binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:22266943
    supporting_text: >-
      bind the haem iron
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/CYP17A1/CYP17A1-uniprot.txt
  title: UniProtKB P05093 CYP17A1 (CP17A_HUMAN) record
  findings:
  - statement: >-
      UniProt describes CYP17A1 as a cytochrome P450 monooxygenase in corticoid and androgen
      biosynthesis that 17-alpha-hydroxylates C21 steroids and then cleaves the C17-C20 bond to
      form C19 steroids (DHEA, androstenedione); localizes to the endoplasmic reticulum/microsome
      membrane; 17,20-lyase is stimulated allosterically by cytochrome b5.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary source for gene identity, catalytic activities (EC 1.14.14.19/1.14.14.32),
      cofactor (heme), subcellular location, and disease association (AH5).
- id: PMID:1347802
  title: Identification by molecular cloning of an autoantigen associated with Addison's
    disease as steroid 17 alpha-hydroxylase.
  findings:
  - statement: >-
      Identifies the Addison's-disease adrenal autoantigen as steroid 17-alpha-hydroxylase
      (CYP17A1) via molecular cloning.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Establishes gene identity as steroid 17-alpha-hydroxylase; supports the MF assignment
      (autoimmune-antigen context is peripheral to core function).
- id: PMID:22170710
  title: A missense mutation in the human cytochrome b5 gene causes 46,XY disorder
    of sex development due to true isolated 17,20 lyase deficiency.
  findings:
  - statement: >-
      A CYB5A missense mutation causes true isolated 17,20-lyase deficiency, demonstrating that
      CYP17A1 17,20-lyase activity depends on cytochrome b5 as an allosteric enhancer.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; directly characterizes CYP17A1 17,20-lyase function and its
      b5-dependence, though the causal mutation is in CYB5A.
- id: PMID:22266943
  title: Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone
    and TOK-001.
  findings:
  - statement: >-
      Crystal structures of CYP17A1 with abiraterone/TOK-001 show inhibitors coordinating the
      heme iron and reveal the basis for the enzyme's dual hydroxylase and lyase activities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Structural/experimental support for heme binding and the core monooxygenase/lyase MF.
- id: PMID:24140098
  title: A review of the literature on common CYP17A1 mutations in adults with 17-hydroxylase/17,20-lyase
    deficiency, a case series of such mutations among Koreans and functional characteristics
    of a novel mutation.
  findings:
  - statement: >-
      Reviews CYP17A1 loss-of-function mutations causing 17-hydroxylase/17,20-lyase deficiency
      (CAH with hypertension and sexual infantilism) and functionally characterizes a novel
      mutation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Mutant-phenotype (IMP) evidence linking CYP17A1 activity loss to disease.
- id: PMID:25301938
  title: Structures of human steroidogenic cytochrome P450 17A1 with substrates.
  findings:
  - statement: >-
      Substrate-bound CYP17A1 structures explain hydroxylase substrate orientation (Asn202) and
      the basis of 17,20-lyase substrate specificity; CYP17A1 controls mineralocorticoid,
      glucocorticoid, androgen and estrogen levels.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Experimental structural/functional support for the core MF and the branch-point role.
- id: PMID:27339894
  title: 'Mechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome
    P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL
    OXYGEN.'
  findings:
  - statement: >-
      Mechanistic study (18O labeling) of the human P450 17A1 17-alpha,20-lyase and additional
      hydroxylation reactions, supporting a perferryl-oxygen mechanism.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Experimental support for the core monooxygenase/lyase MF and reaction mechanism.
- id: PMID:2808364
  title: Deletion of a phenylalanine in the N-terminal region of human cytochrome
    P-450(17 alpha) results in partial combined 17 alpha-hydroxylase/17,20-lyase deficiency.
  findings:
  - statement: >-
      A Phe53 deletion in the N-terminal (membrane-anchoring) region causes partial combined
      17-alpha-hydroxylase/17,20-lyase deficiency; supports the microsomal/ER localization and
      disease mechanism.
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: >-
      Correctly cited for the AH5 variant and (via UniProt) subcellular location, but it is the
      original_reference for a GO:0019825 "oxygen binding" annotation that the paper does not
      address; that annotation is marked over-annotated.
- id: PMID:3500022
  title: 'Cloning and sequence of the human gene for P450c17 (steroid 17 alpha-hydroxylase/17,20
    lyase): similarity with the gene for P450c21.'
  findings:
  - statement: >-
      Clones and sequences the human P450c17 gene; describes P450c17 as a single cytochrome P450
      mediating both 17-alpha-hydroxylase and 17,20-lyase activities in steroid hormone
      biosynthesis.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Foundational gene-cloning paper; supports gene identity and steroid biosynthetic role.
- id: PMID:36640554
  title: Hydroxylation and lyase reactions of steroids catalyzed by mouse cytochrome
    P450 17A1 (Cyp17a1).
  findings:
  - statement: >-
      Characterizes the 17-alpha-hydroxylation and 17,20-lyase reactions of the (mouse ortholog)
      CYP17A1 with progesterone and pregnenolone; the conserved activities corroborate the human
      enzyme's function.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Mouse ortholog study; UniProt cites it as experimental evidence for the conserved catalytic
      activities.
- id: PMID:9326943
  title: The genetic and functional basis of isolated 17,20-lyase deficiency.
  findings:
  - statement: >-
      Establishes true isolated 17,20-lyase deficiency due to CYP17 mutations that impair
      interaction with redox partners; fetal testicular androgen (testosterone) production
      requires CYP17A1 17,20-lyase activity for male sexual differentiation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Supports the androgen-biosynthesis / sex-differentiation roles and the redox-partner
      dependence of lyase activity.
- id: PMID:9452426
  title: Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without
    direct electron transfer.
  findings:
  - statement: >-
      Demonstrates that cytochrome b5 augments human P450c17 17,20-lyase activity as an
      allosteric effector (increasing lyase Vmax) without direct electron transfer, and that POR
      is necessary/sufficient for microsomal 17,20-lyase activity.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Key functional paper for the bifunctional MF and the b5/POR dependence of the lyase branch.
- id: Reactome:R-HSA-193048
  title: Androgen biosynthesis
  findings: []
- id: Reactome:R-HSA-193068
  title: CYP17A1 17-hydroxylates PREG
  findings: []
- id: Reactome:R-HSA-193070
  title: CYP17A1 cleaves 17aHPREG to DHA
  findings: []
- id: Reactome:R-HSA-193072
  title: CYP17A1 17-hydroxylates P4 to 17aHPROG
  findings: []
- id: Reactome:R-HSA-193099
  title: CYP17A1 cleaves 17aHPROG to ANDST
  findings: []
- id: Reactome:R-HSA-194002
  title: Glucocorticoid biosynthesis
  findings: []
- id: Reactome:R-HSA-5601843
  title: Defective CYP17A1 does not 17-hydroxylate PREG
  findings: []
- id: Reactome:R-HSA-9035954
  title: Defective CYP17A1 does not 17-hydroxylate P4
  findings: []
- id: Reactome:R-HSA-9035956
  title: Defective CYP17A1 does not cleave 17aHPROG
  findings: []