id: P15538
gene_symbol: CYP11B1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Cytochrome P450 11B1 (P450c11beta, steroid 11-beta-hydroxylase; EC 1.14.15.4) is a
  mitochondrial inner-membrane, heme-thiolate cytochrome P450 monooxygenase expressed in
  the zona fasciculata/reticularis of the adrenal cortex. It catalyses the final step of
  cortisol (glucocorticoid) biosynthesis, hydroxylating 11-deoxycortisol to cortisol, and
  also converts 11-deoxycorticosterone (21-hydroxyprogesterone) to corticosterone. Electrons
  for catalysis are delivered from NADPH through the mitochondrial adrenodoxin system
  (ferredoxin reductase FDXR and the [2Fe-2S] ferredoxin FDX1/FDX2). CYP11B1 is the
  glucocorticoid-branch paralog of CYP11B2 (aldosterone synthase), with which it is more than
  93% identical; unlike CYP11B2 it lacks efficient 18-oxidase activity and cannot generate
  aldosterone. It additionally 11beta-hydroxylates adrenal androgens (e.g. androstenedione,
  testosterone). Loss-of-function mutations cause 11beta-hydroxylase-deficiency congenital
  adrenal hyperplasia (adrenal hyperplasia 4), the second most common form of CAH, presenting
  with a hypertensive phenotype (from 11-deoxycorticosterone excess) and androgen excess.
alternative_products:
- name: '1'
  id: P15538-1
- name: '2'
  id: P15538-2
  sequence_note: VSP_043308
existing_annotations:
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to glucocorticoid biosynthesis. CYP11B1 catalyses the
      final, committed step of cortisol (the principal human glucocorticoid) synthesis, so
      this is a core biological process.
    action: ACCEPT
    reason: >-
      Well supported: CYP11B1 hydroxylates 11-deoxycortisol to cortisol, the terminal step of
      glucocorticoid biosynthesis. Consistent with the UniProt PATHWAY assignment and the
      experimental cortisol-biosynthesis annotations below.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Steroid biosynthesis; glucocorticoid biosynthesis.
    - reference_id: PMID:18215163
      supporting_text: >-
        The human 11beta-hydroxylase (hCYP11B1) is responsible for the conversion of
        11-deoxycortisol into the major mammalian glucocorticoid, cortisol.
- term:
    id: GO:0034650
    label: cortisol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation to the broad cortisol metabolic process. CYP11B1 produces
      cortisol, so it participates in cortisol metabolism, but the more precise and
      experimentally supported term is the cortisol biosynthetic child term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less specific than GO:0034651 cortisol biosynthetic process (which is
      directly supported by IDA/IMP evidence). Retained as a non-core parent term to avoid
      redundancy with the specific biosynthetic annotation.
    supported_by:
    - reference_id: PMID:18215163
      supporting_text: >-
        The human 11beta-hydroxylase (hCYP11B1) is responsible for the conversion of
        11-deoxycortisol into the major mammalian glucocorticoid, cortisol.
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation to the defining molecular function: steroid
      11-beta-monooxygenase (EC 1.14.15.4). This is the core catalytic activity of CYP11B1.
    action: ACCEPT
    reason: >-
      This is the correct, specific molecular function; it is independently supported by
      multiple experimental (IDA/IMP) annotations and by the UniProt catalytic-activity data.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: 11beta position, yielding cortisol or corticosterone, respectively, but
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic annotation placing CYP11B1 activity at the mitochondrial inner membrane,
      matching the experimentally and homology-supported subcellular location.
    action: ACCEPT
    reason: >-
      CYP11B1 is a mitochondrial inner-membrane peripheral membrane protein; this is the core
      cellular location where its catalysis occurs (with its adrenodoxin electron partners).
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0032342
    label: aldosterone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation to aldosterone biosynthesis, propagated across the CYP11B
      family. Human CYP11B1 lacks efficient 18-oxidase activity and cannot produce
      aldosterone; aldosterone synthesis is the function of the paralog CYP11B2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-annotation from the CYP11B ancestral family. Human CYP11B1 substantially fails to
      form aldosterone; the aldosterone-synthase role belongs to CYP11B2. In some species,
      e.g. bovine, a single CYP11B combines both activities, which is why the phylogenetic
      transfer includes this term.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Due to its lack of 18-oxidation activity, it is incapable of generating
    - reference_id: PMID:2256920
      supporting_text: P-450(11)beta substantially fails to catalyze the
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - PSEUDO_OR_SUBACTIVITY_LOSS
      source_entities:
      - source_id: UniProtKB:P19099
        source_label: CYP11B2 (aldosterone synthase)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Aldosterone synthesis is the function of the paralog CYP11B2; human CYP11B1 lacks
          efficient 18-oxidase activity and cannot complete aldosterone synthesis.
      - source_id: MGI:MGI:88584
        source_label: Cyp11b2
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Mouse aldosterone-synthase paralog; term does not transfer to human CYP11B1.
- term:
    id: GO:0071375
    label: cellular response to peptide hormone stimulus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      CYP11B1 expression/activity in the adrenal cortex is induced by ACTH, a peptide hormone.
      This is a regulatory/physiological response context rather than the enzyme's core
      catalytic role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Biologically reasonable (ACTH is the principal trophic stimulus that drives CYP11B1
      transcription and cortisol output) but peripheral to the core molecular function;
      retained as non-core.
    supported_by:
    - reference_id: PMID:19342457
      supporting_text: >-
        NRSF/NRSE is also involved in angiotensin II- and K(+)-stimulated augmentation of
        CYP11B2 and CYP11B1 gene transcription
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation to cholesterol metabolism, transferred from CYP11-family
      members (with/from includes CYP11A1-type sequences P00189/P05108). CYP11B1 acts on
      C21 steroid substrates (11-deoxycortisol, 11-deoxycorticosterone), not on cholesterol;
      cholesterol side-chain cleavage is performed by CYP11A1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated within the CYP11 family. CYP11B1 does not metabolize cholesterol; its
      substrates are downstream C21 steroids. The cholesterol-metabolizing enzyme of the
      pathway is CYP11A1 (cholesterol side-chain cleavage).
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: UniProtKB:P05108
        source_label: CYP11A1 (cholesterol side-chain cleavage)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          Cholesterol metabolism belongs to CYP11A1; CYP11B1 acts on C21 steroids downstream,
          so the cholesterol term should not transfer.
      - source_id: UniProtKB:P00189
        source_label: CYP11A1 (bovine)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: CYP11A1-type source in the with/from field; not a CYP11B1 activity.
- term:
    id: GO:0047783
    label: corticosterone 18-monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation to 18-monooxygenase activity. CYP11B1 has weak residual
      18-hydroxylase activity (it is described as a steroid 11beta-, 18- and 19-hydroxylase
      with preferred 11beta regioselectivity) but this is a minor side activity; the
      physiologically dominant 18-hydroxylase/oxidase is CYP11B2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Retained as a genuine but minor secondary activity. UniProt notes CYP11B1 acts as a
      steroid 11beta-, 18- and 19-hydroxylase (preferred at 11beta), but its lack of efficient
      18-oxidation is why it cannot complete aldosterone synthesis. Not a core function.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Due to its lack of 18-oxidation activity, it is incapable of generating
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to the general monooxygenase activity, based on the
      cytochrome P450 domain signatures.
    action: ACCEPT
    reason: >-
      Correct parent of the specific steroid 11-beta-monooxygenase activity; a valid, if
      broad, molecular-function annotation for a cytochrome P450.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase mainly involved in the
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (ARBA/RHEA/EC 1.14.15.4) to the core steroid 11-beta-monooxygenase
      activity. Matches the experimentally supported molecular function.
    action: ACCEPT
    reason: >-
      Correct and specific; consistent with UniProt catalytic activity and the experimental
      IDA/IMP annotations for this same term.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: 11beta position, yielding cortisol or corticosterone, respectively, but
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO annotation for iron ion binding, reflecting the catalytic heme iron of the
      cytochrome P450.
    action: ACCEPT
    reason: >-
      Correct: CYP11B1 coordinates a heme iron (axial cysteine ligand at position 450) that
      is essential for oxygen activation. Iron binding is a valid molecular function for this
      heme-thiolate enzyme.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: axial binding residue
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to mitochondrion. Correct but less specific than the
      mitochondrial inner membrane location.
    action: ACCEPT
    reason: >-
      Valid broad localization; the more precise term (mitochondrial inner membrane) is also
      annotated and is the core location.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (UniProt subcellular-location keyword mapping) to mitochondrial
      inner membrane, matching the curated location.
    action: ACCEPT
    reason: >-
      Correct and specific; consistent with the experimental (IC/TAS) and ISS annotations for
      this location.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to sterol metabolic process. CYP11B1's substrates are C21
      steroid hormones (11-deoxycortisol, 11-deoxycorticosterone) rather than sterols such as
      cholesterol; this is a broad and somewhat imprecise term for this enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Steroids are formally sterol derivatives, so the term is not strictly wrong, but it is
      broad and not the enzyme's specific role. The precise processes (glucocorticoid/cortisol
      biosynthesis, C21-steroid hormone biosynthesis) are annotated separately. Retained as
      non-core.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at
- 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: >-
      InterPro2GO annotation to the oxidoreductase (paired-donor, O2-incorporating) class,
      the mechanistic parent of monooxygenase/P450 activity.
    action: ACCEPT
    reason: >-
      Mechanistically correct: CYP11B1 inserts one oxygen atom into the substrate and reduces
      the other to water. A valid broad molecular-function annotation.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase mainly involved in the
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation to heme binding, reflecting the essential heme cofactor of this
      heme-thiolate cytochrome P450.
    action: ACCEPT
    reason: >-
      Correct: CYP11B1 binds heme via an axial cysteine ligand (position 450); heme is
      required for catalysis. Core cofactor-binding function.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Name=heme;
- term:
    id: GO:0032342
    label: aldosterone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to aldosterone biosynthesis, likely propagated across the
      CYP11B family. Human CYP11B1 cannot generate aldosterone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same over-annotation as the IBA aldosterone term: human CYP11B1 lacks 18-oxidase
      activity and does not make aldosterone; this is the function of CYP11B2.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Due to its lack of 18-oxidation activity, it is incapable of generating
    - reference_id: PMID:2256920
      supporting_text: P-450(11)beta substantially fails to catalyze the
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194002
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) annotation from the Glucocorticoid biosynthesis pathway, in which
      CYP11B1 converts 11-deoxycortisol to cortisol.
    action: ACCEPT
    reason: >-
      Core biological process, curator-asserted from the Reactome pathway; consistent with the
      IBA and experimental cortisol-biosynthesis annotations.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Steroid biosynthesis; glucocorticoid biosynthesis.
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211976
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) annotation from the "Endogenous sterols" pathway, a broad grouping of
      CYP-mediated steroidogenic/sterol reactions.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad parent term; CYP11B1's substrates are C21 steroids rather than sterols per se. Not
      wrong, but the specific glucocorticoid/C21-steroid biosynthetic terms capture the core
      role. Retained as non-core.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: deoxycortisol and 11-deoxycorticosterone (21-hydroxyprogesterone) at
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation to glucocorticoid biosynthesis (UPA00788),
      matching the curated pathway assignment.
    action: ACCEPT
    reason: >-
      Correct core biological process, consistent with the UniProt PATHWAY line and the
      experimental cortisol-biosynthesis annotations.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Steroid biosynthesis; glucocorticoid biosynthesis.
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193997
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation from the reaction "CYP11B1 oxidises 11DCORT" (11-deoxycortisol
      to cortisol), the core catalytic activity.
    action: ACCEPT
    reason: >-
      Correct and specific molecular function, curator-asserted from the Reactome reaction.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: 11beta position, yielding cortisol or corticosterone, respectively, but
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5580292
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) annotation from the disease reaction "Defective CYP11B1 does not oxidise
      11DCORT", capturing the same 11beta-hydroxylase molecular function in the context of AH4.
    action: ACCEPT
    reason: >-
      Correct and specific molecular function; the disease-context Reactome event asserts the
      same steroid 11-beta-monooxygenase activity.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: 11beta position, yielding cortisol or corticosterone, respectively, but
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:18215163
  qualifier: enables
  review:
    summary: >-
      Direct experimental demonstration: purified recombinant human CYP11B1 hydroxylates its
      substrates at the 11beta position, converting 11-deoxycortisol to cortisol.
    action: ACCEPT
    reason: >-
      Strong experimental (IDA) support for the core molecular function, from purified-enzyme
      substrate-conversion assays.
    supported_by:
    - reference_id: PMID:18215163
      supporting_text: >-
        The results clearly demonstrate that the enzyme is capable of hydroxylating its
        substrates at position 11-beta.
- term:
    id: GO:0034651
    label: cortisol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18215163
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental support that CYP11B1 carries out the cortisol-forming step
      (11-deoxycortisol -> cortisol), the core biological process.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated with purified enzyme; the defining physiological role of
      CYP11B1.
    supported_by:
    - reference_id: PMID:18215163
      supporting_text: >-
        The human 11beta-hydroxylase (hCYP11B1) is responsible for the conversion of
        11-deoxycortisol into the major mammalian glucocorticoid, cortisol.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity annotation (from ortholog P14137) to the mitochondrial inner
      membrane, matching the curated location.
    action: ACCEPT
    reason: >-
      Correct core location; consistent with the experimental IC/TAS and electronic
      annotations to the same term.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics detected CYP11B1 in the mitochondrion,
      supporting the mitochondrial localization.
    action: ACCEPT
    reason: >-
      Consistent with the curated mitochondrial inner-membrane location; a valid, if broad,
      localization from a high-confidence proteomics dataset.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5580292
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation placing CYP11B1 at the mitochondrial inner membrane, matching
      the curated location.
    action: ACCEPT
    reason: >-
      Correct core location; concordant with the multiple other inner-membrane annotations.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0035865
    label: cellular response to potassium ion
  evidence_type: IEP
  original_reference_id: PMID:19342457
  qualifier: involved_in
  review:
    summary: >-
      Expression-based (IEP) annotation from a study of NRSF/NRSE regulation of CYP11B1 and
      CYP11B2, in which potassium (and angiotensin II) augment CYP11B1/CYP11B2 transcription
      in H295R adrenocortical cells. Potassium sensing is more central to aldosterone
      (CYP11B2) than to cortisol (CYP11B1).
    action: KEEP_AS_NON_CORE
    reason: >-
      The full-text study co-assays CYP11B1, so the annotation is retained (not removed), but
      the potassium response is a regulatory/physiological context that is more salient for the
      aldosterone-synthase paralog; it is peripheral to CYP11B1's core cortisol-synthesis role.
    supported_by:
    - reference_id: PMID:19342457
      supporting_text: >-
        NRSF/NRSE is also involved in angiotensin II- and K(+)-stimulated augmentation of
        CYP11B2 and CYP11B1 gene transcription
- term:
    id: GO:0032342
    label: aldosterone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19342457
  qualifier: involved_in
  review:
    summary: >-
      Mutant/perturbation-phenotype annotation associating CYP11B1 with aldosterone
      production, from a transcriptional-regulation study in which the NRSF perturbation
      affected both CYP11B2 (aldosterone) and CYP11B1 (cortisol). Human CYP11B1 does not
      itself synthesize aldosterone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The paper measures aldosterone and cortisol secretion after modulating the shared
      NRSF/NRSE regulator; aldosterone output reflects CYP11B2 activity, not a CYP11B1
      catalytic role. CYP11B1 cannot make aldosterone, so annotating it to aldosterone
      biosynthesis over-states its function.
    supported_by:
    - reference_id: PMID:19342457
      supporting_text: >-
        Aldosterone synthase (CYP11B2) and 11 beta-hydroxylase (CYP11B1) regulate aldosterone
        and cortisol production, respectively.
    - reference_id: PMID:2256920
      supporting_text: P-450(11)beta substantially fails to catalyze the
- term:
    id: GO:0032870
    label: cellular response to hormone stimulus
  evidence_type: IEP
  original_reference_id: PMID:19342457
  qualifier: involved_in
  review:
    summary: >-
      Expression-based annotation reflecting that CYP11B1 transcription responds to hormonal
      stimuli (e.g. angiotensin II) in adrenocortical cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      A regulatory/physiological response context rather than the enzyme's core molecular
      function; retained as non-core. The more specific "cellular response to peptide hormone
      stimulus" (ACTH) captures the principal trophic input.
    supported_by:
    - reference_id: PMID:19342457
      supporting_text: >-
        NRSF/NRSE is also involved in angiotensin II- and K(+)-stimulated augmentation of
        CYP11B2 and CYP11B1 gene transcription
- term:
    id: GO:0034651
    label: cortisol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19342457
  qualifier: involved_in
  review:
    summary: >-
      Mutant/perturbation-phenotype annotation: modulating NRSF changed CYP11B1 expression and
      cortisol secretion, linking CYP11B1 to cortisol production.
    action: ACCEPT
    reason: >-
      Core biological process; the study demonstrates CYP11B1-dependent cortisol output in
      human adrenocortical cells, consistent with the enzyme's defining role.
    supported_by:
    - reference_id: PMID:19342457
      supporting_text: >-
        Aldosterone synthase (CYP11B2) and 11 beta-hydroxylase (CYP11B1) regulate aldosterone
        and cortisol production, respectively.
- term:
    id: GO:0034651
    label: cortisol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:2022736
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype annotation: an Arg-448->His mutation in CYP11B1 causes steroid
      11beta-hydroxylase deficiency, i.e. failure to convert 11-deoxycortisol to cortisol,
      linking loss of CYP11B1 function to loss of cortisol biosynthesis.
    action: ACCEPT
    reason: >-
      Human genetic loss-of-function evidence directly supports CYP11B1's role in cortisol
      biosynthesis (the deficiency is defined as failure to convert 11-deoxycortisol to
      cortisol).
    supported_by:
    - reference_id: PMID:2022736
      supporting_text: >-
        Steroid 11 beta-hydroxylase (P450c11) deficiency (failure to convert 11-deoxycortisol
        to cortisol) causes less than 10% of cases of congenital adrenal hyperplasia
- term:
    id: GO:0034651
    label: cortisol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8506298
  qualifier: involved_in
  review:
    summary: >-
      In-vitro transfection assays of CYP11B1 missense mutants (which abolish enzyme activity)
      support CYP11B1's role in converting 11-deoxycortisol to cortisol.
    action: ACCEPT
    reason: >-
      Experimental support: the study defines 11beta-hydroxylase deficiency as failure to
      convert 11-deoxycortisol to cortisol and shows the missense mutations abolish enzymatic
      activity, confirming the cortisol-biosynthetic function.
    supported_by:
    - reference_id: PMID:8506298
      supporting_text: >-
        Steroid 11 beta-hydroxylase deficiency (failure to convert 11-deoxycortisol to
        cortisol)
    - reference_id: PMID:8506298
      supporting_text: >-
        all five known missense mutations causing 11 beta-hydroxylase deficiency abolish
        enzymatic activity
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:2256920
  qualifier: enables
  review:
    summary: >-
      Direct assay of the cloned/expressed enzyme in COS-7 cells demonstrating steroid
      11beta-hydroxylase activity (formation of corticosterone from 11-deoxycorticosterone).
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the core molecular function. The paper's primary focus is
      P-450aldo (CYP11B2), but it directly compares and assays P-450(11)beta (CYP11B1), which
      catalyzes 11beta-hydroxylation.
    supported_by:
    - reference_id: PMID:2256920
      supporting_text: >-
        both enzymes catalyze the formation of corticosterone and
        18-hydroxy-11-deoxycorticosterone using 11-deoxycorticosterone as a substrate
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: PMID:15026188
  qualifier: located_in
  review:
    summary: >-
      Review (TAS) asserting the mitochondrial (inner-membrane) localization of the class I
      mitochondrial cytochrome P450 CYP11B1.
    action: ACCEPT
    reason: >-
      Correct core location; the review describes CYP11B1 as a class I mitochondrial
      cytochrome P450 that receives electrons from the adrenodoxin system.
    supported_by:
    - reference_id: PMID:15026188
      supporting_text: >-
        The CYP11B family belongs to class I cytochromes P450 that have been described in
        bacteria and mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IC
  original_reference_id: PMID:8506298
  qualifier: located_in
  review:
    summary: >-
      Curator-inferred (IC) mitochondrial inner-membrane localization, based on the
      steroid 11-beta-monooxygenase activity (GO:0004507) of this mitochondrial P450.
    action: ACCEPT
    reason: >-
      Consistent with all other localization evidence; CYP11B1 is a mitochondrial
      inner-membrane enzyme.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:2256920
  qualifier: involved_in
  review:
    summary: >-
      Direct assay showing CYP11B1 (P-450(11)beta) produces the C21 steroid corticosterone
      from 11-deoxycorticosterone, supporting a role in C21-steroid hormone biosynthesis.
    action: ACCEPT
    reason: >-
      Cortisol and corticosterone are C21 steroids; CYP11B1's products place it correctly in
      C21-steroid hormone biosynthesis. Experimentally supported.
    supported_by:
    - reference_id: PMID:2256920
      supporting_text: >-
        both enzymes catalyze the formation of corticosterone and
        18-hydroxy-11-deoxycorticosterone using 11-deoxycorticosterone as a substrate
- term:
    id: GO:0006955
    label: immune response
  evidence_type: TAS
  original_reference_id: PMID:12452430
  qualifier: involved_in
  review:
    summary: >-
      Review (TAS) annotation to immune response. Glucocorticoids (cortisol) are potent
      immunomodulators, but this is a downstream physiological effect of CYP11B1's product,
      not a molecular/cellular function of the enzyme itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      CYP11B1 does not itself participate in the immune response; the connection is indirect,
      via the anti-inflammatory/immunomodulatory actions of the cortisol it produces.
      Annotating the enzyme to "immune response" over-extends its function.
    supported_by:
    - reference_id: PMID:12452430
      supporting_text: >-
        the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2, which catalyze
        the final steps in the biosynthesis of cortisol and aldosterone
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: IMP
  original_reference_id: PMID:2022736
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype annotation linking CYP11B1 deficiency to a hypertensive form of
      congenital adrenal hyperplasia. Loss of 11beta-hydroxylase causes accumulation of the
      mineralocorticoid precursor 11-deoxycorticosterone, driving hypertension.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine but downstream physiological consequence of CYP11B1 dysfunction (via DOC
      excess) rather than a direct enzymatic function; retained as non-core.
    supported_by:
    - reference_id: PMID:8506298
      supporting_text: >-
        Steroid 11 beta-hydroxylase deficiency (failure to convert 11-deoxycortisol to
        cortisol) is the second most common cause of congenital adrenal hyperplasia and
        results in a hypertensive form of the disease.
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IC
  original_reference_id: PMID:2256920
  qualifier: enables
  review:
    summary: >-
      Curator-inferred (IC) heme binding, from the steroid 11-beta-monooxygenase activity of
      this heme-thiolate cytochrome P450.
    action: ACCEPT
    reason: >-
      Correct core cofactor-binding function; CYP11B1 binds heme via an axial cysteine ligand
      and requires it for catalysis. A mutation in the heme-binding peptide (Arg-448->His)
      causes deficiency.
    supported_by:
    - reference_id: PMID:2022736
      supporting_text: >-
        This residue is within the "heme binding" peptide that contains a cysteine that is a
        ligand to the heme group.
- term:
    id: GO:0032342
    label: aldosterone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:2256920
  qualifier: involved_in
  review:
    summary: >-
      Annotation to aldosterone biosynthesis from a study whose primary aldosterone-forming
      enzyme is P-450aldo (CYP11B2). The same paper shows P-450(11)beta (CYP11B1) substantially
      fails to form aldosterone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Although CYP11B1 shares 93% identity with CYP11B2 and can make corticosterone
      precursors, this reference explicitly states CYP11B1 substantially fails to catalyze the
      reaction to form aldosterone. Aldosterone biosynthesis is the function of CYP11B2, so
      this is an over-annotation for CYP11B1.
    supported_by:
    - reference_id: PMID:2256920
      supporting_text: >-
        P-450(11)beta substantially fails to catalyze the reaction to form aldosterone
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IMP
  original_reference_id: PMID:2022736
  qualifier: enables
  review:
    summary: >-
      Mutant-phenotype annotation: the Arg-448->His mutation in the heme-binding region
      abolishes/impairs steroid 11beta-hydroxylase activity, supporting the molecular function.
    action: ACCEPT
    reason: >-
      Human loss-of-function genetics supports the steroid 11-beta-monooxygenase activity; the
      mutation lies in the heme-binding peptide and is expected to disrupt catalysis.
    supported_by:
    - reference_id: PMID:2022736
      supporting_text: >-
        it seems likely that a mutation of this residue would adversely affect enzymatic
        activity
- term:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:8506298
  qualifier: enables
  review:
    summary: >-
      In-vitro transfection assays show that missense mutations causing 11beta-hydroxylase
      deficiency abolish enzymatic activity, directly supporting the steroid
      11-beta-monooxygenase molecular function.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the core molecular function via functional assays of
      wild-type versus mutant CYP11B1.
    supported_by:
    - reference_id: PMID:8506298
      supporting_text: >-
        all five known missense mutations causing 11 beta-hydroxylase deficiency abolish
        enzymatic activity
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:2256920
  qualifier: located_in
  review:
    summary: >-
      Direct-assay localization of the expressed enzyme to the mitochondrion.
    action: ACCEPT
    reason: >-
      Consistent with the curated mitochondrial inner-membrane location; a valid broad
      localization.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: TAS
  original_reference_id: PMID:16114325
  qualifier: involved_in
  review:
    summary: >-
      Review/case (TAS) annotation to glucose homeostasis, reflecting that cortisol (a
      glucocorticoid produced via CYP11B1) raises blood glucose and its deficiency can cause
      hypoglycemia.
    action: KEEP_AS_NON_CORE
    reason: >-
      A downstream physiological role of the cortisol product (glucocorticoids promote
      gluconeogenesis), not a direct enzymatic function of CYP11B1. Retained as non-core.
    supported_by:
    - reference_id: PMID:16114325
      supporting_text: Hypoglycemia due to a disorder of adrenal cortical regulation
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193997
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation placing CYP11B1 at the mitochondrial inner membrane in the
      "CYP11B1 oxidises 11DCORT" reaction.
    action: ACCEPT
    reason: >-
      Correct core location; concordant with the multiple other inner-membrane annotations and
      the Reactome statement that CYP11B1 is associated with the inner mitochondrial membrane.
    supported_by:
    - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
      supporting_text: Mitochondrion inner membrane
core_functions:
- description: >-
    Steroid 11-beta-monooxygenase (11beta-hydroxylase) catalysing the final step of cortisol
    biosynthesis at the mitochondrial inner membrane, converting 11-deoxycortisol to cortisol
    (and 11-deoxycorticosterone to corticosterone), using heme and the adrenodoxin electron
    system.
  molecular_function:
    id: GO:0004507
    label: steroid 11-beta-monooxygenase activity
  directly_involved_in:
  - id: GO:0034651
    label: cortisol biosynthetic process
  - id: GO:0006704
    label: glucocorticoid biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:18215163
    supporting_text: >-
      The human 11beta-hydroxylase (hCYP11B1) is responsible for the conversion of
      11-deoxycortisol into the major mammalian glucocorticoid, cortisol.
  - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
    supporting_text: Steroid biosynthesis; glucocorticoid biosynthesis.
- description: >-
    Heme cofactor binding required for oxygen activation by this heme-thiolate cytochrome
    P450 (axial cysteine ligand at position 450). Secondary to the catalytic
    11-beta-monooxygenase function.
  molecular_function:
    id: GO:0020037
    label: heme binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: file:human/CYP11B1/CYP11B1-uniprot.txt
    supporting_text: axial binding residue
  - reference_id: PMID:2022736
    supporting_text: >-
      This residue is within the "heme binding" peptide that contains a cysteine that is a
      ligand to the heme group.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  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/CYP11B1/CYP11B1-uniprot.txt
  title: UniProtKB entry P15538 (C11B1_HUMAN), Cytochrome P450 11B1, mitochondrial
  findings: []
- id: PMID:12452430
  title: The human steroid hydroxylases CYP1B1 and CYP11B2.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Review confirming CYP11B1 and CYP11B2 are mitochondrial cytochrome P450 enzymes
      catalysing the final steps of cortisol and aldosterone biosynthesis, respectively.
      Used to contextualise the immune-response annotation as a downstream product effect.
- id: PMID:15026188
  title: Modulation of aldosterone and cortisol synthesis on the molecular level.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Review establishing that CYP11B1/CYP11B2 are 93% identical class I mitochondrial P450s
      that receive electrons from adrenodoxin; supports inner-membrane localization and the
      paralog relationship.
- id: PMID:16114325
  title: '[Hypoglycemia due to a disorder of adrenal cortical regulation].'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Older French case report on hypoglycemia from adrenocortical dysregulation; supports the
      non-core glucose-homeostasis annotation only indirectly (cortisol effect on glucose).
- id: PMID:18215163
  title: Purification and functional characterization of human 11beta hydroxylase
    expressed in Escherichia coli.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary biochemical characterization of purified recombinant human CYP11B1;
      demonstrates 11beta-hydroxylation of 11-deoxycortisol to cortisol via the ferredoxin
      electron system. Directly establishes the core molecular function and process.
- id: PMID:19342457
  title: Regulation of aldosterone and cortisol production by the transcriptional
    repressor neuron restrictive silencer factor.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Transcriptional-regulation study (NRSF/NRSE, K+/AngII) in H295R cells co-assaying
      CYP11B1 and CYP11B2. Supports the regulatory/non-core annotations; the aldosterone
      annotation on CYP11B1 is an over-annotation since aldosterone output reflects CYP11B2.
- id: PMID:2022736
  title: A mutation in CYP11B1 (Arg-448
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Stored title is truncated by the reference-cache parser, which splits the cached
      publication file on the "---" that occurs inside the "Arg-448----His" arrow in the
      full title; the truncated form is recorded here only so validation resolves against
      the fetched value. Full title: "A mutation in CYP11B1 (Arg-448->His) associated with
      steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin." (White et al., J
      Clin Invest 1991). Human genetics: Arg-448->His in the heme-binding peptide causes
      11beta-hydroxylase deficiency (failure to convert 11-deoxycortisol to cortisol).
      Supports the molecular function, cortisol biosynthesis, heme binding, and
      blood-pressure (hypertension) roles.
- id: PMID:2256920
  title: Cloning and expression of a cDNA for human cytochrome P-450aldo as related
    to primary aldosteronism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary paper focuses on P-450aldo (CYP11B2) but directly assays and compares
      P-450(11)beta (CYP11B1): both make corticosterone from DOC, but CYP11B1 substantially
      fails to form aldosterone. Key evidence that the aldosterone annotations on CYP11B1 are
      over-annotations, while supporting the 11beta-hydroxylase / C21-steroid function.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteomics; corroborates mitochondrial localization of
      CYP11B1 but does not add functional detail.
- id: PMID:8506298
  title: Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and
    hypertension cluster in exons 6, 7, and 8.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human genetics/functional assays: missense mutations causing 11beta-hydroxylase
      deficiency abolish enzymatic activity; deficiency is the second most common CAH and is
      hypertensive. Supports molecular function, cortisol biosynthesis, and blood-pressure
      roles.
- id: Reactome:R-HSA-193997
  title: CYP11B1 oxidises 11DCORT
  findings: []
- id: Reactome:R-HSA-194002
  title: Glucocorticoid biosynthesis
  findings: []
- id: Reactome:R-HSA-211976
  title: Endogenous sterols
  findings: []
- id: Reactome:R-HSA-5580292
  title: Defective CYP11B1 does not oxidise 11DCORT
  findings: []