id: P26439
gene_symbol: HSD3B2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HSD3B2 is the type-2 (adrenal and gonadal) 3 beta-hydroxysteroid dehydrogenase /
  steroid Delta-5-->Delta-4 isomerase, a bifunctional NAD+-dependent membrane enzyme
  that catalyzes an obligatory early step common to the synthesis of all classes of
  steroid hormones. It performs two sequential reactions on the same active site:
  NAD+-dependent oxidation of the 3beta-hydroxyl group (dehydrogenase, EC 1.1.1.145)
  followed by isomerization of the Delta5 double bond to Delta4 (isomerase, EC 5.3.3.1),
  converting pregnenolone to progesterone, 17-hydroxypregnenolone to 17-hydroxyprogesterone,
  and dehydroepiandrosterone (DHEA) to androstenedione. Because these Delta5 precursors
  must be converted to their Delta4-3-ketosteroid counterparts before glucocorticoid,
  mineralocorticoid, progestin, and sex-steroid pathways can proceed, HSD3B2 sits at a
  common branch point upstream of gluco/mineralocorticoid and sex-steroid biosynthesis.
  The active enzyme is a homodimer localized primarily to the endoplasmic reticulum
  membrane (with reported mitochondrial-membrane localization) as a single-pass membrane
  protein, and it is expressed almost exclusively in the adrenal gland, testis and ovary
  (type 1, HSD3B1, is the placenta/skin isozyme). Loss-of-function mutations cause
  3beta-hydroxysteroid-dehydrogenase-deficiency congenital adrenal hyperplasia (adrenal
  hyperplasia 2, AH2), presenting with impaired cortisol synthesis, salt-wasting, and
  ambiguous genitalia.
alternative_products:
- name: '1'
  id: P26439-1
- name: '2'
  id: P26439-2
  sequence_note: VSP_037399, VSP_037400
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      IBA cytoplasm annotation from the 3-beta-HSD phylogenetic family tree. HSD3B2 is
      a single-pass membrane protein of the endoplasmic reticulum (and mitochondrial)
      membrane; "cytoplasm" is a generic, correct-but-uninformative location that does
      not capture the specific ER-membrane site where the enzyme acts.
    action: KEEP_AS_NON_CORE
    reason: >-
      Too general to be a core cellular-component statement given the more specific
      endoplasmic-reticulum-membrane annotations; retained as non-core context.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Single-pass membrane protein"
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      IBA molecular-function annotation to a generic NAD/NADP-dependent CH-OH
      oxidoreductase parent term. This correctly captures the dehydrogenase half of the
      enzyme but is a parent of the specific 3-beta-hydroxy-Delta5-steroid dehydrogenase
      (NAD+) activity (GO:0003854) that HSD3B2 actually performs.
    action: MODIFY
    reason: >-
      Correct branch but too shallow; the specific dehydrogenase activity GO:0003854 is
      experimentally supported and should be used as the core molecular function. The
      IBA family node for the broad 3-beta-HSD / SDR clade spans members with varied
      CH-OH oxidoreductase specificities, so the family-level term is pitched at the
      generic NAD/NADP CH-OH oxidoreductase parent rather than the HSD3B2-specific
      3beta-hydroxy-Delta5-steroid dehydrogenase activity.
    proposed_replacement_terms:
    - id: GO:0003854
      label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "3-beta-HSD is a bifunctional enzyme, that catalyzes the"
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA biological-process annotation to steroid biosynthetic process. This is the
      correct core process: HSD3B2 catalyzes an obligatory early step in the synthesis
      of all classes of steroid hormones.
    action: ACCEPT
    reason: >-
      Matches the experimentally supported (IDA/IMP) steroid-biosynthetic role of the
      enzyme and is at an appropriate level of generality for a common upstream step.
    supported_by:
    - reference_id: PMID:1944309
      supporting_text: >-
        catalyzes the oxidation and isomerization of delta 5-3 beta-hydroxysteroid
        precursors into delta 4-ketosteroids, thus leading to the formation of all
        classes of steroid hormones
- term:
    id: GO:0008207
    label: C21-steroid hormone metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA annotation to C21-steroid hormone metabolic process. HSD3B2 converts the C21
      Delta5 precursors pregnenolone and 17-hydroxypregnenolone to progesterone and
      17-hydroxyprogesterone, so it genuinely participates in C21-steroid metabolism,
      but this is one downstream branch rather than the enzyme's core role.
    action: KEEP_AS_NON_CORE
    reason: >-
      True sub-role, but the core process is the more general steroid biosynthetic
      process common to all hormone classes (including C19 androgens); retained as
      non-core.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Reaction=pregnenolone + NAD(+) = pregn-5-ene-3,20-dione + NADH + H(+)"
- term:
    id: GO:0003854
    label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      IEA (RHEA/EC 1.1.1.145) annotation of the specific dehydrogenase activity. This is
      one of the two core molecular functions and is corroborated by experimental
      IDA/IMP annotations to the same term.
    action: ACCEPT
    reason: >-
      Accurately captures the NAD+-dependent 3beta-hydroxy-Delta5-steroid dehydrogenase
      half of this bifunctional enzyme.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "EC=1.1.1.145"
- term:
    id: GO:0004022
    label: alcohol dehydrogenase (NAD+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      IEA annotation derived from RHEA:43924 (pregnenolone + NAD+ = pregn-5-ene-3,20-dione
      + NADH). The mapping resolved the reaction to the generic "alcohol dehydrogenase
      (NAD+) activity" term, but the substrate is a steroid 3beta-hydroxyl, not a simple
      alcohol; the biologically informative term is 3-beta-hydroxy-Delta5-steroid
      dehydrogenase (NAD+) activity (GO:0003854).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      RHEA-to-GO auto-mapping artifact: over-broad/misleading generalization of a
      steroid dehydrogenase to generic alcohol dehydrogenase. The specific term is
      already present.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Reaction=pregnenolone + NAD(+) = pregn-5-ene-3,20-dione + NADH + H(+)"
- term:
    id: GO:0004769
    label: steroid Delta-isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      IEA (RHEA/EC 5.3.3.1) annotation of the steroid Delta-isomerase activity, the
      second catalytic function of this bifunctional enzyme (Delta5-3-ketosteroid to
      Delta4-3-ketosteroid isomerization). Corroborated by experimental IDA/IMP.
    action: ACCEPT
    reason: >-
      Accurately captures the isomerase half of the enzyme; a genuine core molecular
      function.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "EC=5.3.3.1"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      IEA annotation from UniProt subcellular-location mapping to endoplasmic reticulum
      membrane, the primary experimentally supported site of HSD3B2. Consistent with
      EXP/TAS and IDA (ER) annotations.
    action: ACCEPT
    reason: >-
      Correct primary localization; the enzyme is a single-pass ER-membrane protein.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      IEA (InterPro/UniPathway) annotation to steroid biosynthetic process, duplicating
      the experimentally supported core biological process.
    action: ACCEPT
    reason: >-
      Correct core process, consistent with IDA/IMP/IBA annotations to the same term.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Lipid metabolism; steroid biosynthesis"
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA IEA annotation to androgen biosynthetic process. HSD3B2 converts DHEA to
      androstenedione, a committed step in androgen synthesis, so this is a true
      downstream branch of its steroidogenic role. It is corroborated by an experimental
      IMP to the same term (PMID:25322271).
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine sub-role, but one of several downstream hormone-class branches; the core
      process is the general steroid biosynthetic process. Retained as non-core.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        conversion of pregnenolone to progesterone and dehydroepiandrosterone to
        androstenedione
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO IEA to the generic NAD/NADP CH-OH oxidoreductase parent term. Correct
      branch but a parent of the specific dehydrogenase activity GO:0003854.
    action: MODIFY
    reason: >-
      Too shallow; supersede with the specific 3-beta-hydroxy-Delta5-steroid
      dehydrogenase (NAD+) activity that is experimentally supported.
    proposed_replacement_terms:
    - id: GO:0003854
      label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "EC=1.1.1.145"
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      IEA annotation from UniProt subcellular-location mapping to mitochondrial membrane.
      UniProt records a mitochondrion-membrane single-pass localization in addition to
      the ER, but the primary, experimentally supported site is the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary/weaker localization relative to the experimentally supported ER membrane;
      retained as non-core.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Mitochondrion membrane; Single-pass membrane protein"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      IntAct IPI "protein binding" annotations to GLE1 (Q53GS7) and SPRED1 (Q7Z699),
      derived from a large-scale neurodegenerative-disease yeast two-hybrid interactome
      screen. These are high-throughput binary interactions with no established
      relevance to the steroidogenic function of HSD3B2, and "protein binding" is an
      uninformative molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" from a high-throughput Y2H interactome; not informative
      about HSD3B2 function. Flagged as over-annotated rather than removed, per policy
      for experimental IPI evidence.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "P26439; Q53GS7: GLE1; NbExp=3"
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "P26439; Q7Z699: SPRED1; NbExp=3"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence IDA localizing HSD3B2 to the endoplasmic reticulum,
      consistent with the enzyme being an ER-membrane steroidogenic protein.
    action: ACCEPT
    reason: >-
      Direct imaging evidence for the primary subcellular compartment.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "endoplasmic reticulum; IDA:HPA"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:25322271
  qualifier: located_in
  review:
    summary: >-
      Experimental (immunofluorescence/Western in COS-7 cells) localization to the
      endoplasmic reticulum membrane; the pathogenic G250V variant retained normal ER
      localization, confirming the wild-type ER-membrane site.
    action: ACCEPT
    reason: >-
      Experimentally supported primary localization; core cellular component.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        p.G250V mutation has no effect on the expression and intracellular localization
        of the mutant protein
- term:
    id: GO:0003854
    label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
  evidence_type: IMP
  original_reference_id: PMID:25322271
  qualifier: enables
  review:
    summary: >-
      IMP evidence: the G250V HSD3B2 mutant showed markedly reduced activity for the
      NAD+-dependent conversion of pregnenolone to progesterone and DHEA to
      androstenedione, demonstrating the wild-type 3beta-hydroxy-Delta5-steroid
      dehydrogenase activity.
    action: ACCEPT
    reason: >-
      Mutant loss-of-function directly supports this core dehydrogenase activity.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal
        and gonad steroid biosynthesis, converting Δ5-steroids to Δ4-steroids
- term:
    id: GO:0004769
    label: steroid Delta-isomerase activity
  evidence_type: IMP
  original_reference_id: PMID:25322271
  qualifier: enables
  review:
    summary: >-
      IMP evidence for the isomerase half of the bifunctional enzyme; the two-step
      conversion of Delta5 precursors to Delta4 products (impaired by the G250V variant)
      requires the Delta5-3-ketosteroid isomerase activity.
    action: ACCEPT
    reason: >-
      Mutant loss-of-function supports this core isomerase activity of the bifunctional
      enzyme.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal
        and gonad steroid biosynthesis, converting Δ5-steroids to Δ4-steroids
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IMP
  original_reference_id: PMID:25322271
  qualifier: located_in
  review:
    summary: >-
      IMP/EXP evidence localizing HSD3B2 to the endoplasmic reticulum; the G250V variant
      did not alter ER localization.
    action: ACCEPT
    reason: >-
      Experimentally supported ER localization.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        p.G250V mutation has no effect on the expression and intracellular localization
        of the mutant protein
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:25322271
  qualifier: involved_in
  review:
    summary: >-
      IMP evidence: loss-of-function HSD3B2 mutation impairs steroid biosynthesis
      (pregnenolone-to-progesterone and DHEA-to-androstenedione conversion), directly
      supporting the steroid biosynthetic process role.
    action: ACCEPT
    reason: >-
      Core biological process supported by mutant phenotype and the human CAH disease
      mechanism.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        3βHSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by
        recessive loss-of-function HSD3B2 mutations
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:25322271
  qualifier: involved_in
  review:
    summary: >-
      IMP evidence: the G250V mutant had impaired conversion of DHEA to androstenedione,
      supporting a role in androgen biosynthesis. This is a genuine downstream branch of
      the enzyme's steroidogenic function rather than its single core process.
    action: KEEP_AS_NON_CORE
    reason: >-
      True sub-role (DHEA-to-androstenedione), but one of several hormone-class branches;
      core process is the general steroid biosynthetic process.
    supported_by:
    - reference_id: PMID:25322271
      supporting_text: >-
        conversion of pregnenolone to progesterone and dehydroepiandrosterone to
        androstenedione
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193052
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS: the isomerization of pregn-5-ene-3,20-dione to progesterone is
      catalyzed by 3-beta-HSD associated with the endoplasmic reticulum membrane.
      Consistent with the experimentally supported ER-membrane localization.
    action: ACCEPT
    reason: >-
      Reactome-curated ER-membrane localization for a specific HSD3B2-catalyzed reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-193052
      supporting_text: >-
        This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated
        with the endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193073
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS: the two-step oxidation/isomerization of DHEA to androstenedione is
      catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane.
    action: ACCEPT
    reason: >-
      Reactome-curated ER-membrane localization for an HSD3B2-catalyzed androgen-pathway
      reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-193073
      supporting_text: >-
        two-step reaction catalyzed by 3beta-HSD associated with the endoplasmic
        reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193961
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS: isomerization of pregn-5-ene-3,20-dione-17-ol to 17-hydroxyprogesterone
      is catalyzed by 3-beta-HSD associated with the endoplasmic reticulum membrane.
    action: ACCEPT
    reason: >-
      Reactome-curated ER-membrane localization for an HSD3B2-catalyzed reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-193961
      supporting_text: >-
        This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated
        with the endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196350
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS: NAD+-dependent dehydrogenation of pregnenolone to pregn-5-ene-3,20-dione
      by 3beta-HSD associated with the endoplasmic reticulum membrane.
    action: ACCEPT
    reason: >-
      Reactome-curated ER-membrane localization for the HSD3B2 dehydrogenase reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-196350
      supporting_text: >-
        catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid
        dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic
        reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196372
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS: NAD+-dependent dehydrogenation of 17-hydroxypregnenolone to
      pregn-5-ene-3,20-dione-17-ol by 3beta-HSD associated with the endoplasmic reticulum
      membrane.
    action: ACCEPT
    reason: >-
      Reactome-curated ER-membrane localization for the HSD3B2 dehydrogenase reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-196372
      supporting_text: >-
        catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid
        dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic
        reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: NAS
  original_reference_id: PMID:1944309
  qualifier: located_in
  review:
    summary: >-
      NAS annotation of endoplasmic-reticulum localization from the original type-II
      cloning paper. Consistent with the later IDA/EXP ER-membrane evidence.
    action: ACCEPT
    reason: >-
      Correct primary compartment, corroborated by direct experimental evidence.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "endoplasmic reticulum; IDA:HPA"
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: NAS
  original_reference_id: PMID:1944309
  qualifier: located_in
  review:
    summary: >-
      NAS annotation of mitochondrial-membrane localization from the original type-II
      cloning paper. UniProt records a mitochondrion-membrane site in addition to the
      ER, but the ER membrane is the primary experimentally supported location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary localization relative to the well-supported ER membrane; retained as
      non-core.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Mitochondrion membrane; Single-pass membrane protein"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:1944309
  qualifier: located_in
  review:
    summary: >-
      NAS annotation to the generic "membrane" term. HSD3B2 is indeed a single-pass
      membrane protein, but this is an uninformative parent of the specific
      endoplasmic-reticulum-membrane localization.
    action: MODIFY
    reason: >-
      Too general; supersede with the specific ER-membrane term that is experimentally
      supported.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "Single-pass membrane protein"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation of mitochondrial-inner-membrane localization transferred from the
      rat ortholog (UniProtKB:P14060). This sub-mitochondrial placement is not supported
      by direct human evidence, which localizes HSD3B2 primarily to the ER membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-specific sub-mitochondrial localization inferred by similarity, beyond what
      is supported for the human enzyme; the primary experimentally supported site is
      the ER membrane.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation of mitochondrial-intermembrane-space localization transferred from
      the rat ortholog (UniProtKB:P14060). Not supported by direct human evidence; the
      primary experimentally supported site is the ER membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-specific sub-mitochondrial localization inferred by similarity, beyond what
      is supported for the human enzyme.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0030868
    label: smooth endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation to smooth-ER membrane transferred from the human type-I ortholog
      (UniProtKB:P14893). Consistent with an ER-membrane localization; smooth-ER is the
      steroidogenic ER subdomain, though human HSD3B2 evidence is annotated to the more
      general ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible ER-subdomain refinement by similarity; retained as non-core relative to
      the directly supported ER-membrane annotation.
    supported_by:
    - reference_id: file:human/HSD3B2/HSD3B2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0003854
    label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
  evidence_type: IDA
  original_reference_id: PMID:1944309
  qualifier: enables
  review:
    summary: >-
      IDA: direct enzymatic assay of expressed type-II 3beta-HSD with NAD+ and
      3H-pregnenolone/DHEA demonstrated 3beta-hydroxysteroid dehydrogenase activity
      (with measured Km values). Core molecular function.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of the NAD+-dependent dehydrogenase activity.
    supported_by:
    - reference_id: PMID:1944309
      supporting_text: >-
        In vitro incubation with NAD+ and 3H-labeled pregnenolone or
        dehydroepiandrosterone shows that the type I protein possesses a 3 beta
        HSD/delta 5-delta 4 isomerase activity higher than type II
- term:
    id: GO:0004769
    label: steroid Delta-isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:1944309
  qualifier: enables
  review:
    summary: >-
      IDA: the same expressed type-II enzyme catalyzed the oxidation and isomerization
      of Delta5-3beta-hydroxysteroid precursors into Delta4-ketosteroids, demonstrating
      the steroid Delta-isomerase activity of the bifunctional enzyme.
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of the Delta5-Delta4 isomerase activity.
    supported_by:
    - reference_id: PMID:1944309
      supporting_text: >-
        catalyzes the oxidation and isomerization of delta 5-3 beta-hydroxysteroid
        precursors into delta 4-ketosteroids
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1944309
  qualifier: involved_in
  review:
    summary: >-
      IDA: the demonstrated dehydrogenase/isomerase activity leads to the formation of
      all classes of steroid hormones, directly supporting participation in steroid
      biosynthesis. Core biological process.
    action: ACCEPT
    reason: >-
      Direct experimental support for the steroid biosynthetic role.
    supported_by:
    - reference_id: PMID:1944309
      supporting_text: >-
        thus leading to the formation of all classes of steroid hormones
core_functions:
- description: >-
    NAD+-dependent 3-beta-hydroxy-Delta5-steroid dehydrogenase: oxidizes the 3beta-hydroxyl
    group of Delta5-3beta-hydroxysteroids (pregnenolone, 17-hydroxypregnenolone, DHEA) to
    3-oxo-Delta5-steroids using NAD+, the first catalytic step of the bifunctional enzyme in
    steroid hormone biosynthesis.
  molecular_function:
    id: GO:0003854
    label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
  directly_involved_in:
  - id: GO:0006694
    label: steroid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:1944309
    supporting_text: >-
      In vitro incubation with NAD+ and 3H-labeled pregnenolone or dehydroepiandrosterone
      shows that the type I protein possesses a 3 beta HSD/delta 5-delta 4 isomerase
      activity higher than type II
  - reference_id: PMID:25322271
    supporting_text: >-
      3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and
      gonad steroid biosynthesis, converting Δ5-steroids to Δ4-steroids
- description: >-
    Steroid Delta-isomerase: isomerizes the Delta5 double bond of the 3-oxo-Delta5-steroid
    intermediate to Delta4, yielding the 3-oxo-Delta4-steroid products (progesterone,
    17-hydroxyprogesterone, androstenedione); the second catalytic step of the bifunctional
    enzyme in steroid hormone biosynthesis.
  molecular_function:
    id: GO:0004769
    label: steroid Delta-isomerase activity
  directly_involved_in:
  - id: GO:0006694
    label: steroid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:1944309
    supporting_text: >-
      catalyzes the oxidation and isomerization of delta 5-3 beta-hydroxysteroid precursors
      into delta 4-ketosteroids
  - reference_id: PMID:25322271
    supporting_text: >-
      3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and
      gonad steroid biosynthesis, converting Δ5-steroids to Δ4-steroids
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: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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea 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: PMID:1944309
  title: Structure and expression of a new complementary DNA encoding the almost exclusive
    3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase in human adrenals
    and gonads.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original type-II 3beta-HSD cloning and kinetic characterization; PubMed-verified.
      Directly establishes the bifunctional dehydrogenase/isomerase activity and the
      adrenal/gonad-specific expression of HSD3B2.
- id: PMID:25322271
  title: A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting
    congenital adrenal hyperplasia. new insight into the structure-function relationships
    of 3β-hydroxysteroid dehidrogenase type II.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional study of the G250V CAH variant; PubMed-verified. Supports the
      bifunctional NAD+-dependent activity, the ER-membrane localization, and the
      steroid/androgen biosynthetic role of HSD3B2.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale neurodegenerative-disease yeast two-hybrid interactome; PubMed-verified.
      Source of the IntAct "protein binding" IPIs (GLE1, SPRED1) but does not inform the
      steroidogenic function of HSD3B2.
- id: file:human/HSD3B2/HSD3B2-uniprot.txt
  title: UniProtKB P26439 (3BHS2_HUMAN) HSD3B2 record
  findings:
  - statement: >-
      HSD3B2 is a bifunctional NAD+-dependent enzyme catalyzing the dehydrogenation and
      Delta5-Delta4 isomerization steps common to synthesis of all steroid hormone classes.
    supporting_text: >-
      3-beta-HSD is a bifunctional enzyme, that catalyzes the
  - statement: >-
      Localized to the endoplasmic reticulum membrane as a single-pass membrane protein,
      with reported mitochondrion-membrane localization; expressed in adrenal gland, testis
      and ovary.
    supporting_text: >-
      SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
- id: Reactome:R-HSA-193052
  title: Pregn-5-ene-3,20-dione isomerizes to progesterone
  findings: []
- id: Reactome:R-HSA-193073
  title: HSD2B1 dimer, HSD3B2 dimer isomerise DHA to ANDST
  findings: []
- id: Reactome:R-HSA-193961
  title: Pregn-5-ene-3,20-dione-17-ol isomerizes to 17-hydroxyprogesterone
  findings: []
- id: Reactome:R-HSA-196350
  title: Pregnenolone is dehydrogenated to form pregn-5-ene-3,20-dione
  findings: []
- id: Reactome:R-HSA-196372
  title: 17-Hydroxypregnenolone is dehydrogenated to form pregn-5-ene-3,20-dione-17-ol
  findings: []