id: P37058
gene_symbol: HSD17B3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Testis-specific 17-beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3), a
  member of the short-chain dehydrogenase/reductase (SDR) superfamily. It is an
  NADPH-dependent oxidoreductase anchored in the endoplasmic reticulum membrane
  that catalyses the final step of testosterone biosynthesis: reduction of the
  17-keto group of androstenedione (androst-4-ene-3,17-dione) to the 17beta-hydroxyl,
  yielding testosterone. It reduces additional 17-ketosteroids (e.g.
  dehydroepiandrosterone, epiandrosterone, androstanedione, and 11-oxygenated C19
  steroids), and can also interconvert estrone and 17beta-estradiol. Expressed
  predominantly in the testis, where it supplies the androgen needed for
  masculinization. Loss-of-function mutations cause an autosomal-recessive 46,XY
  disorder of sex development (17beta-HSD3 deficiency; male pseudohermaphroditism
  with gynecomastia), in which affected 46,XY individuals are undervirilized and
  show a characteristically decreased plasma testosterone-to-androstenedione ratio.
alternative_products:
- name: '1'
  id: P37058-1
- name: '2'
  id: P37058-2
  sequence_note: VSP_056640
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) localization to the endoplasmic reticulum. HSD17B3 is an
      ER-membrane-anchored SDR enzyme; direct human experimental data and Reactome
      agree, so this is accurate.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally determined ER localization of the human
      enzyme and its N-terminal membrane anchor. A more specific ER membrane term
      exists (see GO:0005789) but the parent ER term is correct.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum"
- term:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the core catalytic function: NADP-dependent
      testosterone 17beta-dehydrogenase activity (testosterone + NADP+ <->
      androstenedione + NADPH), the physiological direction being reduction of
      androstenedione to testosterone.
    action: ACCEPT
    reason: >-
      This is the defining molecular function of HSD17B3, supported by direct human
      enzymology. The IBA agrees with IDA and TAS annotations of the same term.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH"
    - reference_id: PMID:8075637
      supporting_text: "uses NADPh as a cofactor, and"
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment to steroid biosynthesis. HSD17B3 acts in
      androgen/testosterone biosynthesis, which is a steroid biosynthetic process.
    action: ACCEPT
    reason: >-
      Correct but general. The more specific androgen/testosterone biosynthetic
      process terms (GO:0006702, GO:0061370) better capture the role; this parent
      term is retained as accurate context.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "Hormone biosynthesis; testosterone biosynthesis."
- term:
    id: GO:0004303
    label: estradiol 17-beta-dehydrogenase [NAD(P)+] activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      IEA (EC 1.1.1.62 / Rhea) mapping to estradiol 17-beta-dehydrogenase activity.
      HSD17B3 can catalyse the 17beta-estradiol <-> estrone interconversion, so the
      activity is real, but it is a minor/secondary activity, not the physiological
      role of this testicular androgenic enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      The 17beta-estradiol + NADP+ = estrone + NADPH reaction (RHEA:24616, EC
      1.1.1.62) is documented for the enzyme in UniProt, justifying the mapping, but
      the physiologically important, testis-relevant activity is testosterone
      dehydrogenase (androstenedione->testosterone). Retain as non-core.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "17beta-estradiol + NADP(+) = estrone + NADPH + H(+);"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      IEA (UniProt SubCell / ARBA) localization to the endoplasmic reticulum,
      duplicating the IBA/IDA ER annotations. Correct.
    action: ACCEPT
    reason: >-
      Matches the experimentally determined ER localization of the human enzyme.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum"
- term:
    id: GO:0008610
    label: lipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      IEA (ARBA) mapping to lipid biosynthetic process. Steroids are technically
      lipids, so this is not strictly wrong, but it is far too general and
      uninformative for a testosterone-biosynthetic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The specific role of HSD17B3 is in androgen/testosterone (steroid hormone)
      biosynthesis, already captured by GO:0006702 and GO:0061370. The generic
      lipid biosynthetic process term over-generalizes and adds no useful signal.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "Hormone biosynthesis; testosterone biosynthesis."
- term:
    id: GO:0016614
    label: oxidoreductase activity, acting on CH-OH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      IEA (ARBA) mapping to the general oxidoreductase activity acting on CH-OH
      group of donors. HSD17B3 is a hydroxysteroid dehydrogenase (reduces 17-keto
      to 17beta-hydroxy using NADPH), so this parent term is correct.
    action: ACCEPT
    reason: >-
      Accurate but general parent of the specific 17beta-HSD / testosterone
      dehydrogenase activity. Retained as correct context.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "Uses NADPH"
- term:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      IEA (EC 1.1.1.64 / Rhea RHEA:14981) mapping to testosterone dehydrogenase
      (NADP+) activity, duplicating the core IBA/IDA/TAS molecular-function
      annotation.
    action: ACCEPT
    reason: >-
      Core catalytic function, independently supported by direct human enzymology
      and by the EC/Rhea mapping (testosterone + NADP+ = androstenedione + NADPH).
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH"
- term:
    id: GO:0072582
    label: 17-beta-hydroxysteroid dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      IEA (Rhea) mapping to 17-beta-hydroxysteroid dehydrogenase (NADP+) activity,
      the general reaction (a 17beta-hydroxy steroid + NADP+ = a 17-oxo steroid +
      NADPH). This is the family-level activity that HSD17B3 carries out on multiple
      17-ketosteroid substrates.
    action: ACCEPT
    reason: >-
      Accurately describes the enzyme's broad 17beta-HSD activity across several
      17-oxosteroid substrates (androstenedione, DHEA, androstanedione, 11-oxygenated
      C19 steroids), reducing them at C-17 using NADPH. Complements the more specific
      testosterone dehydrogenase term.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "Favors the reduction of"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a high-throughput affinity-purification
      mass-spectrometry human interactome map (BioPlex), with interactor NCS1
      (UniProtKB:P62166).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" from a proteome-scale interactome screen is
      uninformative about the molecular function of HSD17B3 and does not represent
      a characterized, biologically interpreted interaction. Per curation guidelines,
      such generic protein-binding terms should not be treated as core function.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "P37058; P62166: NCS1;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a second proteome-scale AP-MS human
      interactome study (BioPlex 3.0), again with interactor NCS1 (UniProtKB:P62166).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the companion interactome dataset, this generic "protein binding"
      annotation from a high-throughput screen is uninformative for molecular
      function and is not core.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "P37058; P62166: NCS1;"
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193048
  qualifier: involved_in
  review:
    summary: >-
      TAS (Reactome, Androgen biosynthesis) assignment to androgen biosynthetic
      process. HSD17B3 catalyses the terminal androstenedione->testosterone step
      of androgen (testosterone) biosynthesis.
    action: ACCEPT
    reason: >-
      Testosterone is an androgen and HSD17B3 performs the final reductive step of
      its synthesis, so this is a correct and central biological-process annotation.
    supported_by:
    - reference_id: PMID:8075637
      supporting_text: "Defects in the conversion of androstenedione to testosterone in the fetal testes"
- term:
    id: GO:0061370
    label: testosterone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      IEA (UniPathway UPA00367) assignment to testosterone biosynthetic process,
      the most specific biological process for this enzyme's role.
    action: ACCEPT
    reason: >-
      HSD17B3 catalyses the final, committed step producing testosterone; UniProt
      records the pathway "Hormone biosynthesis; testosterone biosynthesis". This is
      the most precise BP term and represents a core function.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "Hormone biosynthesis; testosterone biosynthesis."
- term:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193064
  qualifier: enables
  review:
    summary: >-
      TAS (Reactome, HSD17B3-like proteins reduce ANDST to TEST) assignment of
      testosterone dehydrogenase (NADP+) activity, duplicating the core molecular
      function.
    action: ACCEPT
    reason: >-
      Core catalytic function; consistent with the IBA/IDA/IEA annotations of the
      same term and with the reduction of androstenedione to testosterone.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:26545797
  qualifier: located_in
  review:
    summary: >-
      IDA localization to the endoplasmic reticulum. Engeli et al. expressed
      wild-type 17beta-HSD3 (and the G133R mutant) in HEK-293 cells and assessed
      intracellular localization; both showed comparable ER localization.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for ER localization of the human enzyme in a
      cellular expression system, consistent with its membrane anchor.
    supported_by:
    - reference_id: PMID:26545797
      supporting_text: "showed comparable expression levels and intracellular localization."
- term:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:26545797
  qualifier: enables
  review:
    summary: >-
      IDA for testosterone dehydrogenase (NADP+) activity. Engeli et al. measured
      the conversion of androstenedione to testosterone by wild-type 17beta-HSD3
      (nearly abolished in the disease mutant G133R), directly demonstrating the
      enzyme activity.
    action: ACCEPT
    reason: >-
      Direct assay of the enzyme's testosterone-producing 17beta-reductase activity
      in a human expression system; the defining core molecular function.
    supported_by:
    - reference_id: PMID:26545797
      supporting_text: "conversion of Δ4-androstene-3,17-dione (androstenedione) to testosterone was"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193064
  qualifier: located_in
  review:
    summary: >-
      TAS (Reactome) localization to the endoplasmic reticulum membrane, the most
      precise cellular-component term. HSD17B3 has an N-terminal hydrophobic segment
      that anchors it in the ER membrane.
    action: ACCEPT
    reason: >-
      Most specific and accurate location for this membrane-anchored ER enzyme;
      preferred over the parent GO:0005783 term.
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum"
- term:
    id: GO:0030539
    label: male genitalia development
  evidence_type: TAS
  original_reference_id: PMID:8075637
  qualifier: involved_in
  review:
    summary: >-
      TAS (Geissler et al. 1994) involvement in male genitalia development.
      Deficiency of 17beta-HSD3 impairs fetal testicular testosterone synthesis,
      giving 46,XY individuals female external genitalia (male pseudohermaphroditism).
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a real but downstream physiological/developmental consequence of the
      enzyme's biochemical activity (testosterone drives male sexual differentiation),
      not the molecular/biosynthetic core function. Retained as non-core to preserve
      the well-established disease/developmental link.
    supported_by:
    - reference_id: PMID:8075637
      supporting_text: "Defects in the conversion of androstenedione to testosterone in the fetal testes"
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "inadequate testicular synthesis of"
- term:
    id: GO:0043231
    label: intracellular membrane-bounded organelle
  evidence_type: TAS
  original_reference_id: PMID:8075637
  qualifier: located_in
  review:
    summary: >-
      TAS (Geissler et al. 1994) localization to an intracellular membrane-bounded
      organelle. The original paper described the enzyme as microsomal (ER); the
      annotation is correct but far more general than the known ER localization.
    action: MODIFY
    reason: >-
      The enzyme is specifically an ER (microsomal) membrane protein, established by
      direct experimental evidence. This generic organelle term should be replaced
      with the specific endoplasmic reticulum term.
    proposed_replacement_terms:
    - id: GO:0005783
      label: endoplasmic reticulum
    supported_by:
    - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum"
core_functions:
- description: >-
    NADPH-dependent 17beta-hydroxysteroid (testosterone) dehydrogenase that
    catalyses the final step of testosterone biosynthesis in the testis, reducing
    the 17-keto group of androstenedione to give testosterone at the endoplasmic
    reticulum membrane.
  molecular_function:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  directly_involved_in:
  - id: GO:0006702
    label: androgen biosynthetic process
  - id: GO:0061370
    label: testosterone biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/HSD17B3/HSD17B3-uniprot.txt
    supporting_text: "testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH"
  - reference_id: PMID:26545797
    supporting_text: "conversion of Δ4-androstene-3,17-dione (androstenedione) to testosterone was"
references:
- 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: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: file:human/HSD17B3/HSD17B3-uniprot.txt
  title: UniProtKB entry P37058 (DHB3_HUMAN), 17-beta-hydroxysteroid dehydrogenase type 3
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record; source for catalytic activity (RHEA:14981/EC 1.1.1.64
      testosterone/androstenedione; RHEA:24616/EC 1.1.1.62 estradiol/estrone),
      NADPH cofactor use, ER subcellular location, testis tissue specificity, and
      the 46,XY DSD disease association.
- id: PMID:26545797
  title: Biochemical analyses and molecular modeling explain the functional loss of
    17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with
    46, XY Disorders of Sex Development.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Directly measures wild-type 17beta-HSD3 androstenedione->
      testosterone conversion and ER localization in HEK-293 cells; basis for the IDA
      MF and ER-localization annotations.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput AP-MS interactome (BioPlex). Source of a generic IPI
      protein-binding annotation (interactor NCS1/P62166); uninformative for
      molecular function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput AP-MS interactome (BioPlex 3.0). Source of a second generic
      IPI protein-binding annotation (interactor NCS1/P62166); uninformative for
      molecular function.
- id: PMID:8075637
  title: Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid
    dehydrogenase 3.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache. Landmark paper identifying HSD17B3, its testis-predominant
      expression, NADPH cofactor use, and disease-causing mutations; basis for the MF,
      testis tissue, disease, and male-genitalia-development annotations.
- id: Reactome:R-HSA-193048
  title: Androgen biosynthesis
  findings: []
- id: Reactome:R-HSA-193064
  title: HSD17B3-like proteins reducde ANDST to TEST
  findings: []