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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: Too general to be a core cellular-component statement given the more specific endoplasmic-reticulum-membrane annotations; retained as non-core context. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Single-pass membrane protein |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IBA GO_REF:0000033 | MODIFY | 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. 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt 3-beta-HSD is a bifunctional enzyme, that catalyzes the |
| GO:0006694 steroid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:1944309 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 |
| GO:0008207 C21-steroid hormone metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Reaction=pregnenolone + NAD(+) = pregn-5-ene-3,20-dione + NADH + H(+) |
| GO:0003854 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Accurately captures the NAD+-dependent 3beta-hydroxy-Delta5-steroid dehydrogenase half of this bifunctional enzyme. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt EC=1.1.1.145 |
| GO:0004022 alcohol dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | 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). 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. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Reaction=pregnenolone + NAD(+) = pregn-5-ene-3,20-dione + NADH + H(+) |
| GO:0004769 steroid Delta-isomerase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Accurately captures the isomerase half of the enzyme; a genuine core molecular function. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt EC=5.3.3.1 |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Correct primary localization; the enzyme is a single-pass ER-membrane protein. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006694 steroid biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (InterPro/UniPathway) annotation to steroid biosynthetic process, duplicating the experimentally supported core biological process. Reason: Correct core process, consistent with IDA/IMP/IBA annotations to the same term. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Lipid metabolism; steroid biosynthesis |
| GO:0006702 androgen biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | 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). 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. Supporting Evidence: PMID:25322271 conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MODIFY | 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. Reason: Too shallow; supersede with the specific 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity that is experimentally supported. Proposed replacements: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt EC=1.1.1.145 |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Secondary/weaker localization relative to the experimentally supported ER membrane; retained as non-core. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Mitochondrion membrane; Single-pass membrane protein |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt P26439; Q53GS7: GLE1; NbExp=3 file:human/HSD3B2/HSD3B2-uniprot.txt P26439; Q7Z699: SPRED1; NbExp=3 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence IDA localizing HSD3B2 to the endoplasmic reticulum, consistent with the enzyme being an ER-membrane steroidogenic protein. Reason: Direct imaging evidence for the primary subcellular compartment. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt endoplasmic reticulum; IDA:HPA |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | ACCEPT | 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. Reason: Experimentally supported primary localization; core cellular component. Supporting Evidence: PMID:25322271 p.G250V mutation has no effect on the expression and intracellular localization of the mutant protein |
| GO:0003854 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity | IMP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | ACCEPT | 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. Reason: Mutant loss-of-function directly supports this core dehydrogenase activity. Supporting Evidence: PMID:25322271 3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting Ξ5-steroids to Ξ4-steroids |
| GO:0004769 steroid Delta-isomerase activity | IMP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | ACCEPT | 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. Reason: Mutant loss-of-function supports this core isomerase activity of the bifunctional enzyme. Supporting Evidence: PMID:25322271 3betaHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting Ξ5-steroids to Ξ4-steroids |
| GO:0005783 endoplasmic reticulum | IMP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | ACCEPT | Summary: IMP/EXP evidence localizing HSD3B2 to the endoplasmic reticulum; the G250V variant did not alter ER localization. Reason: Experimentally supported ER localization. Supporting Evidence: PMID:25322271 p.G250V mutation has no effect on the expression and intracellular localization of the mutant protein |
| GO:0006694 steroid biosynthetic process | IMP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | ACCEPT | 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. Reason: Core biological process supported by mutant phenotype and the human CAH disease mechanism. Supporting Evidence: PMID:25322271 3Ξ²HSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by recessive loss-of-function HSD3B2 mutations |
| GO:0006702 androgen biosynthetic process | IMP PMID:25322271 A novel missense mutation in the HSD3B2 gene, underlying non... | KEEP AS NON CORE | 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. Reason: True sub-role (DHEA-to-androstenedione), but one of several hormone-class branches; core process is the general steroid biosynthetic process. Supporting Evidence: PMID:25322271 conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193052 | ACCEPT | 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. Reason: Reactome-curated ER-membrane localization for a specific HSD3B2-catalyzed reaction. Supporting Evidence: Reactome:R-HSA-193052 This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193073 | ACCEPT | Summary: Reactome TAS: the two-step oxidation/isomerization of DHEA to androstenedione is catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane. Reason: Reactome-curated ER-membrane localization for an HSD3B2-catalyzed androgen-pathway reaction. Supporting Evidence: Reactome:R-HSA-193073 two-step reaction catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193961 | ACCEPT | 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. Reason: Reactome-curated ER-membrane localization for an HSD3B2-catalyzed reaction. Supporting Evidence: Reactome:R-HSA-193961 This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-196350 | ACCEPT | Summary: Reactome TAS: NAD+-dependent dehydrogenation of pregnenolone to pregn-5-ene-3,20-dione by 3beta-HSD associated with the endoplasmic reticulum membrane. Reason: Reactome-curated ER-membrane localization for the HSD3B2 dehydrogenase reaction. Supporting Evidence: Reactome:R-HSA-196350 catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-196372 | ACCEPT | 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. Reason: Reactome-curated ER-membrane localization for the HSD3B2 dehydrogenase reaction. Supporting Evidence: Reactome:R-HSA-196372 catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | NAS PMID:1944309 Structure and expression of a new complementary DNA encoding... | ACCEPT | Summary: NAS annotation of endoplasmic-reticulum localization from the original type-II cloning paper. Consistent with the later IDA/EXP ER-membrane evidence. Reason: Correct primary compartment, corroborated by direct experimental evidence. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt endoplasmic reticulum; IDA:HPA |
| GO:0031966 mitochondrial membrane | NAS PMID:1944309 Structure and expression of a new complementary DNA encoding... | KEEP AS NON CORE | 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. Reason: Secondary localization relative to the well-supported ER membrane; retained as non-core. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Mitochondrion membrane; Single-pass membrane protein |
| GO:0016020 membrane | NAS PMID:1944309 Structure and expression of a new complementary DNA encoding... | MODIFY | 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. Reason: Too general; supersede with the specific ER-membrane term that is experimentally supported. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt Single-pass membrane protein |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005758 mitochondrial intermembrane space | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | 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. Reason: Over-specific sub-mitochondrial localization inferred by similarity, beyond what is supported for the human enzyme. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0030868 smooth endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. Reason: Plausible ER-subdomain refinement by similarity; retained as non-core relative to the directly supported ER-membrane annotation. Supporting Evidence: file:human/HSD3B2/HSD3B2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0003854 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity | IDA PMID:1944309 Structure and expression of a new complementary DNA encoding... | ACCEPT | 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. Reason: Direct biochemical demonstration of the NAD+-dependent dehydrogenase activity. Supporting Evidence: PMID:1944309 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 |
| GO:0004769 steroid Delta-isomerase activity | IDA PMID:1944309 Structure and expression of a new complementary DNA encoding... | ACCEPT | 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. Reason: Direct biochemical demonstration of the Delta5-Delta4 isomerase activity. Supporting Evidence: PMID:1944309 catalyzes the oxidation and isomerization of delta 5-3 beta-hydroxysteroid precursors into delta 4-ketosteroids |
| GO:0006694 steroid biosynthetic process | IDA PMID:1944309 Structure and expression of a new complementary DNA encoding... | ACCEPT | 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. Reason: Direct experimental support for the steroid biosynthetic role. Supporting Evidence: PMID:1944309 thus leading to the formation of all classes of steroid hormones |
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