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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH PMID:8075637 uses NADPh as a cofactor, and |
| GO:0006694 steroid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment to steroid biosynthesis. HSD17B3 acts in androgen/testosterone biosynthesis, which is a steroid biosynthetic process. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt Hormone biosynthesis; testosterone biosynthesis. |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt 17beta-estradiol + NADP(+) = estrone + NADPH + H(+); |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (UniProt SubCell / ARBA) localization to the endoplasmic reticulum, duplicating the IBA/IDA ER annotations. Correct. Reason: Matches the experimentally determined ER localization of the human enzyme. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0008610 lipid biosynthetic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt Hormone biosynthesis; testosterone biosynthesis. |
| GO:0016614 oxidoreductase activity, acting on CH-OH group of donors | IEA GO_REF:0000117 | ACCEPT | 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. Reason: Accurate but general parent of the specific 17beta-HSD / testosterone dehydrogenase activity. Retained as correct context. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt Uses NADPH |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Core catalytic function, independently supported by direct human enzymology and by the EC/Rhea mapping (testosterone + NADP+ = androstenedione + NADPH). Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH |
| GO:0072582 17-beta-hydroxysteroid dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | ACCEPT | 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. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt Favors the reduction of |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a high-throughput affinity-purification mass-spectrometry human interactome map (BioPlex), with interactor NCS1 (UniProtKB:P62166). 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt P37058; P62166: NCS1; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a second proteome-scale AP-MS human interactome study (BioPlex 3.0), again with interactor NCS1 (UniProtKB:P62166). 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt P37058; P62166: NCS1; |
| GO:0006702 androgen biosynthetic process | TAS Reactome:R-HSA-193048 | ACCEPT | Summary: TAS (Reactome, Androgen biosynthesis) assignment to androgen biosynthetic process. HSD17B3 catalyses the terminal androstenedione->testosterone step of androgen (testosterone) biosynthesis. 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. Supporting Evidence: PMID:8075637 Defects in the conversion of androstenedione to testosterone in the fetal testes |
| GO:0061370 testosterone biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: IEA (UniPathway UPA00367) assignment to testosterone biosynthetic process, the most specific biological process for this enzyme's role. 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. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt Hormone biosynthesis; testosterone biosynthesis. |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-193064 | ACCEPT | Summary: TAS (Reactome, HSD17B3-like proteins reduce ANDST to TEST) assignment of testosterone dehydrogenase (NADP+) activity, duplicating the core molecular function. Reason: Core catalytic function; consistent with the IBA/IDA/IEA annotations of the same term and with the reduction of androstenedione to testosterone. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH |
| GO:0005783 endoplasmic reticulum | IDA PMID:26545797 Biochemical analyses and molecular modeling explain the func... | ACCEPT | 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. Reason: Direct experimental evidence for ER localization of the human enzyme in a cellular expression system, consistent with its membrane anchor. Supporting Evidence: PMID:26545797 showed comparable expression levels and intracellular localization. |
| GO:0047045 testosterone dehydrogenase (NADP+) activity | IDA PMID:26545797 Biochemical analyses and molecular modeling explain the func... | ACCEPT | 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. Reason: Direct assay of the enzyme's testosterone-producing 17beta-reductase activity in a human expression system; the defining core molecular function. Supporting Evidence: PMID:26545797 conversion of Ξ4-androstene-3,17-dione (androstenedione) to testosterone was |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193064 | ACCEPT | 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. Reason: Most specific and accurate location for this membrane-anchored ER enzyme; preferred over the parent GO:0005783 term. Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0030539 male genitalia development | TAS PMID:8075637 Male pseudohermaphroditism caused by mutations of testicular... | KEEP AS NON CORE | 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). 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. Supporting Evidence: PMID:8075637 Defects in the conversion of androstenedione to testosterone in the fetal testes file:human/HSD17B3/HSD17B3-uniprot.txt inadequate testicular synthesis of |
| GO:0043231 intracellular membrane-bounded organelle | TAS PMID:8075637 Male pseudohermaphroditism caused by mutations of testicular... | MODIFY | 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. 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 replacements: endoplasmic reticulum Supporting Evidence: file:human/HSD17B3/HSD17B3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
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