SRD5A2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003865 3-oxo-5-alpha-steroid 4-dehydrogenase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the core enzymatic molecular function of the steroid 5-alpha-reductase family. This is the defining, experimentally established activity of SRD5A2. Reason: This is the core molecular function of SRD5A2, directly supported by biochemical characterization of the human enzyme and consistent with the named enzyme. The IBA assignment is at the correct level of specificity. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the PMID:10898110 catalyses the irreversible conversion of testosterone to
GO:0006702 androgen biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of androgen biosynthesis, the core biological process of SRD5A2 (testosterone to DHT is the terminal androgen-activation step producing the most potent androgen). Reason: SRD5A2 produces DHT, the most potent androgen; androgen biosynthesis is a core biological process for this enzyme, supported experimentally in human. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0008584 male gonad development	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment linking the family to male gonad development. SRD5A2 deficiency causes undervirilization in 46,XY individuals, so a developmental role is supported, but it is downstream of the enzyme's core catalytic function rather than a distinct molecular role. Reason: The human deficiency phenotype supports a role in male sexual development, but this is a developmental/physiological consequence of DHT production rather than the enzyme's core molecular function; retain as non-core. Supporting Evidence: PMID:1944596 the major isozyme in genital
GO:0043025 neuronal cell body	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic localization to neuronal cell body, propagated from rodent CNS data on family members. This is not the primary localization of the human enzyme, which is an ER/microsomal membrane protein of androgen-target epithelia. Reason: SRD5A2's established subcellular localization is the endoplasmic reticulum (microsome) membrane; neuronal cell body is a CNS-context localization transferred phylogenetically and does not represent the core localization of the human enzyme. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.
GO:0003865 3-oxo-5-alpha-steroid 4-dehydrogenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/InterPro) assignment of the core enzymatic activity, duplicating the IBA/experimental molecular function. Reason: Correct core molecular function, consistent with the experimental EC 1.3.1.22 activity of the human enzyme. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Subcellular-location mapping from UniProt to the ER membrane. This matches the experimentally/curated microsomal (ER) membrane localization of SRD5A2. Reason: SRD5A2 is a multi-pass ER/microsome membrane protein; ER membrane is the correct core localization. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Endoplasmic reticulum membrane
GO:0006629 lipid metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO assignment of the broad lipid metabolic process parent (steroids are lipids). Correct but very general relative to the specific steroid/androgen metabolic role. Reason: Steroid metabolism is a subtype of lipid metabolism, so this is not wrong, but it is a high-level parent that is less informative than the specific steroid/androgen terms; keep as non-core. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0008202 steroid metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO assignment of steroid metabolic process. SRD5A2 reduces a range of 3-oxo-Delta4 steroids (testosterone, progesterone and others), so steroid metabolism is a correct, well-supported process term. Reason: SRD5A2 metabolizes multiple 3-oxo-Delta4 steroids; steroid metabolic process is an accurate biological process assignment. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt it can also act on other steroids, including progesterone, producing
GO:0016020 membrane	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO generic membrane localization. Correct but non-specific; the informative localization is the ER membrane. Reason: SRD5A2 is a multi-pass membrane protein, so membrane is correct but far less informative than the ER-membrane term; retain as non-core. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.
GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO assignment of a broad oxidoreductase parent. SRD5A2 reduces a C-C double bond of the steroid A-ring, so this parent is correct but less specific than the 3-oxo-5-alpha-steroid 4-dehydrogenase terms. Reason: Accurate but general oxidoreductase parent of the specific EC 1.3.1.22 activity; keep as non-core alongside the specific MF terms. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0047751 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA/EC) mapping to the NADP+-specific reaction (EC 1.3.1.22). This is the precise catalytic activity of SRD5A2, matching the UniProt catalytic activity blocks. Reason: Precise, correct molecular function; SRD5A2 uses NADPH to reduce 3-oxo-Delta4 steroids (EC 1.3.1.22), consistent with the experimental annotation from PMID:10898110. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare protein-binding annotation from a high-throughput binary interactome map (HuRI). It records a physical interaction (with CYSRT1/GNMT) but conveys no specific molecular function. Reason: Per curation guidelines, bare protein binding is uninformative and does not describe a functional activity; it derives from a proteome-scale screen rather than a characterized functional complex. Retain the interaction record but do not treat as a core function. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt P31213; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-13130472, EBI-3867333;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare protein-binding annotation from a proteome-scale affinity-purification interactome map (BioPlex; interaction with CLPTM1). Uninformative as a molecular function. Reason: Per curation guidelines, bare protein binding from a high-throughput screen does not describe a specific molecular function; keep the interaction record but not as a core function. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt P31213; O96005: CLPTM1; NbExp=3; IntAct=EBI-13130472, EBI-2873194;
GO:0006694 steroid biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-orthology transfer of steroid biosynthetic process from the rat ortholog (P31214). Consistent with SRD5A2's role in producing bioactive 5alpha-steroids. Reason: Correct but general biosynthetic parent of the more specific androgen/testosterone biosynthetic terms; retain as non-core. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Converts testosterone into 5-alpha-
GO:0006702 androgen biosynthetic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-orthology transfer of androgen biosynthesis from the rat ortholog, duplicating the IBA androgen-biosynthesis annotation. This is a core process for SRD5A2 (DHT production). Reason: SRD5A2 catalyzes the terminal step of androgen activation (testosterone to DHT); androgen biosynthesis is a core biological process. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0006706 steroid catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of steroid catabolic process. SRD5A2's reaction is a reductive activation (testosterone to the more potent DHT), which is better described as biosynthesis/metabolism than catabolism. Reason: The signature reaction produces a more active androgen rather than degrading steroids; classifying SRD5A2 under steroid catabolism mischaracterizes its role. The steroid/androgen metabolic and biosynthetic terms are the appropriate process annotations. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt the most active androgen in the prostate, as
GO:0008209 androgen metabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-orthology transfer of androgen metabolic process, duplicating the human IDA annotation. Core process for SRD5A2. Reason: SRD5A2 is central to androgen metabolism (testosterone to DHT); this is a correct core process annotation. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0008584 male gonad development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-orthology transfer of male gonad development, duplicating the human IMP/IBA annotations. Supported developmental role, downstream of the core catalytic function. Reason: Developmental consequence of DHT production supported by the human deficiency phenotype; retain as non-core. Supporting Evidence: PMID:1944596 the major isozyme in genital
GO:0009410 response to xenobiotic stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent response-to-xenobiotic annotation. This reflects toxicology/expression-response experiments in rat rather than the core enzymatic function of the human enzyme. Reason: A xenobiotic-response phenotype transferred from the rat ortholog does not capture SRD5A2's molecular function; it is a peripheral, context-specific inference. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0018894 dibenzo-p-dioxin metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent dioxin-metabolism association. SRD5A2 is a steroid 5-alpha-reductase and does not metabolize dibenzo-p-dioxin; this is a response/exposure phenotype misattributed as a metabolic process. Reason: SRD5A2 does not enzymatically metabolize dioxins; the annotation reflects a rodent toxicological-response context and over-annotates the enzyme's function. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0018963 phthalate metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent phthalate-metabolism association. SRD5A2 does not metabolize phthalates; this reflects an endocrine-disruptor exposure context rather than enzymatic function. Reason: SRD5A2's substrates are 3-oxo-Delta4 steroids, not phthalates; the annotation over-annotates a toxicological-response context. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt it can also act on other steroids, including progesterone, producing
GO:0021766 hippocampus development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent CNS-development annotation (neurosteroid context). Not part of the core function of the human enzyme, whose principal roles are in androgen-target peripheral tissues. Reason: A CNS neurodevelopment role transferred from the rat ortholog is peripheral and context-specific; it over-annotates the enzyme relative to its established androgen-metabolic function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0021854 hypothalamus development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent CNS-development annotation. As with hippocampus development, this reflects a neurosteroid context and is not core to the human enzyme. Reason: Peripheral, CNS-context developmental inference transferred from the rat ortholog; over-annotation relative to the core androgen-metabolic function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0030539 male genitalia development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl-orthology transfer of male genitalia development. This is strongly supported in human by the deficiency phenotype (undervirilized external genitalia), but is a developmental consequence of DHT production rather than the core molecular function. Reason: Well supported physiologically (DHT drives male external genitalia development; SRD5A2 deficiency causes undervirilization), but developmental/downstream of the catalytic role; retain as non-core. Supporting Evidence: PMID:1944596 have male internal urogenital tracts, but female external genitalia file:human/SRD5A2/SRD5A2-uniprot.txt making this reaction a key step in male sexual differentiation during
GO:0030540 female genitalia development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of female genitalia development. Poorly supported for the human enzyme, whose defining physiology is male (DHT-dependent) virilization; this looks like an over-broad transfer. Reason: SRD5A2's established developmental role is in male external genitalia via DHT; a female genitalia development role is not supported and over-annotates the enzyme. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt making this reaction a key step in male sexual differentiation during
GO:0031667 response to nutrient levels	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent physiological-response annotation. Not a core molecular or biological function of the human enzyme. Reason: A generic environmental-response phenotype transferred from the rat ortholog; peripheral and not informative about SRD5A2 function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0032354 response to follicle-stimulating hormone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent hormone-response annotation (gonadal regulation of expression). Peripheral to the enzyme's core function. Reason: A hormone-response/expression-regulation phenotype from the rat ortholog does not describe SRD5A2's molecular function; over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0033574 response to testosterone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a response-to-testosterone annotation. Testosterone is SRD5A2's principal substrate rather than a stimulus it merely responds to; this recasts the substrate relationship as a generic response process. Reason: SRD5A2 acts on testosterone as an enzymatic substrate (captured by the MF and androgen-metabolic terms); a separate response-to-testosterone process is a context-specific inference that over-annotates the enzyme. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Supporting Evidence: PMID:10898110 catalyses the irreversible conversion of testosterone to
GO:0043434 response to peptide hormone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent peptide-hormone-response annotation. Peripheral to the enzyme's core function. Reason: A generic hormone-response phenotype from the rat ortholog; not informative about SRD5A2's molecular function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0048545 response to steroid hormone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a steroid-hormone-response annotation. SRD5A2 metabolizes steroid hormones enzymatically; recasting this as a generic response process is peripheral and less informative than the metabolic terms. Reason: The enzyme acts on steroid hormones as substrates (captured by steroid/androgen metabolic terms); a separate response-to-steroid-hormone process over-annotates it. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt it can also act on other steroids, including progesterone, producing
GO:0060348 bone development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a bone-development annotation (androgens influence bone). A distal physiological effect of androgen signaling rather than a core function of the enzyme itself. Reason: Any bone-development link is a downstream systemic effect of DHT/androgen action, not a direct function of SRD5A2; over-annotation transferred from the rat ortholog. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0070852 cell body fiber	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a CNS neuronal localization. Not the core localization of the human enzyme, which is the ER/microsome membrane. Reason: SRD5A2's established localization is the ER membrane; cell body fiber is a CNS-context localization transferred phylogenetically and does not represent the core localization. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of neuronal cell body localization from the rat ortholog (P31214), duplicating the IBA neuronal-cell-body annotation. Not the core localization of the human enzyme, which is the ER/microsome membrane. Reason: SRD5A2's established localization is the ER (microsome) membrane; neuronal cell body is a CNS-context localization transferred from the rat ortholog and does not represent the core localization of the human enzyme. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.
GO:1904614 response to biphenyl	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl-orthology transfer of a rodent response-to-biphenyl (endocrine disruptor) annotation. A toxicological-exposure context, not a core function. Reason: A xenobiotic-exposure response phenotype from the rat ortholog; peripheral and not informative about SRD5A2's molecular function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Catalyzes the irreversible stereospecific reduction of the
GO:0006702 androgen biosynthetic process	TAS Reactome:R-HSA-193048	ACCEPT	Summary: Reactome traceable-author-statement placing SRD5A2 in androgen biosynthesis. Consistent with its role in producing DHT. Reason: SRD5A2 catalyzes the terminal androgen-activation step; androgen biosynthesis is a core process, corroborated by Reactome's Androgen biosynthesis pathway. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0003865 3-oxo-5-alpha-steroid 4-dehydrogenase activity	TAS Reactome:R-HSA-9705713	ACCEPT	Summary: Reactome TAS for the core enzymatic activity, based on the SRD5A2-catalyzed testosterone-to-DHT reaction. Matches the experimental and IBA molecular function. Reason: Correct core molecular function, corroborated by the Reactome reaction "SRD5A2 dehydrogenates TEST to DHTEST". Supporting Evidence: PMID:10898110 catalyses the irreversible conversion of testosterone to
GO:0047045 testosterone dehydrogenase (NADP+) activity	IDA PMID:10898110 Biochemical and pharmacogenetic dissection of human steroid ...	ACCEPT	Summary: Direct-assay annotation of the NADP+-dependent testosterone-reducing activity, from biochemical characterization of the human enzyme (Km for testosterone 0.9 uM; Km for NADPH 8 uM). This is a specific facet of the core SRD5A2 activity. Reason: Experimentally supported; PMID:10898110 biochemically dissected the human enzyme reducing testosterone with NADPH as cofactor. This is a valid, specific molecular-function facet of the core catalytic activity. Supporting Evidence: PMID:10898110 dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
GO:0047751 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity	EXP PMID:10898110 Biochemical and pharmacogenetic dissection of human steroid ...	ACCEPT	Summary: Experimental (EXP) annotation of the NADP+-dependent 3-oxo-5-alpha-steroid 4-dehydrogenase activity (EC 1.3.1.22), the precise core catalytic activity of SRD5A2. Reason: Directly experimentally supported core molecular function from biochemical characterization of the human enzyme. Supporting Evidence: PMID:10898110 catalyses the irreversible conversion of testosterone to
GO:0061370 testosterone biosynthetic process	IDA PMID:10898110 Biochemical and pharmacogenetic dissection of human steroid ...	KEEP AS NON CORE	Summary: Direct-assay annotation to testosterone biosynthetic process. Note that the physiological SRD5A2 reaction consumes testosterone to make DHT (an androgen biosynthetic step); the reverse (DHT to testosterone) direction underlies this term. Given the curator read the full text, this is retained as a supported but non-core facet, with androgen/testosterone-to-DHT biosynthesis being the primary process. Reason: Experimentally annotated by UniProt from PMID:10898110; retained per policy (do not remove experimental annotations whose full text is unverified). Because the dominant physiological role is testosterone-to-DHT conversion (androgen biosynthesis) rather than net testosterone production, this specific term is kept as non-core. Supporting Evidence: PMID:10898110 catalyses the irreversible conversion of testosterone to
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9705713	ACCEPT	Summary: Reactome TAS localizing SRD5A2 to the ER membrane, matching the curated microsomal (ER) membrane localization. Reason: Correct core localization; SRD5A2 is a multi-pass ER/microsome membrane protein. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9705794	ACCEPT	Summary: Reactome TAS (inhibitor-binding reaction) localizing SRD5A2 to the ER membrane. Duplicates the ER-membrane localization. Reason: Correct core localization, corroborated by a second Reactome reaction. Supporting Evidence: file:human/SRD5A2/SRD5A2-uniprot.txt Endoplasmic reticulum membrane
GO:0007267 cell-cell signaling	TAS PMID:1944596 Deletion of steroid 5 alpha-reductase 2 gene in male pseudoh...	MARK AS OVER ANNOTATED	Summary: Legacy TAS to cell-cell signaling citing the 1991 SRD5A2 cloning/deficiency paper. That paper concerns the enzyme's role in androgen action and male sexual differentiation, not cell-cell signaling; this is a miscast, over-general process. Reason: The cited paper describes SRD5A2 as an enzyme in androgen action and its deletion in pseudohermaphroditism; it does not establish a cell-cell signaling function. This is an inappropriate, over-general process term for the enzyme. Supporting Evidence: PMID:1944596 The conversion of testosterone into dihydrotestosterone by steroid 5
GO:0008209 androgen metabolic process	IDA PMID:1944596 Deletion of steroid 5 alpha-reductase 2 gene in male pseudoh...	ACCEPT	Summary: Direct-assay annotation to androgen metabolic process from the SRD5A2 cloning/functional characterization. Core biological process for the enzyme. Reason: SRD5A2 is central to androgen metabolism (testosterone to DHT); experimentally supported core process. Supporting Evidence: PMID:1944596 The conversion of testosterone into dihydrotestosterone by steroid 5
GO:0008584 male gonad development	IMP PMID:1944596 Deletion of steroid 5 alpha-reductase 2 gene in male pseudoh...	KEEP AS NON CORE	Summary: Mutant-phenotype (IMP) annotation to male gonad development, based on the pseudohermaphroditism phenotype of SRD5A2 gene deletion in 46,XY individuals. Supported developmental role, downstream of the core catalytic function. Reason: Experimentally supported via the human deficiency phenotype (undervirilization in 46,XY males); retained but as a developmental/physiological consequence rather than the core molecular function. Supporting Evidence: PMID:1944596 have male internal urogenital tracts, but female external genitalia
GO:0047751 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity	IDA PMID:1944596 Deletion of steroid 5 alpha-reductase 2 gene in male pseudoh...	ACCEPT	Summary: Direct-assay annotation of the NADP+-dependent 3-oxo-5-alpha-steroid 4-dehydrogenase activity from the original SRD5A2 characterization. Core molecular function. Reason: Experimentally supported core catalytic activity (EC 1.3.1.22) of SRD5A2. Supporting Evidence: PMID:1944596 The conversion of testosterone into dihydrotestosterone by steroid 5

📄 View Raw YAML

id: P31213
gene_symbol: SRD5A2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Steroid 5-alpha-reductase type 2 (3-oxo-5-alpha-steroid 4-dehydrogenase
  2; EC 1.3.1.22), an endoplasmic-reticulum-membrane, NADPH-dependent oxidoreductase
  that catalyzes the irreversible, stereospecific reduction of the C4-C5 double bond
  of 3-oxo-Delta4 steroids to their 5alpha-dihydro products. Its most important reaction
  is the conversion of testosterone to 5alpha-dihydrotestosterone (DHT), the most potent
  androgen and the preferred ligand for androgen receptor transactivation; it also reduces
  progesterone and other 3-oxo-Delta4 steroids. The enzyme is a multi-pass membrane protein
  highly expressed in androgen-target tissues (prostate, genital skin, hair follicle) and
  is the principal isozyme responsible for DHT production in genital tissue. Loss-of-function
  variants cause 5alpha-reductase-2 deficiency (pseudovaginal perineoscrotal hypospadias),
  a form of 46,XY difference of sex development in which affected individuals have normal
  testosterone but low DHT and undervirilized external genitalia. SRD5A2 is the molecular
  target of the therapeutic inhibitors finasteride and dutasteride, used to treat benign
  prostatic hyperplasia and androgenetic alopecia.
existing_annotations:
- term:
    id: GO:0003865
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the core enzymatic molecular function of
      the steroid 5-alpha-reductase family. This is the defining, experimentally established
      activity of SRD5A2.
    action: ACCEPT
    reason: This is the core molecular function of SRD5A2, directly supported by biochemical
      characterization of the human enzyme and consistent with the named enzyme. The IBA
      assignment is at the correct level of specificity.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
    - reference_id: PMID:10898110
      supporting_text: catalyses the irreversible conversion of testosterone to
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of androgen biosynthesis, the core biological process
      of SRD5A2 (testosterone to DHT is the terminal androgen-activation step producing the
      most potent androgen).
    action: ACCEPT
    reason: SRD5A2 produces DHT, the most potent androgen; androgen biosynthesis is a core
      biological process for this enzyme, supported experimentally in human.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0008584
    label: male gonad development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment linking the family to male gonad development. SRD5A2
      deficiency causes undervirilization in 46,XY individuals, so a developmental role
      is supported, but it is downstream of the enzyme's core catalytic function rather
      than a distinct molecular role.
    action: KEEP_AS_NON_CORE
    reason: The human deficiency phenotype supports a role in male sexual development, but
      this is a developmental/physiological consequence of DHT production rather than the
      enzyme's core molecular function; retain as non-core.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: the major isozyme in genital
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic localization to neuronal cell body, propagated from rodent CNS
      data on family members. This is not the primary localization of the human enzyme,
      which is an ER/microsomal membrane protein of androgen-target epithelia.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2's established subcellular localization is the endoplasmic reticulum
      (microsome) membrane; neuronal cell body is a CNS-context localization transferred
      phylogenetically and does not represent the core localization of the human enzyme.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.'
- term:
    id: GO:0003865
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (ARBA/InterPro) assignment of the core enzymatic activity, duplicating
      the IBA/experimental molecular function.
    action: ACCEPT
    reason: Correct core molecular function, consistent with the experimental EC 1.3.1.22
      activity of the human enzyme.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Subcellular-location mapping from UniProt to the ER membrane. This matches
      the experimentally/curated microsomal (ER) membrane localization of SRD5A2.
    action: ACCEPT
    reason: SRD5A2 is a multi-pass ER/microsome membrane protein; ER membrane is the correct
      core localization.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO assignment of the broad lipid metabolic process parent (steroids
      are lipids). Correct but very general relative to the specific steroid/androgen
      metabolic role.
    action: KEEP_AS_NON_CORE
    reason: Steroid metabolism is a subtype of lipid metabolism, so this is not wrong, but
      it is a high-level parent that is less informative than the specific steroid/androgen
      terms; keep as non-core.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO assignment of steroid metabolic process. SRD5A2 reduces a range
      of 3-oxo-Delta4 steroids (testosterone, progesterone and others), so steroid
      metabolism is a correct, well-supported process term.
    action: ACCEPT
    reason: SRD5A2 metabolizes multiple 3-oxo-Delta4 steroids; steroid metabolic process
      is an accurate biological process assignment.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: it can also act on other steroids, including progesterone, producing
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro2GO generic membrane localization. Correct but non-specific; the
      informative localization is the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: SRD5A2 is a multi-pass membrane protein, so membrane is correct but far less
      informative than the ER-membrane term; retain as non-core.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.'
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO assignment of a broad oxidoreductase parent. SRD5A2 reduces a
      C-C double bond of the steroid A-ring, so this parent is correct but less specific
      than the 3-oxo-5-alpha-steroid 4-dehydrogenase terms.
    action: KEEP_AS_NON_CORE
    reason: Accurate but general oxidoreductase parent of the specific EC 1.3.1.22 activity;
      keep as non-core alongside the specific MF terms.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0047751
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (RHEA/EC) mapping to the NADP+-specific reaction (EC 1.3.1.22).
      This is the precise catalytic activity of SRD5A2, matching the UniProt catalytic
      activity blocks.
    action: ACCEPT
    reason: Precise, correct molecular function; SRD5A2 uses NADPH to reduce 3-oxo-Delta4
      steroids (EC 1.3.1.22), consistent with the experimental annotation from PMID:10898110.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein-binding annotation from a high-throughput binary interactome
      map (HuRI). It records a physical interaction (with CYSRT1/GNMT) but conveys no
      specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, bare protein binding is uninformative and does not
      describe a functional activity; it derives from a proteome-scale screen rather than
      a characterized functional complex. Retain the interaction record but do not treat
      as a core function.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'P31213; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-13130472, EBI-3867333;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare protein-binding annotation from a proteome-scale affinity-purification
      interactome map (BioPlex; interaction with CLPTM1). Uninformative as a molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, bare protein binding from a high-throughput screen
      does not describe a specific molecular function; keep the interaction record but
      not as a core function.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'P31213; O96005: CLPTM1; NbExp=3; IntAct=EBI-13130472, EBI-2873194;'
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of steroid biosynthetic process from the rat
      ortholog (P31214). Consistent with SRD5A2's role in producing bioactive 5alpha-steroids.
    action: KEEP_AS_NON_CORE
    reason: Correct but general biosynthetic parent of the more specific androgen/testosterone
      biosynthetic terms; retain as non-core.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Converts testosterone into 5-alpha-
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of androgen biosynthesis from the rat ortholog,
      duplicating the IBA androgen-biosynthesis annotation. This is a core process for
      SRD5A2 (DHT production).
    action: ACCEPT
    reason: SRD5A2 catalyzes the terminal step of androgen activation (testosterone to DHT);
      androgen biosynthesis is a core biological process.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0006706
    label: steroid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of steroid catabolic process. SRD5A2's reaction is
      a reductive activation (testosterone to the more potent DHT), which is better
      described as biosynthesis/metabolism than catabolism.
    action: MARK_AS_OVER_ANNOTATED
    reason: The signature reaction produces a more active androgen rather than degrading
      steroids; classifying SRD5A2 under steroid catabolism mischaracterizes its role.
      The steroid/androgen metabolic and biosynthetic terms are the appropriate process
      annotations.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: the most active androgen in the prostate, as
- term:
    id: GO:0008209
    label: androgen metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of androgen metabolic process, duplicating the
      human IDA annotation. Core process for SRD5A2.
    action: ACCEPT
    reason: SRD5A2 is central to androgen metabolism (testosterone to DHT); this is a
      correct core process annotation.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0008584
    label: male gonad development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of male gonad development, duplicating the human
      IMP/IBA annotations. Supported developmental role, downstream of the core catalytic
      function.
    action: KEEP_AS_NON_CORE
    reason: Developmental consequence of DHT production supported by the human deficiency
      phenotype; retain as non-core.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: the major isozyme in genital
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent response-to-xenobiotic annotation.
      This reflects toxicology/expression-response experiments in rat rather than the
      core enzymatic function of the human enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: A xenobiotic-response phenotype transferred from the rat ortholog does not
      capture SRD5A2's molecular function; it is a peripheral, context-specific inference.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0018894
    label: dibenzo-p-dioxin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent dioxin-metabolism association. SRD5A2
      is a steroid 5-alpha-reductase and does not metabolize dibenzo-p-dioxin; this is a
      response/exposure phenotype misattributed as a metabolic process.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2 does not enzymatically metabolize dioxins; the annotation reflects a
      rodent toxicological-response context and over-annotates the enzyme's function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0018963
    label: phthalate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent phthalate-metabolism association.
      SRD5A2 does not metabolize phthalates; this reflects an endocrine-disruptor exposure
      context rather than enzymatic function.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2's substrates are 3-oxo-Delta4 steroids, not phthalates; the annotation
      over-annotates a toxicological-response context.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: it can also act on other steroids, including progesterone, producing
- term:
    id: GO:0021766
    label: hippocampus development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent CNS-development annotation
      (neurosteroid context). Not part of the core function of the human enzyme, whose
      principal roles are in androgen-target peripheral tissues.
    action: MARK_AS_OVER_ANNOTATED
    reason: A CNS neurodevelopment role transferred from the rat ortholog is peripheral
      and context-specific; it over-annotates the enzyme relative to its established
      androgen-metabolic function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0021854
    label: hypothalamus development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent CNS-development annotation. As with
      hippocampus development, this reflects a neurosteroid context and is not core to the
      human enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: Peripheral, CNS-context developmental inference transferred from the rat
      ortholog; over-annotation relative to the core androgen-metabolic function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0030539
    label: male genitalia development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of male genitalia development. This is strongly
      supported in human by the deficiency phenotype (undervirilized external genitalia),
      but is a developmental consequence of DHT production rather than the core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: Well supported physiologically (DHT drives male external genitalia development;
      SRD5A2 deficiency causes undervirilization), but developmental/downstream of the
      catalytic role; retain as non-core.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: have male internal urogenital tracts, but female external genitalia
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: making this reaction a key step in male sexual differentiation during
- term:
    id: GO:0030540
    label: female genitalia development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of female genitalia development. Poorly supported
      for the human enzyme, whose defining physiology is male (DHT-dependent) virilization;
      this looks like an over-broad transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2's established developmental role is in male external genitalia via DHT;
      a female genitalia development role is not supported and over-annotates the enzyme.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: making this reaction a key step in male sexual differentiation during
- term:
    id: GO:0031667
    label: response to nutrient levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent physiological-response annotation.
      Not a core molecular or biological function of the human enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: A generic environmental-response phenotype transferred from the rat ortholog;
      peripheral and not informative about SRD5A2 function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0032354
    label: response to follicle-stimulating hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent hormone-response annotation
      (gonadal regulation of expression). Peripheral to the enzyme's core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A hormone-response/expression-regulation phenotype from the rat ortholog does
      not describe SRD5A2's molecular function; over-annotation.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a response-to-testosterone annotation.
      Testosterone is SRD5A2's principal substrate rather than a stimulus it merely
      responds to; this recasts the substrate relationship as a generic response process.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2 acts on testosterone as an enzymatic substrate (captured by the MF and
      androgen-metabolic terms); a separate response-to-testosterone process is a
      context-specific inference that over-annotates the enzyme.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: catalyses the irreversible conversion of testosterone to
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent peptide-hormone-response annotation.
      Peripheral to the enzyme's core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A generic hormone-response phenotype from the rat ortholog; not informative
      about SRD5A2's molecular function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0048545
    label: response to steroid hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a steroid-hormone-response annotation. SRD5A2
      metabolizes steroid hormones enzymatically; recasting this as a generic response
      process is peripheral and less informative than the metabolic terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: The enzyme acts on steroid hormones as substrates (captured by steroid/androgen
      metabolic terms); a separate response-to-steroid-hormone process over-annotates it.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: it can also act on other steroids, including progesterone, producing
- term:
    id: GO:0060348
    label: bone development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a bone-development annotation (androgens
      influence bone). A distal physiological effect of androgen signaling rather than a
      core function of the enzyme itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: Any bone-development link is a downstream systemic effect of DHT/androgen
      action, not a direct function of SRD5A2; over-annotation transferred from the
      rat ortholog.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0070852
    label: cell body fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-orthology transfer of a CNS neuronal localization. Not the core
      localization of the human enzyme, which is the ER/microsome membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2's established localization is the ER membrane; cell body fiber is a
      CNS-context localization transferred phylogenetically and does not represent the
      core localization.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.'
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-orthology transfer of neuronal cell body localization from the rat
      ortholog (P31214), duplicating the IBA neuronal-cell-body annotation. Not the core
      localization of the human enzyme, which is the ER/microsome membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: SRD5A2's established localization is the ER (microsome) membrane; neuronal cell
      body is a CNS-context localization transferred from the rat ortholog and does not
      represent the core localization of the human enzyme.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome membrane; Multi-pass membrane protein.'
- term:
    id: GO:1904614
    label: response to biphenyl
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology transfer of a rodent response-to-biphenyl (endocrine
      disruptor) annotation. A toxicological-exposure context, not a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A xenobiotic-exposure response phenotype from the rat ortholog; peripheral
      and not informative about SRD5A2's molecular function.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - CONTEXT_OR_TISSUE_MISMATCH
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Catalyzes the irreversible stereospecific reduction of the
- term:
    id: GO:0006702
    label: androgen biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193048
  qualifier: involved_in
  review:
    summary: Reactome traceable-author-statement placing SRD5A2 in androgen biosynthesis.
      Consistent with its role in producing DHT.
    action: ACCEPT
    reason: SRD5A2 catalyzes the terminal androgen-activation step; androgen biosynthesis
      is a core process, corroborated by Reactome's Androgen biosynthesis pathway.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0003865
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705713
  qualifier: enables
  review:
    summary: Reactome TAS for the core enzymatic activity, based on the SRD5A2-catalyzed
      testosterone-to-DHT reaction. Matches the experimental and IBA molecular function.
    action: ACCEPT
    reason: Correct core molecular function, corroborated by the Reactome reaction "SRD5A2
      dehydrogenates TEST to DHTEST".
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: catalyses the irreversible conversion of testosterone to
- term:
    id: GO:0047045
    label: testosterone dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:10898110
  qualifier: enables
  review:
    summary: Direct-assay annotation of the NADP+-dependent testosterone-reducing activity,
      from biochemical characterization of the human enzyme (Km for testosterone 0.9 uM;
      Km for NADPH 8 uM). This is a specific facet of the core SRD5A2 activity.
    action: ACCEPT
    reason: Experimentally supported; PMID:10898110 biochemically dissected the human
      enzyme reducing testosterone with NADPH as cofactor. This is a valid, specific
      molecular-function facet of the core catalytic activity.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH
- term:
    id: GO:0047751
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity
  evidence_type: EXP
  original_reference_id: PMID:10898110
  qualifier: enables
  review:
    summary: Experimental (EXP) annotation of the NADP+-dependent 3-oxo-5-alpha-steroid
      4-dehydrogenase activity (EC 1.3.1.22), the precise core catalytic activity of SRD5A2.
    action: ACCEPT
    reason: Directly experimentally supported core molecular function from biochemical
      characterization of the human enzyme.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: catalyses the irreversible conversion of testosterone to
- term:
    id: GO:0061370
    label: testosterone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:10898110
  qualifier: involved_in
  review:
    summary: Direct-assay annotation to testosterone biosynthetic process. Note that the
      physiological SRD5A2 reaction consumes testosterone to make DHT (an androgen
      biosynthetic step); the reverse (DHT to testosterone) direction underlies this term.
      Given the curator read the full text, this is retained as a supported but non-core
      facet, with androgen/testosterone-to-DHT biosynthesis being the primary process.
    action: KEEP_AS_NON_CORE
    reason: Experimentally annotated by UniProt from PMID:10898110; retained per policy
      (do not remove experimental annotations whose full text is unverified). Because the
      dominant physiological role is testosterone-to-DHT conversion (androgen biosynthesis)
      rather than net testosterone production, this specific term is kept as non-core.
    supported_by:
    - reference_id: PMID:10898110
      supporting_text: catalyses the irreversible conversion of testosterone to
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705713
  qualifier: located_in
  review:
    summary: Reactome TAS localizing SRD5A2 to the ER membrane, matching the curated
      microsomal (ER) membrane localization.
    action: ACCEPT
    reason: Correct core localization; SRD5A2 is a multi-pass ER/microsome membrane protein.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705794
  qualifier: located_in
  review:
    summary: Reactome TAS (inhibitor-binding reaction) localizing SRD5A2 to the ER membrane.
      Duplicates the ER-membrane localization.
    action: ACCEPT
    reason: Correct core localization, corroborated by a second Reactome reaction.
    supported_by:
    - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: TAS
  original_reference_id: PMID:1944596
  qualifier: involved_in
  review:
    summary: Legacy TAS to cell-cell signaling citing the 1991 SRD5A2 cloning/deficiency
      paper. That paper concerns the enzyme's role in androgen action and male sexual
      differentiation, not cell-cell signaling; this is a miscast, over-general process.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper describes SRD5A2 as an enzyme in androgen action and its
      deletion in pseudohermaphroditism; it does not establish a cell-cell signaling
      function. This is an inappropriate, over-general process term for the enzyme.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: The conversion of testosterone into dihydrotestosterone by steroid 5
- term:
    id: GO:0008209
    label: androgen metabolic process
  evidence_type: IDA
  original_reference_id: PMID:1944596
  qualifier: involved_in
  review:
    summary: Direct-assay annotation to androgen metabolic process from the SRD5A2
      cloning/functional characterization. Core biological process for the enzyme.
    action: ACCEPT
    reason: SRD5A2 is central to androgen metabolism (testosterone to DHT); experimentally
      supported core process.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: The conversion of testosterone into dihydrotestosterone by steroid 5
- term:
    id: GO:0008584
    label: male gonad development
  evidence_type: IMP
  original_reference_id: PMID:1944596
  qualifier: involved_in
  review:
    summary: Mutant-phenotype (IMP) annotation to male gonad development, based on the
      pseudohermaphroditism phenotype of SRD5A2 gene deletion in 46,XY individuals.
      Supported developmental role, downstream of the core catalytic function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported via the human deficiency phenotype (undervirilization
      in 46,XY males); retained but as a developmental/physiological consequence rather
      than the core molecular function.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: have male internal urogenital tracts, but female external genitalia
- term:
    id: GO:0047751
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity
  evidence_type: IDA
  original_reference_id: PMID:1944596
  qualifier: enables
  review:
    summary: Direct-assay annotation of the NADP+-dependent 3-oxo-5-alpha-steroid
      4-dehydrogenase activity from the original SRD5A2 characterization. Core molecular
      function.
    action: ACCEPT
    reason: Experimentally supported core catalytic activity (EC 1.3.1.22) of SRD5A2.
    supported_by:
    - reference_id: PMID:1944596
      supporting_text: The conversion of testosterone into dihydrotestosterone by steroid 5
core_functions:
- description: NADPH-dependent 3-oxo-5-alpha-steroid 4-dehydrogenase (steroid 5-alpha-reductase)
    that irreversibly reduces the C4-C5 double bond of 3-oxo-Delta4 steroids, most importantly
    converting testosterone to the potent androgen 5alpha-dihydrotestosterone (DHT).
  molecular_function:
    id: GO:0003865
    label: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
  directly_involved_in:
  - id: GO:0006702
    label: androgen biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10898110
    supporting_text: catalyses the irreversible conversion of testosterone to
  - reference_id: file:human/SRD5A2/SRD5A2-uniprot.txt
    supporting_text: Catalyzes the irreversible stereospecific reduction of the
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10898110
  title: Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase
    type II.
  findings:
  - statement: The human enzyme catalyses the irreversible, NADPH-dependent conversion
      of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate.
      Biochemical dissection defined its substrate and cofactor binding sites.
    supporting_text: catalyses the irreversible conversion of testosterone to
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; directly establishes the core catalytic activity
      and NADPH dependence of the human SRD5A2 enzyme. Verified via PubMed metadata title match.
- id: PMID:1944596
  title: Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism.
  findings:
  - statement: SRD5A2 (5 alpha-reductase 2) is the major isozyme in genital tissue; its
      deletion causes 5 alpha-reductase deficiency and 46,XY male pseudohermaphroditism
      with female external genitalia, establishing its role in male sexual differentiation.
    supporting_text: A deletion in this gene is present in two related individuals with male
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache; original cloning and disease-gene paper for SRD5A2.
      Verified via PubMed metadata title match.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome (HuRI); source of a bare protein-binding
      IPI. No specific SRD5A2 function established.
- 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: Proteome-scale AP-MS interactome (BioPlex); source of a bare protein-binding
      IPI. No specific SRD5A2 function established.
- id: Reactome:R-HSA-193048
  title: Androgen biosynthesis
  findings: []
- id: Reactome:R-HSA-9705713
  title: SRD5A2 dehydrogenates TEST to DHTEST
  findings: []
- id: Reactome:R-HSA-9705794
  title: SRD5A2 binds SRD5A2 inhibitors
  findings: []
- id: file:human/SRD5A2/SRD5A2-uniprot.txt
  title: UniProtKB entry P31213 (S5A2_HUMAN), 3-oxo-5-alpha-steroid 4-dehydrogenase 2
  findings:
  - statement: SRD5A2 catalyzes the irreversible stereospecific reduction of the Delta4,5
      bond of 3-oxo steroids, converting testosterone to DHT (the most active androgen),
      also acting on progesterone; it is an endoplasmic reticulum / microsome multi-pass
      membrane protein highly expressed in the prostate and other androgen-sensitive tissues,
      and its variants cause male pseudohermaphroditism (5-alpha-reductase-2 deficiency).
    supporting_text: Catalyzes the irreversible stereospecific reduction of the

Gene Description

Existing Annotations Review

Core Functions

NADPH-dependent 3-oxo-5-alpha-steroid 4-dehydrogenase (steroid 5-alpha-reductase) that irreversibly reduces the C4-C5 double bond of 3-oxo-Delta4 steroids, most importantly converting testosterone to the potent androgen 5alpha-dihydrotestosterone (DHT).

References

📚 Additional Documentation

Notes

SRD5A2 (human) review notes

Core biology (verified)

Annotation adjudication summary

📄 View Raw YAML