SRD5A3 is an endoplasmic reticulum membrane, NADPH-dependent polyprenal reductase that acts in the terminal steps of de novo dolichol biosynthesis. In the currently accepted pathway it catalyzes the reduction of the alpha-isoprene unit of a di-trans,poly-cis-polyprenal to the corresponding dolichal, an intermediate in converting polyprenol to dolichol; the resulting dolichol is phosphorylated to dolichol-phosphate, the essential lipid carrier used to assemble the lipid-linked oligosaccharide precursor for protein N-linked glycosylation. It is a multi-pass member of the steroid 5-alpha-reductase family (polyprenal reductase subfamily; yeast ortholog DFG10). Loss-of-function mutations cause SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG, CDG type Iq) and Kahrizi syndrome, characterized by ocular coloboma, cerebellar vermis hypoplasia, and intellectual disability. Despite its name, SRD5A3 is not a physiological steroid 5-alpha-reductase; a weak in-vitro testosterone-to-dihydrotestosterone activity was reported at its discovery in prostate cancer, but its established physiological role is in dolichol synthesis and glycosylation, not steroid metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred ER localization, consistent with the experimentally determined localization of SRD5A3 (an ER-membrane dolichol-pathway enzyme). Reason: SRD5A3 acts in the ER membrane where dolichol biosynthesis and lipid-linked oligosaccharide assembly occur; this is directly supported experimentally. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0006488 dolichol-linked oligosaccharide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in dolichol-linked oligosaccharide (LLO) biosynthesis. SRD5A3 supplies dolichol/dolichol-phosphate, the lipid carrier on which the LLO precursor is built, so this pathway-level BP is appropriate, though not the most specific reaction SRD5A3 catalyzes. Reason: SRD5A3 is required for LLO synthesis; loss of SRD5A3 severely reduces newly synthesized LLO and can be rescued by exogenous dolichol-phosphate, placing it upstream of LLO assembly. Supporting Evidence: PMID:20637498 SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation |
| GO:0160198 polyprenal reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred polyprenal reductase activity, the current core molecular function of SRD5A3. This is the term carried by GOA (polyprenAL reductase activity, GO:0160198), matching the revised pathway in which SRD5A3 reduces polyprenal to dolichal rather than polyprenol directly to dolichol. Reason: Represents the core molecular function at the correct current level of specificity; consistent with the IDA/EXP experimental annotations and UniProt EC 1.3.1.94. Supporting Evidence: PMID:38821050 SRD5A3 catalyzes only the second reaction |
| GO:0043048 dolichyl monophosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in dolichyl monophosphate biosynthesis, the current core biological process for SRD5A3. GO:0019408 (dolichol biosynthetic process) was obsoleted in favor of GO:0043048, so this is the correct current BP for the polyprenol-to-dolichol/dolichol-phosphate route. Reason: SRD5A3 catalyzes a committed reductive step supplying dolichol for dolichol-phosphate synthesis; supported by strong IDA evidence in human cells. Supporting Evidence: PMID:20637498 SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt subcellular-location keyword. SRD5A3 is a multi-pass ER membrane protein, so this is correct and represents the core localization. Reason: Consistent with experimental ER localization and the multi-pass membrane topology annotated in UniProt. Supporting Evidence: file:human/SRD5A3/SRD5A3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane file:human/SRD5A3/SRD5A3-uniprot.txt Multi-pass membrane protein |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Broad InterPro-to-GO mapping. Correct in that SRD5A3 acts in polyisoprenoid lipid (dolichol) metabolism, but far too general to convey its function. Reason: Not wrong but uninformative; the specific dolichyl monophosphate biosynthetic process (GO:0043048) already captures the lipid-metabolic role more precisely. Supporting Evidence: file:human/SRD5A3/SRD5A3-uniprot.txt PATHWAY: Protein modification; protein glycosylation |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-to-GO mapping to a high-level oxidoreductase class. SRD5A3 is an NADPH-dependent reductase that reduces a C=C double bond (the alpha-isoprene unit), so this parent term is correct but general. Reason: Accurate but non-specific; the specific polyprenal reductase activity (GO:0160198) is the informative core MF. Supporting Evidence: PMID:38821050 as a NADPH-dependent reductase in two non-consecutive steps |
| GO:0043048 dolichyl monophosphate biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-to-GO mapping (IPR039698, Dfg10/SRD5A3) to dolichyl monophosphate biosynthesis. This matches the experimentally supported core BP. Reason: Correct BP for the SRD5A3/Dfg10 family; duplicates the IDA/IBA annotations to the same term. Supporting Evidence: PMID:20637498 required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation |
| GO:0047751 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity | IEA GO_REF:0000120 | REMOVE | Summary: Electronic annotation derived from the EC 1.3.1.22 (steroid) mapping via RHEA/EC (GO_REF:0000120). SRD5A3 is not a physiological steroid 5-alpha-reductase; its established function is polyprenal reduction in dolichol synthesis. The steroid EC was assigned on the basis of the gene name and weak in-vitro activity, and this purely electronic EC-mapping is a wrong inference of the enzyme's biological function. Reason: Demonstrably wrong electronic EC/RHEA-to-GO inference. Physiological substrate is polyprenal, not a steroid; null patients have a congenital disorder of glycosylation, not a steroid/androgen phenotype, and phylogeny argues the ancestral substrate was not a steroid. Per policy, wrong IEA EC-mappings are appropriate REMOVE targets. Supporting Evidence: PMID:20637498 suggesting that the substrate of the enzyme encoded by the common ancestral gene was potentially not a steroid |
| GO:0160198 polyprenal reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from EC 1.3.1.94 (RHEA:80727) mapping. This is the correct core molecular function, matching the experimental annotations and UniProt RecName (Polyprenal reductase). Reason: Correct EC-based mapping to the physiological reaction; corroborates the IDA/EXP/IBA annotations to GO:0160198. Supporting Evidence: file:human/SRD5A3/SRD5A3-uniprot.txt EC=1.3.1.94 |
| GO:0006488 dolichol-linked oligosaccharide biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based transfer (Ensembl Compara) from mouse Srd5a3 of the LLO biosynthesis BP. Consistent with the human experimental data and the IBA annotation to the same term. Reason: Correct pathway-level BP inferred from a well-supported ortholog; duplicates the IBA annotation. Supporting Evidence: PMID:20637498 the oligosaccharide precursor used for N-glycosylation |
| GO:0006702 androgen biosynthetic process | TAS Reactome:R-HSA-193048 | MARK AS OVER ANNOTATED | Summary: Reactome-derived annotation placing SRD5A3 in androgen biosynthesis, based on the prostate-cancer report that SRD5A3 can convert testosterone to dihydrotestosterone in vitro (Uemura et al. 2008). SRD5A3 is named a steroid 5-alpha-reductase and shows weak in-vitro DHT-forming activity, but its physiological function is dolichol synthesis, not androgen metabolism; this is an over-annotation of a marginal side activity. Reason: The steroid/androgen activity is weak, in-vitro, and derives from the gene name and the context of its discovery in hormone-refractory prostate cancer; loss-of-function causes a glycosylation disorder, not an androgen-deficiency phenotype. Retained (experimental basis, TAS) but flagged as over-annotation rather than removed. Supporting Evidence: PMID:17986282 validated its ability to produce DHT from testosterone, similar to type |
| GO:0043048 dolichyl monophosphate biosynthetic process | TAS Reactome:R-HSA-446199 | ACCEPT | Summary: Reactome-authored annotation (Synthesis of dolichyl-phosphate) to the core dolichyl monophosphate biosynthetic process. Consistent with the experimental and IBA annotations. Reason: Correct core BP; duplicates the IDA/IBA/IEA annotations to GO:0043048. Supporting Evidence: PMID:20637498 SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols |
| GO:0003865 3-oxo-5-alpha-steroid 4-dehydrogenase activity | TAS Reactome:R-HSA-9705714 | MARK AS OVER ANNOTATED | Summary: Reactome-derived steroid 5-alpha-reductase MF annotation (SRD5A3 dehydrogenates TEST to DHTEST), tracing to the in-vitro testosterone-to-DHT activity of Uemura et al. 2008. This is a weak, non-physiological side activity and an over-annotation relative to the enzyme's dolichol-pathway function. Reason: Steroid 5-alpha-reductase activity is in-vitro and marginal; SRD5A3 is physiologically a polyprenal reductase. Retained (TAS/experimental origin) but flagged as over-annotation, not removed. Supporting Evidence: PMID:17986282 validated its ability to produce DHT from testosterone, similar to type |
| GO:0160198 polyprenal reductase activity | EXP PMID:38821050 A pseudoautosomal glycosylation disorder prompts the revisio... | ACCEPT | Summary: Experimental demonstration (Wilson et al. 2024) that SRD5A3 is the NADPH-dependent polyprenal reductase catalyzing the second step of the revised dolichol-biosynthesis pathway (polyprenal to dolichal). This is the core molecular function. Reason: Direct experimental evidence for the precise current MF term (GO:0160198). Supporting Evidence: PMID:38821050 SRD5A3 catalyzes only the second reaction |
| GO:0043048 dolichyl monophosphate biosynthetic process | IDA PMID:20637498 SRD5A3 is required for converting polyprenol to dolichol and... | ACCEPT | Summary: Direct experimental evidence (Cantagrel et al. 2010) that SRD5A3 is required for converting polyprenol to dolichol, supplying dolichol-phosphate for glycosylation; SRD5A3-deficient cells show reduced dolichol-phosphate-dependent LLO synthesis rescuable by exogenous Dol-P. Core BP. Reason: Strong IDA evidence for the core dolichyl monophosphate biosynthetic process (note GO:0019408 dolichol biosynthetic process was obsoleted into GO:0043048). Supporting Evidence: PMID:20637498 SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols |
| GO:0043048 dolichyl monophosphate biosynthetic process | IDA PMID:38821050 A pseudoautosomal glycosylation disorder prompts the revisio... | ACCEPT | Summary: Direct experimental evidence (Wilson et al. 2024) that SRD5A3 acts in dolichol biosynthesis, catalyzing the NADPH-dependent polyprenal-to-dolichal step feeding dolichol/dolichol-phosphate production. Core BP. Reason: Strong IDA evidence for the core dolichyl monophosphate biosynthetic process in the revised pathway. Supporting Evidence: PMID:38821050 SRD5A3 catalyzes only the second reaction |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:20637498 SRD5A3 is required for converting polyprenol to dolichol and... | ACCEPT | Summary: Direct experimental evidence that epitope-tagged SRD5A3 localizes predominantly to the ER, where dolichol synthesis and LLO assembly occur. Core localization. Reason: Experimentally supported active-in ER membrane localization for a multi-pass membrane enzyme. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0160198 polyprenal reductase activity | IDA PMID:38821050 A pseudoautosomal glycosylation disorder prompts the revisio... | ACCEPT | Summary: Direct experimental evidence (Wilson et al. 2024) for SRD5A3 polyprenal reductase activity, the core molecular function. Duplicates the EXP annotation to the same term. Reason: Direct experimental support for the precise current MF. Supporting Evidence: PMID:38821050 as a NADPH-dependent reductase in two non-consecutive steps |
| GO:0047751 3-oxo-5-alpha-steroid 4-dehydrogenase (NADP+) activity | IDA PMID:17986282 Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpr... | MARK AS OVER ANNOTATED | Summary: Experimental annotation from the discovery paper (Uemura et al. 2008), which showed in-vitro conversion of testosterone to dihydrotestosterone by SRD5A3 overexpressed in prostate-cancer cells. This established the "steroid 5-alpha-reductase 3" naming but reflects a weak, non-physiological side activity; SRD5A3's physiological role is polyprenal reduction in dolichol synthesis. Reason: Experimental (IDA), so retained rather than removed, but flagged as an over-annotation. The 5-alpha-steroid reductase activity is in-vitro and marginal, and does not represent the enzyme's physiological function (null mutations cause a glycosylation disorder, not androgen deficiency). Supporting Evidence: PMID:17986282 validated its ability to produce DHT from testosterone, similar to type PMID:17986282 resulted in a significant decrease in DHT production and a drastic reduction in cell |
| GO:0016628 oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor | TAS Reactome:R-HSA-4755572 | KEEP AS NON CORE | Summary: Reactome-derived high-level oxidoreductase MF annotation. Correct as a parent class of the polyprenal reductase reaction (NADPH-dependent reduction of a C=C bond) but general. Reason: Accurate parent term; the specific polyprenal reductase activity (GO:0160198) is the informative core MF. Supporting Evidence: PMID:38821050 as a NADPH-dependent reductase in two non-consecutive steps |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-4755572 | ACCEPT | Summary: Reactome-authored ER membrane localization, consistent with the experimental IDA localization. Core localization. Reason: Correct localization for this multi-pass ER membrane enzyme; duplicates the IDA/IEA ER-membrane annotations. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9705714 | ACCEPT | Summary: Reactome-authored ER membrane localization (from the steroid-reaction module), consistent with experimental data. Core localization. Reason: Correct ER membrane localization; duplicates other ER-membrane annotations. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9937295 | ACCEPT | Summary: Reactome-authored ER membrane localization (from the revised polyprenal-to-dolichal reaction module), consistent with experimental data. Core localization. Reason: Correct ER membrane localization; duplicates other ER-membrane annotations. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0005783 endoplasmic reticulum | IDA PMID:20637498 SRD5A3 is required for converting polyprenol to dolichol and... | ACCEPT | Summary: Direct experimental evidence that epitope-tagged SRD5A3 localizes predominantly to the ER. Correct, though the more specific ER membrane term (GO:0005789) better captures its location as a multi-pass membrane protein. Reason: Experimentally supported ER localization; the coexisting ER-membrane annotations provide the more specific compartment. Supporting Evidence: PMID:20637498 Epitope tagged SRD5A3 localized predominantly to the ER |
| GO:0016628 oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor | IDA PMID:20637498 SRD5A3 is required for converting polyprenol to dolichol and... | KEEP AS NON CORE | Summary: Experimental annotation to a high-level NADP-dependent CH-CH oxidoreductase class, based on the demonstration that SRD5A3 reduces the alpha-isoprene C=C bond of polyprenol to form dolichol. Correct but general. Reason: Accurate parent term for the reductase activity; the specific polyprenal reductase activity (GO:0160198) is the informative core MF. Supporting Evidence: PMID:20637498 SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols |
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Download this section (compressed HTML)Q: Given the revised pathway (Wilson et al. 2024), is the physiological substrate of SRD5A3 strictly polyprenal, and does it have any residual direct polyprenol-reducing activity in vivo?
Q: Is the in-vitro testosterone-to-dihydrotestosterone activity of SRD5A3 physiologically relevant in any tissue (e.g. prostate cancer), or purely an artifact of overexpression?
Experiment: Structural/biochemical characterization of SRD5A3 with polyprenal versus steroid substrates to quantify catalytic efficiency and confirm the physiological substrate.
Experiment: Tissue-specific conditional knockouts to test whether any androgen/steroid phenotype arises independently of the glycosylation defect.
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