RDH5 (retinol dehydrogenase 5), also known as 11-cis retinol dehydrogenase, is a microsomal NAD(H)-dependent short-chain dehydrogenase/reductase (SDR family, SDR9C5) anchored in the endoplasmic reticulum membrane as a multi-pass membrane protein with a lumenal-facing catalytic domain, and it functions as a homodimer. It oxidizes cis-isomers of retinol (11-cis-, 9-cis-, and 13-cis-retinol) but has no activity toward all-trans retinoids. Its principal physiological role is in the visual (retinoid) cycle of the retinal pigment epithelium, where it catalyzes the step following the isomerase RPE65: the oxidation of 11-cis-retinol to 11-cis-retinal, the chromophore that recombines with opsins to regenerate rod and cone visual pigments. Beyond the eye RDH5 is widely expressed and also displays 3-alpha-hydroxysteroid dehydrogenase activity, oxidizing androsterone and 5-alpha-androstane-3-alpha,17-beta-diol, contributing to androgen (dihydrotestosterone) metabolism. Loss-of-function variants in RDH5 cause fundus albipunctatus, a form of congenital stationary night blindness with delayed dark adaptation and white retinal dots.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PANTHER) inference that RDH5 is active in the ER membrane. This agrees with experimental data (IDA, PMID:11675386) and UniProt subcellular location. Correct and part of the core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005788 endoplasmic reticulum lumen | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that the active site faces the ER lumen. Consistent with UniProt (multi-pass membrane protein with lumenal-side catalytic domain) and with the IDA annotation from PMID:11675386. Correct. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Lumenal side |
| GO:0001523 retinoid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of a retinoid metabolic role, correct for RDH5, which oxidizes cis-retinols within the retinoid (visual) cycle. Accurate but relatively general; the more specific retinol metabolic process and visual perception capture the core role. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Catalyzes the oxidation of cis-isomers of retinol, including |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | MODIFY | Summary: Family-level (IBA) assignment of all-trans-retinol dehydrogenase activity. This is the wrong substrate for RDH5: UniProt states the enzyme has no activity toward all-trans retinal and acts specifically on cis-isomers of retinol. The physiologically relevant and biochemically demonstrated activity is 11-cis-retinol dehydrogenase (GO:0106429). Modify to the cis-specific term. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt no activity towards all-trans retinal (By similarity). Plays a |
| GO:0004022 alcohol dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: Rhea-mapped electronic annotation to the broad parent alcohol dehydrogenase (NAD+) activity. Not incorrect (the cis-retinol reactions are formally alcohol oxidations) but uninformative compared with the specific 11-cis-retinol dehydrogenase term. Over-annotation. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt 11-cis-, 9-cis-, and 13-cis-retinol in an NAD-dependent manner |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from the UniProt subcellular-location keyword. Correct and redundant with the IDA/IBA ER membrane annotations. Core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning annotation to a very general oxidoreductase parent. True but uninformative relative to the specific 11-cis-retinol dehydrogenase activity. Over-annotation. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt 11-cis-, 9-cis-, and 13-cis-retinol in an NAD-dependent manner |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (EC/Rhea) annotation of androsterone dehydrogenase activity. This is experimentally supported (see EXP annotation from PMID:29541409 and IDA from PMID:9931293) but represents an extra-ocular steroid-metabolizing (3-alpha-HSD) activity, not the core visual-cycle function. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Also recognizes steroids (androsterone, |
| GO:0047044 androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (EC/Rhea) annotation of 5-alpha-androstane-3-alpha,17-beta-diol dehydrogenase activity, supported experimentally by the IDA from PMID:9931293. A genuine secondary 3-alpha-HSD activity, extra-ocular and non-core. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt androstanediol) as its substrates (PubMed:29541409, PubMed:9931293). |
| GO:0106429 11-cis-retinol dehydrogenase (NAD+) activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-based electronic annotation of 11-cis-retinol dehydrogenase (NAD+) activity (EC 1.1.1.315). This is the correct, specific molecular function of RDH5 and its core evolved activity, supported by direct biochemistry (PubMed:10588954, 11675386, 9931293). Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Reaction=11-cis-retinol + NAD(+) = 11-cis-retinal + NADH + H(+); |
| GO:0001523 retinoid metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology projection (from mouse Rdh5) of a retinoid metabolic role. Correct and consistent with the IBA and IDA retinoid-metabolic-process annotations. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Catalyzes the oxidation of cis-isomers of retinol, including |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl orthology projection of all-trans-retinol dehydrogenase activity from the mouse ortholog. As with the IBA version, this is the wrong substrate: RDH5 acts on cis-retinols and has no all-trans activity. Modify to the cis-specific term. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt no activity towards all-trans retinal (By similarity). Plays a |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology projection of ER lumen localization. Consistent with the IDA annotation (PMID:11675386) and UniProt (lumenal-side active site). Correct. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Lumenal side |
| GO:0044297 cell body | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl orthology projection of "cell body" localization from a rat ortholog (UniProtKB:A0A0G2K1R4 / ENSRNOP00000071951). There is no experimental support for RDH5 residing in a neuronal cell body; RDH5 is an ER-membrane enzyme. This is a spurious cross-species electronic projection and should be removed. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-2453902 | ACCEPT | Summary: Reactome (canonical retinoid cycle in rods) traceable assignment of a retinoid metabolic role. Correct: RDH5 oxidizes 11-cis-retinol to 11-cis-retinal within the retinoid/visual cycle in the RPE. Supporting Evidence: Reactome:R-HSA-2454081 RDH5, can (reversibly) catalyse the oxidation of 11-cis-retinol (11cROL) to 11-cis-retinal |
| GO:0042572 retinol metabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-based electronic annotation of retinol metabolic process. Correct and the most substrate-precise process term for RDH5 (its substrate is a retinol). Core process. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt PATHWAY: Cofactor metabolism; retinol metabolism. |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | TAS Reactome:R-HSA-2454081 | MODIFY | Summary: Reactome maps RDH5 catalysis to the generic all-trans-retinol dehydrogenase GO term, but the Reactome reaction it annotates ("RDH5 oxidises 11cROL to 11cRAL") is explicitly the 11-cis reaction, and UniProt shows RDH5 has no all-trans activity. Modify to the cis-specific term. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: Reactome:R-HSA-2454081 RDH5, can (reversibly) catalyse the oxidation of 11-cis-retinol (11cROL) to 11-cis-retinal |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | TAS Reactome:R-HSA-2466832 | MODIFY | Summary: Reactome reaction ("Defective RDH5 does not oxidise 11cROL to 11cRAL") again describes the 11-cis reaction but is mapped to the generic all-trans GO term. Same wrong-substrate issue; modify to the 11-cis-specific molecular function. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Reaction=11-cis-retinol + NAD(+) = 11-cis-retinal + NADH + H(+); |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | TAS Reactome:R-HSA-5362721 | MODIFY | Summary: Reactome reaction ("RDH5,RDH11 oxidise 11cROL to 11cRAL") is the 11-cis oxidation mapped to the generic all-trans GO term. Modify to the substrate-correct 11-cis term. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Reaction=11-cis-retinol + NAD(+) = 11-cis-retinal + NADH + H(+); |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | EXP PMID:29541409 Inhibition of dihydrotestosterone synthesis in prostate canc... | KEEP AS NON CORE | Summary: Experimental annotation: RDH5 is one of four 3-alpha-oxidoreductases shown to convert androsterone (AND) to 5-alpha-dione, with activity abolished by the catalytic Y175F/K179R double mutant. This androsterone dehydrogenase activity is genuine but extra-ocular (prostate androgen "backdoor" metabolism), not the core visual-cycle function. Keep as non-core. Supporting Evidence: PMID:29541409 metabolism of 5Ξ±-androstan-3Ξ±-ol-17-one (androsterone; AND) to 5Ξ±-dione |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-2454081 | ACCEPT | Summary: Reactome localization of the RDH5 reaction to the ER membrane. Correct and consistent with IDA (PMID:11675386) and UniProt. Core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5362721 | ACCEPT | Summary: Reactome localization (RDH5,RDH11 reaction) to the ER membrane. Correct; redundant with other ER membrane annotations. Core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0001523 retinoid metabolic process | IDA PMID:9931293 Activity of human 11-cis-retinol dehydrogenase (Rdh5) with s... | ACCEPT | Summary: Direct-assay annotation of a retinoid metabolic role. PMID:9931293 characterized RDH5 catalysis of 9-cis- and 11-cis-retinol oxidation. Correct; the retinoid/retinol metabolic process is a core process for RDH5. Supporting Evidence: PMID:9931293 Rdh5 catalyses 9-cis-retinol metabolism equally efficiently as 11-cis-retinol metabolism |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IDA PMID:11675386 Biochemical defects in 11-cis-retinol dehydrogenase mutants ... | MODIFY | Summary: Experimental (IDA) annotation labeled as all-trans-retinol dehydrogenase activity, but PMID:11675386 assayed 11-cis-retinol dehydrogenase activity of RDH5 and its fundus-albipunctatus mutants (the paper is titled "Biochemical defects in 11-cis-retinol dehydrogenase mutants"), and UniProt states RDH5 has no all-trans activity. The measured enzyme is real but the substrate label is wrong; modify to the 11-cis-specific term rather than removing an experimental annotation. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: PMID:11675386 Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with file:human/RDH5/RDH5-uniprot.txt no activity towards all-trans retinal (By similarity). Plays a |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:11675386 Biochemical defects in 11-cis-retinol dehydrogenase mutants ... | ACCEPT | Summary: Direct experimental evidence that the RDH5 catalytic domain resides on the lumenal side of the ER. Correct core localization (multi-pass ER membrane protein with lumenal active site). Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt Lumenal side |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:11675386 Biochemical defects in 11-cis-retinol dehydrogenase mutants ... | ACCEPT | Summary: Direct experimental evidence for ER membrane localization of RDH5. This is the anchoring IDA that the IBA/IEA/TAS ER-membrane annotations reinforce. Core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0008202 steroid metabolic process | IDA PMID:9931293 Activity of human 11-cis-retinol dehydrogenase (Rdh5) with s... | KEEP AS NON CORE | Summary: Direct evidence that RDH5 metabolizes steroids (3-alpha-hydroxysteroid dehydrogenase activity on androsterone and 5-alpha-androstane-3-alpha,17-beta-diol). A genuine but extra-ocular activity; steroid metabolism is a secondary, non-core process for RDH5. Supporting Evidence: PMID:9931293 recognizes 5alpha-androstan-3alpha,17beta-diol and androsterone as substrates |
| GO:0042803 protein homodimerization activity | IDA PMID:11675386 Biochemical defects in 11-cis-retinol dehydrogenase mutants ... | KEEP AS NON CORE | Summary: Cross-linking and molecular-modeling evidence that RDH5 is a homodimer. Correct; supports quaternary structure. Not the core catalytic function but a real, direct biochemical property. Supporting Evidence: PMID:11675386 molecular modeling showed that RDH5 is |
| GO:0047023 androsterone dehydrogenase [NAD(P)+] activity | IDA PMID:9931293 Activity of human 11-cis-retinol dehydrogenase (Rdh5) with s... | KEEP AS NON CORE | Summary: Direct-assay androsterone dehydrogenase activity (3-alpha-HSD). Genuine secondary activity, extra-ocular, non-core. Redundant with the EXP annotation from PMID:29541409. Supporting Evidence: PMID:9931293 recognizes 5alpha-androstan-3alpha,17beta-diol and androsterone as substrates |
| GO:0047044 androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity | IDA PMID:9931293 Activity of human 11-cis-retinol dehydrogenase (Rdh5) with s... | KEEP AS NON CORE | Summary: Direct-assay 5-alpha-androstane-3-alpha,17-beta-diol dehydrogenase activity. Genuine secondary 3-alpha-HSD activity, extra-ocular and non-core. Supporting Evidence: PMID:9931293 recognizes 5alpha-androstan-3alpha,17beta-diol and androsterone as substrates |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-2466832 | ACCEPT | Summary: Reactome localization (defective-RDH5 reaction) to the ER membrane. Correct; redundant with other ER membrane annotations. Core localization. Supporting Evidence: file:human/RDH5/RDH5-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | TAS PMID:9115228 Identification and characterization of a stereospecific huma... | MODIFY | Summary: Older traceable assignment (PINC) mapping RDH5 to all-trans-retinol dehydrogenase activity. PMID:9115228 in fact showed RDH5 oxidizes 9-cis- (and 13-cis-) retinol but "does not catalyze all-trans-retinol oxidation". The all-trans label is contradicted by the very reference cited; modify to the substrate-correct cis-retinol dehydrogenase term. Proposed replacements: 11-cis-retinol dehydrogenase (NAD+) activity Supporting Evidence: PMID:9115228 does not catalyze all-trans-retinol oxidation |
| GO:0007601 visual perception | TAS PMID:10369264 Mutations in the gene encoding 11-cis retinol dehydrogenase ... | ACCEPT | Summary: Traceable assignment of a role in visual perception. RDH5 supplies 11-cis-retinal for regeneration of rod and cone visual pigments; loss of function causes fundus albipunctatus with delayed dark adaptation. This is the core physiological process. Supporting Evidence: PMID:10369264 this retinoid is the chromophore residing in rhodopsin and the cone opsins |
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