DHRS3 (short-chain dehydrogenase/reductase 3; also known as retSDR1, RDH17 and SDR16C1) is a membrane-bound, NADPH-dependent oxidoreductase of the short-chain dehydrogenase/reductase (SDR) superfamily that catalyzes the reduction of all-trans-retinaldehyde to all-trans-retinol (EC 1.1.1.300). By consuming retinaldehyde, it acts as a counterweight to the retinol dehydrogenases (chiefly RDH10) and the retinaldehyde dehydrogenases (ALDH1A) that drive synthesis of the morphogen all-trans-retinoic acid, and thereby helps set retinoid/retinoic-acid concentrations. It functions within a mutually activating complex with RDH10 in the endoplasmic reticulum membrane, is a multi-pass membrane protein with an N-terminal membrane anchor and a Rossmann-fold nucleotide-binding core, and is itself induced by retinoic acid, forming a negative-feedback buffer on retinoid levels. DHRS3 is widely expressed and is essential for normal embryonic development; in the retina it is expressed in cone (but not rod) outer segments, where the same retinaldehyde-to-retinol reduction contributes to the visual (retinoid) cycle.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001523 retinoid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: DHRS3 is a retinaldehyde reductase acting in retinoid metabolism, so this phylogenetically inferred process term is correct and reflects the gene's biological context. It is broader than the more specific retinol metabolic process; retained as a valid pathway-level annotation. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Catalyzes the reduction of all-trans-retinal to all-trans- retinol in the presence of NADPH. |
| GO:0005811 lipid droplet | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Lipid-droplet localization is a family-level (IBA) inference from SDR orthologs. It is biologically plausible for a lipid/retinoid-metabolizing enzyme, but the informative, experimentally and Reactome-supported location for DHRS3 is the endoplasmic reticulum membrane. Kept as a non-core localization pending direct evidence in human DHRS3. |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | MODIFY | Summary: The reductase activity is correct, but the cofactor is wrong: DHRS3 is NADPH/NADP+-dependent, not NAD+-dependent. UniProt and the primary characterization define the NADP(+) reaction (EC 1.1.1.300). Modify to the NADP+ term GO:0052650. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002802671 · SDR16C retinol dehydrogenase family node SUPPORTS SOURCE BUT NOT TARGET The family-level retinol dehydrogenase activity transfers, but the specific cofactor (NAD+) is wrong for human DHRS3, which is NADP+/NADPH-dependent (UniProt EC 1.1.1.300). Correct term is the NADP+ activity GO:0052650. Proposed replacements: all-trans-retinol dehydrogenase (NADP+) activity Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + |
| GO:0048385 regulation of retinoic acid receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: By reducing retinaldehyde and limiting retinoic-acid production, DHRS3 indirectly modulates retinoic-acid-receptor signaling. This is a downstream consequence of its enzymatic control of retinoid levels rather than the direct molecular function; retained as a non-core process annotation. Supporting Evidence: PMID:40519748 is the major embryonic enzyme catalyzing the opposite reaction (RAL to ROL) |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Correct: UniProt classifies DHRS3 as a multi-pass membrane protein with four predicted transmembrane helices. However, this is the general parent of the informative curated location, endoplasmic reticulum membrane, so it is kept as non-core. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Membrane {ECO:0000305}; Multi-pass membrane |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the core molecular function of DHRS3 and matches EC 1.1.1.300 and the UniProt catalytic activity exactly (all-trans-retinol + NADP+ = all-trans-retinal + NADPH + H+, read in the reductase direction). Accept. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + |
| GO:0002138 retinoic acid biosynthetic process | IMP PMID:40519748 Identification and characterization of short-chain dehydroge... | KEEP AS NON CORE | Summary: Experimental (IMP) annotation from the DHRS3-deficiency embryopathy study: loss-of-function human variants and the mouse knockout perturb retinoic-acid levels, establishing that DHRS3 participates in the retinoic-acid biosynthetic pathway. Its direct action, however, is to reduce retinaldehyde back to retinol and thereby LIMIT retinoic-acid synthesis, so its role in this pathway is regulatory/negative rather than biosynthetic. Retained (per policy, experimental annotations are not removed) but marked non-core; negative regulation of retinoic acid biosynthetic process (GO:1900053) would be a more precise placement. Supporting Evidence: PMID:40519748 Cells transfected with a DHRS3-Val171Met construct exhibited reduced retinaldehyde reduction capacity compared with wild-type, yielding reduced retinol and elevated RA |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-2187335 | ACCEPT | Summary: Correct pathway-level process term, supported by the Reactome retinoid-cycle pathway. Consistent with DHRS3's retinaldehyde-reductase activity in retinoid metabolism; broader than retinol metabolic process. Accept. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Catalyzes the reduction of all-trans-retinal to all-trans- retinol in the presence of NADPH. |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-2465940 | ACCEPT | Summary: Core molecular function, curated by Reactome (atRAL is reduced to atROL using NADP+/NADPH). Consistent with UniProt EC 1.1.1.300. Accept. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-5419165 | ACCEPT | Summary: Core molecular function, curated by Reactome (DHRS3 among reductases that reduce atRAL to atROL). Consistent with the NADP+ reaction in UniProt. Accept. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | EXP PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | ACCEPT | Summary: Direct experimental evidence: the original characterization cloned retSDR1 (DHRS3) and showed it reduces all-trans-retinal with the substrate specificity of the photoreceptor all-trans-retinol dehydrogenase, defining EC 1.1.1.300. This is the core molecular function. Accept. Supporting Evidence: PMID:9705317 retSDR1 expressed in insect cells displayed substrate specificities of the photoreceptor all-trans-retinol dehydrogenase. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5419165 | ACCEPT | Summary: Correct and the informative core localization: DHRS3 is a multi-pass membrane protein that functions in a complex with RDH10 inserted in the endoplasmic reticulum membrane. Accept. Supporting Evidence: PMID:40519748 RDH10 and DHRS3 function together as a molecular complex inserted within the membrane of the endoplasmic reticulum. |
| GO:0042622 photoreceptor outer segment membrane | TAS Reactome:R-HSA-2465940 | KEEP AS NON CORE | Summary: Retina-specific localization from the visual (retinoid) cycle; consistent with DHRS3 being expressed in cone outer segments. This is a tissue-specific context rather than the general (ER membrane) localization, so it is kept as non-core. Supporting Evidence: file:human/DHRS3/DHRS3-uniprot.txt In the retina, expressed in cone but not rod outer segments. |
| GO:0009055 electron transfer activity | TAS PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | MARK AS OVER ANNOTATED | Summary: DHRS3 is a hydride-transferring NADPH-dependent retinaldehyde reductase, not a dedicated electron carrier in an electron transport process. This TAS term is an over-general/miscast mapping of the oxidoreductase chemistry; the specific and correct molecular function is captured by GO:0052650. Marked as over-annotated (TAS, not removed). |
| GO:0042572 retinol metabolic process | TAS PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | ACCEPT | Summary: Correct core process: DHRS3 produces all-trans-retinol from retinaldehyde and is implicated in retinol metabolism beyond photoreceptors. Accept. Supporting Evidence: PMID:9705317 the enzyme may also be involved in retinol |
| GO:0000166 nucleotide binding | TAS PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | MARK AS OVER ANNOTATED | Summary: DHRS3 binds its NADP(H) cofactor via a Rossmann fold, but nucleotide binding is the uninformative parent term. The specific, informative molecular function is NADP binding (GO:0050661). Marked as over-annotated rather than removed (TAS); the specific cofactor-binding term is proposed in core_functions. Supporting Evidence: PMID:9705317 predicted a classical Rossmann fold for the nucleotide binding |
| GO:0007601 visual perception | TAS PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | KEEP AS NON CORE | Summary: DHRS3/retSDR1 contributes to regeneration of the visual chromophore in cone photoreceptors, so a visual-perception role is defensible in that tissue. However, this is a tissue-specific downstream context of the same retinaldehyde-reductase activity; the authors themselves note the enzyme also acts in retinol metabolism outside photoreceptors. Kept as a non-core process. Supporting Evidence: PMID:9705317 regeneration of bleached visual pigments |
| GO:0050661 NADP binding | IDA PMID:9705317 Molecular characterization of a novel short-chain dehydrogen... | NEW | Summary: Proposed NEW annotation capturing the specific cofactor-binding function. DHRS3 binds its NADP(H) cofactor via a Rossmann fold, and the UniProt NADP+ catalytic reaction confirms NADP(H) as the coenzyme. This replaces the uninformative nucleotide binding parent (GO:0000166) with the specific term. Supporting Evidence: PMID:9705317 predicted a classical Rossmann fold for the nucleotide binding file:human/DHRS3/DHRS3-uniprot.txt Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + NADPH + |
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