Short-chain dehydrogenase/reductase (SDR) family enzyme containing an NAD(P)-binding Rossmann-like domain. The gene name "drd-5" indicates "dietary restriction down regulated." Based on domain architecture (adh_short PF00106, IPR002347) and phylogenetic placement (PANTHER subfamily PTHR43313:SF18), this protein is predicted to function as an NAD(P)-dependent oxidoreductase. The closest characterized ortholog is C. elegans dhs-16, which participates in dafachronic acid (steroid hormone) biosynthesis controlling dauer/reproductive development via the DAF-12 nuclear receptor pathway. No direct experimental characterization exists for this specific C. briggsae protein.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008202 steroid metabolic process | IBA GO_REF:0000033 | MODIFY | Summary: This biological process annotation is inferred from phylogenetic analysis (IBA via PANTHER). The annotation is supported by orthology to C. elegans dhs-16, which functions in dafachronic acid biosynthesis. However, GO:0008202 (steroid metabolic process) is overly generic - we know from the characterized ortholog DHS-16 that the direction is biosynthesis (not catabolism) and the product is dafachronic acids (steroid hormones). A more specific term is warranted. Reason: The term GO:0008202 (steroid metabolic process) is too generic. Based on orthology to C. elegans DHS-16, which specifically functions in dafachronic acid BIOSYNTHESIS (not catabolism), this annotation should be replaced with GO:0120178 (steroid hormone biosynthetic process). DHS-16 contributes to production of DAF-12 ligands (dafachronic acids) that govern dauer vs reproductive development [Butcher 2017, Karp 2021]. Proposed replacements: steroid hormone biosynthetic process Supporting Evidence: DOI:10.1038/nchembio.2356 DHS-16 is a short-chain dehydrogenase acting downstream of DAF-36 in the dafachronic acid pathway; contributes to PRODUCTION of DAF-12 ligands file:CAEBR/drd-5/drd-5-deep-research-falcon.md DHS-16 (C. elegans): A short-chain dehydrogenase acting downstream of DAF-36 in the dafachronic acid pathway |
| GO:0016491 oxidoreductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This molecular function annotation is inferred from phylogenetic analysis (IBA via PANTHER). The annotation is strongly supported by the protein's domain architecture: adh_short (PF00106), NAD(P)-binding Rossmann-like domain (IPR036291), and SDR consensus (IPR020904). SDR family enzymes are characterized NAD(P)-dependent oxidoreductases with hallmark sequence motifs including glycine-rich TGxxxGxG cofactor-binding region and active-site YxxxK catalytic motif [Graff 2019, Gabrielli 2022]. While oxidoreductase activity is accurate, a more specific molecular function term such as "3-beta-hydroxysteroid dehydrogenase activity" would be preferable if substrate specificity were experimentally confirmed. Reason: The annotation is accurate and well-supported by domain architecture. All SDR family enzymes function as oxidoreductases catalyzing reversible carbonyl-alcohol transformations using NAD(P) cofactors [Graff 2019]. The term "oxidoreductase activity" (GO:0016491) is appropriately conservative given no direct experimental characterization of this protein's specific substrates or reaction mechanism. A more specific hydroxysteroid dehydrogenase term would require experimental validation. Supporting Evidence: DOI:10.1002/prot.25666 SDRs are ubiquitous NAD(P)-dependent oxidoreductases characterized by a Rossmann-like cofactor-binding fold and hallmark sequence motifs, notably an N-terminal glycine-rich TGxxxGxG/TGxxGxxG motif and an active-site YxxxK catalytic motif file:CAEBR/drd-5/drd-5-deep-research-falcon.md SDR superfamily: SDRs are ubiquitous NAD(P)-dependent oxidoreductases characterized by a Rossmann-like cofactor-binding fold |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: This molecular function annotation is derived from UniProtKB keyword mapping (IEA). The UniProt entry for A8Y332 contains the keyword "Oxidoreductase" (KW-0560) based on domain analysis, which is automatically mapped to GO:0016491. This represents the same annotation as the IBA above but derived through a different evidence pathway (keyword mapping vs phylogenetic inference). The annotation is valid and consistent with domain architecture. Reason: The IEA annotation is accurate and consistent with the IBA annotation for the same term. The UniProtKB keyword "Oxidoreductase" is appropriately assigned based on the SDR domain architecture (adh_short PF00106). While this creates a duplicate annotation with IBA, both evidence sources independently support the oxidoreductase activity. Retaining both is acceptable as they represent independent lines of evidence (sequence-based keyword mapping vs phylogenetic inference). Supporting Evidence: file:CAEBR/drd-5/drd-5-uniprot.txt Oxidoreductase {ECO:0000256|ARBA:ARBA00023002} |
| GO:0016229 steroid dehydrogenase activity | ISS GO_REF:0000024 | NEW | Summary: Proposed new annotation based on synthesis of domain architecture and orthology evidence. GO:0016229 (steroid dehydrogenase activity) is more specific than GO:0016491 (oxidoreductase activity) and is supported by: (1) orthology to C. elegans DHS-16, a characterized steroid dehydrogenase in the dafachronic acid pathway, and (2) phylogenetic placement in PANTHER subfamily PTHR43313:SF18 with characterized steroidogenic SDRs. This term captures the inferred substrate class (steroids) while remaining appropriately broad given lack of direct experimental characterization. Reason: Synthesis of evidence supports more specific annotation than the existing GO:0016491. The ortholog DHS-16 in C. elegans acts on steroid substrates in dafachronic acid biosynthesis. ISS evidence via sequence similarity to characterized ortholog is appropriate. Supporting Evidence: DOI:10.1038/nchembio.2356 DHS-16 is a short-chain dehydrogenase acting downstream of DAF-36 in the dafachronic acid pathway GO_REF:0000033 PANTHER places drd-5 with characterized steroidogenic SDRs |
| GO:0120178 steroid hormone biosynthetic process | ISS GO_REF:0000024 | NEW | Summary: Proposed new annotation based on orthology to C. elegans DHS-16. GO:0120178 (steroid hormone biosynthetic process) is more specific than GO:0008202 (steroid metabolic process) and reflects the known role of the ortholog DHS-16 in dafachronic acid (steroid hormone) biosynthesis. Dafachronic acids are ligands for the DAF-12 nuclear hormone receptor that controls dauer vs reproductive development in nematodes. Reason: The ortholog DHS-16 functions specifically in biosynthesis (not catabolism) of dafachronic acids, which are steroid hormones. This more specific process term better captures the predicted biological role than the broader GO:0008202 term. Supporting Evidence: DOI:10.1038/nchembio.2356 DHS-16 contributes to production of DAF-12 ligands (dafachronic acids) that govern dauer vs reproductive development DOI:10.3389/fevo.2021.735924 The short chain dehydrogenase DHS-16 works further downstream in this pathway. The enzymes involved in the production of other dafachronic acids are unknown. |
Loading supporting content…
Download this section (compressed HTML)Q: What is the substrate specificity of drd-5 - does it act on steroid intermediates like its C. elegans ortholog dhs-16?
Q: Is drd-5 involved in the dafachronic acid biosynthesis pathway in C. briggsae as dhs-16 is in C. elegans?
Q: What is the cofactor preference (NAD vs NADP) for drd-5?
Q: In which tissues is drd-5 expressed, and does expression correlate with developmental decisions?
Experiment: Recombinant protein expression and enzymatic assay with steroid substrates to determine substrate specificity and confirm predicted oxidoreductase activity
Experiment: NAD/NADP cofactor preference assay - SDR family members vary in cofactor usage and determining preference would inform mechanism
Experiment: Phylogenetic analysis with nematode SDRs including DHS-16 and RML enzymes to refine functional predictions based on characterized ortholog clusters
Experiment: Gene knockout or RNAi in C. briggsae with phenotypic analysis to determine biological role, particularly in dauer/developmental decisions
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)