{"uniprot":"A6NNS2","gene":"DHRS7C","name":"Dehydrogenase/reductase SDR family member 7C","organism":"Homo sapiens (Human)","status":"dark","length":312,"sequence":"MGVMAMLMLPLLLLGISGLLFIYQEVSRLWSKSAVQNKVVVITDAISGLGKECARVFHTGGARLVLCGKNWERLENLYDALISVADPSKQTFTPKLVLLDLSDISCVPDVAKEVLDCYGCVDILINNASVKVKGPAHKISLELDKKIMDANYFGPITLTKALLPNMISRRTGQIVLVNNIQGKFGIPFRTTYAASKHAALGFFDCLRAEVEEYDVVISTVSPTFIRSYHVYPEQGNWEASIWKFFFRKLTYGVHPVEVAEEVMRTVRRKKQEVFMANPIPKAAVYVRTFFPEFFFAVVACGVKEKLNVPEEG","function_summary":"A membrane-associated human oxidoreductase that uses a short-chain dehydrogenase/reductase catalytic core to bind nicotinamide cofactors and interconvert retinoids and small carbonyl substrates. By positioning at endoplasmic and sarcoplasmic reticulum membranes, it tunes local redox and retinoid pools to modulate calcium-release machinery and broader intracellular calcium balance. Through this redox–calcium coupling, it also influences glucose uptake pathways in excitable and secretory tissues.","plain_language":"DHRS7C has barely been studied. The model's best guess: A membrane-associated human oxidoreductase that uses a short-chain dehydrogenase/reductase catalytic core to bind nicotinamide cofactors and interconvert retinoids and small carbonyl substrates. By positioning at endoplasmic and sarcoplasmic reticulum membranes, it tunes local redox and retinoid pools to modulate calcium-release machinery and broader intracellular calcium balance.","uniprot_summary":"Exhibits dehydrogenase activity, forming a spectrum of substrates including 5,6-dihydroxyindole, retinaldehyde, and 2- and 3-ketone.","go_terms":{"molecular_function":[{"id":"GO:0004745","label":"NAD-retinol dehydrogenase activity"}],"biological_process":[{"id":"GO:0010880","label":"regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum"},{"id":"GO:0006874","label":"intracellular calcium ion homeostasis"},{"id":"GO:0046323","label":"glucose import"}],"cellular_component":[{"id":"GO:0005783","label":"endoplasmic reticulum"},{"id":"GO:0033017","label":"sarcoplasmic reticulum membrane"},{"id":"GO:0005789","label":"endoplasmic reticulum membrane"}]},"interpro":[{"id":"IPR036291","name":"NAD(P)-binding domain superfamily","type":"homologous_superfamily","start":35,"end":287},{"id":"IPR052148","name":"Dehydrogenase/reductase SDR family member 7C","type":"family","start":1,"end":311},{"id":"IPR002347","name":"Short-chain dehydrogenase/reductase SDR","type":"family","start":38,"end":230},{"id":"IPR020904","name":"Short-chain dehydrogenase/reductase, conserved site","type":"conserved_site","start":179,"end":207}],"reasoning":"I begin with the InterPro architecture. The sequence is dominated by IPR052148 (Dehydrogenase/reductase SDR family member 7C, residues 1–311), which frames the entire polypeptide as a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Nested within this, IPR036291 (NAD(P)-binding domain superfamily, residues 35–287) and IPR002347 (Short-chain dehydrogenase/reductase SDR family, residues 38–230) define a classical Rossmann-like fold that binds nicotinamide cofactors and catalyzes reversible hydride transfer. The catalytic core is pinpointed by IPR020904 (SDR conserved site, residues 179–207), which encodes the hallmark Tyr–X3–Lys catalytic dyad and adjacent structural elements that position NAD(H) and substrate for oxidation–reduction. The ordered layout—N-terminal SDR scaffold, central NAD(P)-binding core, and the conserved catalytic site—causes a soluble oxidoreductase chemistry that is tuned toward retinoid/aldose–ketose interconversions.\n\nThis SDR architecture dictates the molecular function. The Rossmann-like NAD(P)-binding superfamily (IPR036291) and the SDR catalytic signature (IPR020904) together specify a dehydrogenase that transfers hydride to and from a nicotinamide cofactor. The family assignment (IPR052148 and IPR002347) and the substrate scope typical of SDRs converge on NAD-dependent retinol dehydrogenase chemistry, matching GO:0004745 NAD-retinol dehydrogenase activity. The same catalytic platform readily interconverts retinaldehyde and retinol and can act on small carbonyl substrates such as 5,6-dihydroxyindole and related ketones, consistent with an SDR that forms a broad, but focused, substrate spectrum.\n\nFrom this chemistry, I infer the biological processes. Oxidoreductase control over retinoid pools and cellular redox couples to calcium handling pathways in excitable and secretory cells. The explicit ER/sarcoplasmic reticulum membrane association (see below) positions the enzyme near calcium-release machinery. By modulating local NAD(H)/NADP(H) balance and retinoid-derived signaling, the enzyme can tune the sensitivity of calcium-release channels and their regulators, aligning with GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum and GO:0006874 intracellular calcium ion homeostasis. In parallel, SDR-driven control of membrane redox and metabolite availability can influence glucose uptake pathways in muscle and endothelial contexts, supporting GO:0046323 glucose import through redox-coupled signaling that gates transporter activity and trafficking.\n\nThe cellular component is resolved by the membrane-proximal behavior of SDRs and the provided localization. The absence of predicted transmembrane helices in the SDR core implies a soluble enzyme that associates with membranes via protein–protein or lipid-mediated interactions. The stated membrane association and the functional tie to calcium handling place the enzyme at the GO:0033017 sarcoplasmic reticulum membrane and more generally at the GO:0005789 endoplasmic reticulum membrane. This positioning explains how the enzyme accesses substrates and partners that govern calcium storage and release.\n\nMechanistically, I propose that the SDR core binds NAD(H) via its Rossmann-like fold and uses the Tyr–Lys catalytic pair to shuttle hydride between NAD(H) and retinoid or aldehyde substrates. Membrane-proximal localization concentrates the enzyme with calcium-release complexes. By locally tuning NAD/NADP redox and retinoid pools, it adjusts the assembly and gating of calcium-release machinery, thereby regulating sarcoplasmic reticulum calcium efflux and broader intracellular calcium homeostasis. In muscle and endothelial cells, this redox–calcium coupling secondarily modulates glucose import pathways.\n\nLikely interaction partners follow from this model. At the sarcoplasmic reticulum membrane, the enzyme is poised to contact ryanodine receptor complexes (RYR1/RYR2), the junctional architecture (triadin and junctin), and SERCA pumps (ATP2A isoforms), which together orchestrate calcium cycling. At the ER, associations with VAP-family tethers and ER calcium channels (ITPRs) would further support its regulatory role. For retinoid flux, transient assemblies with cellular retinoic acid-binding proteins and membrane-associated retinoid carriers are expected. These partnerships provide the physical basis for coupling SDR-mediated redox chemistry to calcium and glucose handling at membrane interfaces.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NNS2.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NNS2"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NNS2/entry","atlas":"/p/A6NNS2"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}