InterPro domain: IPR045022

Proteins in this entry show strong conservation of the active site tetrad and glycine rich NAD-binding motif of the classical SDRs. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central beta-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing [ 1 , 2 , 3 ].

Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, 15-PGDH numbering) and/or an Asn (Asn-107, 15-PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction [ 4 , 4 , 4 ].

This entry represents a group of 3-ketodihydrosphingosine reductases, including KDSR from animals and Tsc10 from yeasts and plants. They catalyse the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS) and are required for sphingolipid biosynthesis [ 5 , 6 , 7 ].

1. Short-chain dehydrogenases/reductases (SDR). Biochemistry 34, 6003-13
2. Medium- and short-chain dehydrogenase/reductase gene and protein families : the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cell. Mol. Life Sci. 65, 3895-906
3. Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). Chem. Biol. Interact. 143-144, 271-8
4. GXXXG and GXXXA motifs stabilize FAD and NAD(P)-binding Rossmann folds through C(alpha)-H... O hydrogen bonds and van der waals interactions. J. Mol. Biol. 323, 69-76
5. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet 100, 978-984
6. Sphingolipids in the root play an important role in regulating the leaf ionome in Arabidopsis thaliana. Plant Cell 23, 1061-81
7. The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Delta mutant. J Biol Chem 273, 30688-94