cd05239

GDP-fucose synthetase, extended (e) SDRs

CDD entry
Member databaseCDD
CDD typedomain
Short nameGDP_FS_SDR_e
SetNADB_Rossmann

Description

GDP-fucose synthetase (aka 3, 5-epimerase-4-reductase) acts in the NADP-dependent synthesis of GDP-fucose from GDP-mannose. Two activities have been proposed for the same active site: epimerization and reduction. Proteins in this subgroup are extended SDRs, which have a characteristic active site tetrad and an NADP-binding motif, [AT]GXXGXXG, that is a close match to the archetypical form. Extended SDRs are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central beta-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. 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 numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. 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.
[5, 3, 1, 8, 10, 7, 2, 6, 9, 4, 11]

References

1.Short-chain dehydrogenases/reductases (SDR): the 2002 update. Oppermann U, Filling C, Hult M, Shafqat N, Wu X, Lindh M, Shafqat J, Nordling E, Kallberg Y, Persson B, Jornvall H. Chem. Biol. Interact. 143-144, 247-53, (2003). View articlePMID: 12604210

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. Kavanagh KL, Jornvall H, Persson B, Oppermann U. Cell. Mol. Life Sci. 65, 3895-906, (2008). View articlePMID: 19011750

3.Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). Persson B, Kallberg Y, Oppermann U, Jornvall H. Chem. Biol. Interact. 143-144, 271-8, (2003). View articlePMID: 12604213

4.The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jornvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U. Chem. Biol. Interact. 178, 94-8, (2009). View articlePMID: 19027726

5.GDP-fucose synthetase from Escherichia coli: structure of a unique member of the short-chain dehydrogenase/reductase family that catalyzes two distinct reactions at the same active site. Somers WS, Stahl ML, Sullivan FX. Structure 6, 1601-12, (1998). View articlePMID: 9862812

6.Medium- and short-chain dehydrogenase/reductase gene and protein families : Structure-function relationships in short-chain alcohol dehydrogenases. Ladenstein R, Winberg JO, Benach J. Cell. Mol. Life Sci. 65, 3918-35, (2008). View articlePMID: 19011748

7.Comparison of super-secondary structures in proteins. Rao ST, Rossmann MG. J. Mol. Biol. 76, 241-56, (1973). View articlePMID: 4737475

8.Short-chain dehydrogenases/reductases (SDR). Jornvall H, Persson B, Krook M, Atrian S, Gonzalez-Duarte R, Jeffery J, Ghosh D. Biochemistry 34, 6003-13, (1995). View articlePMID: 7742302

9.Classification of the short-chain dehydrogenase/reductase superfamily using hidden Markov models. Kallberg Y, Oppermann U, Persson B. FEBS J. 277, 2375-86, (2010). View articlePMID: 20423462

10.NAD-binding domains of dehydrogenases. Lesk AM. Curr. Opin. Struct. Biol. 5, 775-83, (1995). View articlePMID: 8749365

11.The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Bray JE, Marsden BD, Oppermann U. Chem. Biol. Interact. 178, 99-109, (2009). View articlePMID: 19061874

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