InterPro domain: IPR010080

This domain includes the C-terminal domain from the fungal alpha aminoadipate reductase enzyme (also known as aminoadipate semialdehyde dehydrogenase) which is involved in the biosynthesis of lysine [ 1 ], as well as the reductase-containing component of the myxochelin biosynthetic gene cluster, MxcG [ 2 ]. The mechanism of reduction involves activation of the substrate by adenylation and transfer to a covalently-linked pantetheine cofactor as a thioester. This thioester is then reduced to give an aldehyde (thus releasing the product) and a regenerated pantetheine thiol [ 3 ]; in myxochelin biosynthesis this aldehyde is further reduced to an alcohol or converted to an amine by an aminotransferase. This is a fundamentally different reaction than beta-ketoreductase domains of polyketide synthases which act at a carbonyl two carbons removed from the thioester and forms an alcohol as a product. The majority of bacterial sequences containing this domain are non-ribosomal peptide synthetases in which this domain is similarly located proximal to a thiolation domain. In some cases this domain is found at the end of a polyketide synthetase enzyme, but is unlike ketoreductase domains which are found before the thiolase domains. Exceptions to this observed relationship with the thiolase domain include three proteins which consist of stand-alone reductase domains (from Mycobacterium leprae, Anabaena and from Streptomyces coelicolor) and one protein (from Nostoc) which contains N-terminal homology with a small group of hypothetical proteins but no evidence of a thiolation domain next to the putative reductase domain.

This family consists of a short-chain dehydrogenase/reductase (SDR) module of multidomain proteins identified as putative polyketide sythases fatty acid synthases (FAS), and nonribosomal peptide synthases, among others. However, unlike the usual ketoreductase modules of FAS and polyketide synthase, these domains are related to the extended SDRs, and have canonical NAD(P)-binding motifs and an active site tetrad.

Extended short-chain dehydrogenases/reductases (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 [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].

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2. The myxochelin iron transport regulon of the myxobacterium Stigmatella aurantiaca Sg a15. Eur. J. Biochem. 267, 6476-85
3. Characterization of the lys2 gene of Acremonium chrysogenum encoding a functional alpha-aminoadipate activating and reducing enzyme. Mol. Gen. Genet. 264, 755-62
4. Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). Chem. Biol. Interact. 143-144, 271-8
5. Short-chain dehydrogenases/reductases (SDR): the 2002 update. Chem. Biol. Interact. 143-144, 247-53
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7. 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
8. Medium- and short-chain dehydrogenase/reductase gene and protein families : Structure-function relationships in short-chain alcohol dehydrogenases. Cell. Mol. Life Sci. 65, 3918-35
9. Classification of the short-chain dehydrogenase/reductase superfamily using hidden Markov models. FEBS J. 277, 2375-86
10. The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chem. Biol. Interact. 178, 94-8
11. The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Chem. Biol. Interact. 178, 99-109