InterPro domain: IPR011912

Lipopolysaccharides (LPS) are glycolipids that consitutes the outer monolayer of the outer membranes of most Gram-negative bacteria [ 1 ]. They consist of lipid A (endotoxin) which anchors LPS to the outer membrane, a non-repeating core oligosachharide, and an immunogenic O-antigen repeat polymer, which is an oligosaccharide of 1-40 units that variesbetween different strains of bacteria. Although the O-antigen and most of the core domain are not necessary for growth in the lab, they appear to help bacteria resist environmental stresses including the complement system and antibiotics.

This family consists of examples of ADP-L-glycero-D-mannoheptose-6-epimerase, an enzyme involved in biosynthesis of the inner core of LPS in Gram-negative bacteria [ 2 ]. This enzyme is homologous to UDP-glucose 4-epimerase ( IPR005886 ) and belongs to the NAD dependent epimerase/dehydratase family. It participates in the biosynthetic pathway leading to incorporation of heptose, a conserved sugar, into the core region of LPS, performing the NAD-dependent reaction shown below: ADP-D-glycero-D-manno-heptose = ADP-L-glycero-D-manno-heptose It is a homopentameric enzyme with each monomer composed of two domains: an N-terminal modified Rossman fold domain for NADP binding, and a C-terminal substrate binding domain. This subgroup has the canonical active site tetrad and NAD(P)-binding motif [ 3 ].

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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