Dihydrodipicolinate reductase is an enzyme found in bacteria and higher plants involved in the biosynthesis of diaminopimelic acid and lysine. Because these pathways are unique to bacteria and plants, they may represent attractive targets for new antimicrobial or herbicidal compounds. The three-dimensional structure of Escherichia coli dihydrodipicolinate reductase, complexed with NADPH, has been determined and refined to a crystallographic R-factor of 18.6% with diffraction data to 2.2 Å resolution. The refined model contains the complete protein chain, the cofactor NADPH, and 55 water molecules. The enzyme is composed of two domains. The dinucleotide binding domain has a central seven-stranded parallel β-sheet surrounded by four α-helices, with the cofactor binding site located at the carboxy-terminal edge of the sheet. The second domain contains four β-strands and two α-helices that form an open mixed β-sandwich. A possible binding site for dihydrodipicolinate has been identified in this second domain, about 12 Å away from the dinucleotide binding site. This would imply that the protein must undergo some conformational change in order to perform catalysis. In the crystal, the native enzyme is a homotetramer generated by a 222 crystallographic axis. Implications of the tetrameric structure for the enzyme function are presented. Dihydrodipicolinate reductase uses both NADH and NADPH as cofactors, and analysis of its cofactor binding site allows for a molecular understanding of the enzyme's dual specificity.
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