The crystal structure of m.tuberculosisdhpr: Analysis of cofactor and substrate binding in the dihydrodipicolinate reductase family of enzymes

Dihydrodipicolinate reductase (DHPR) catalyzes the dinucleotide-dependent reduction of the a,b-unsaturated cyclic iminine,dihydrodipicolinate,to tetrahydrodipicolinate,and represents the second step in the biosynthesis of DAP and lysine in bacteria. Since both end-products are essential for bacterial survival,it has been proposed that DHPR is a suitable target for the design of new inhibitors that may display antibiotic activity. The E.coli enzyme has been extensively studied and its crystal structure previously reported. The crystal structure of M tuberculosis DHPR, in complex with NADH and the inhibitor 2,6-PDC.has now been solved and refined to 2.6 A resolution. The overal struc îure of the M.tuberculosis DHPR is remarkably similar to the structure of the K.coli enzyme, the only difference being the absence of a surface loop that had been proposed to be non-essential based on sequence alignments. The residues involved in inhibitor binding and the overall shape of the binding cavity are highly conserved, suggesting that inhibitors designed against one enzyme would be effective against the other. The dinucleotide binding region is also very similar in both proteins, though small differences explain the different dinucleotide specificity of the two enzymes allowing predictions to be made about the nncleotide preference of other members of this enzyme family.