The high‐resolution structure of dihydrodipicolinate synthase from Escherichia coli bound to its first substrate, pyruvate

Dihydrodipicolinate synthase (DHDPS) mediates the key first reaction common to the biosynthesis of ( S )‐lysine and meso ‐diaminopimelate, molecules which play a crucial cross‐linking role in bacterial cell walls. An effective inhibitor of DHDPS would represent a useful antibacterial agent; despite extensive effort, a suitable inhibitor has yet to be found. In an attempt to examine the specificity of the active site of DHDPS, the enzyme was cocrystallized with the substrate analogue oxaloacetate. The resulting crystals diffracted to 2.0 Å resolution, but solution of the protein structure revealed that pyruvate was bound in the active site rather than oxaloacetic acid. Kinetic analysis confirmed that the decarboxylation of oxaloacetate was not catalysed by DHDPS and was instead a slow spontaneous chemical process.