Structural and Functional Features of a N-Succinyl-L, L-diaminopimelate desuccinylase, acritical enzyme for bacterial growth and anantimicrobial target

Abstract

N-Succinyl-L, L-diaminopimelate desuccinylase (DapE) is a strictly dimeric zinc-dependent amidohydrolase, which catalyzes the decomposition of N-succinyl-L, L-2,6-diaminopimelate (NSDAP), into succinate and diaminopimelate (DAP). This reaction constitutes the only source of meso-diaminopimelate (mDAP) and L-Lys in most bacteria. DapE is essential for bacterial growth and a pharmacological antimicrobial target. The development of anti-DapE inhibitors must take into account the dynamic properties of the enzyme. There is a special interest in compounds that block the formation of the oxyanion hole, where is assembled with groups of both subunits of the dimer and accommodated in its catalytic position by the conformational change of the enzyme from an open to a closed state, upon productive substrate binding. The hole stabilizes reaction intermediaries, thus contributing to the decrease in the activation energy. Based on the crystallographic analysis and the coupling of the substrate into DapE presented in this work, the role of the conformational flexibility of the enzyme in substrate hydrolysis is discussed. It is observed that the susceptible carbonyl group of the substrate and a water molecule located in the active site are near to the trajectory of attack, the Bürgi-Dunitz angle.