Acylation and deacylation mechanism and kinetics of penicillin G reaction with StreptomycesR61 DD‐peptidase.

Two quantum mechanical (QM)‐cluster models are built for studying the acylation and deacylation mechanism and kinetics of Streptomyces R61 DD‐peptidase with the penicillin G at atomic level detail. DD‐peptidases are bacterial enzymes involved in the cross‐linking of peptidoglycan to form the cell wall, necessary for bacterial survival. The cross‐linking can be inhibited by antibiotic beta‐lactam derivatives through acylation, preventing the acyl‐enzyme complex from undergoing further deacylation. The deacylation step was predicted to be rate‐limiting. Transition state and intermediate structures are found using density functional theory in this study, and thermodynamic and kinetic properties of the proposed mechanism are evaluated. The acyl‐enzyme complex is found lying in a deep thermodynamic sink, and deacylation is indeed the severely rate‐limiting step, leading to suicide inhibition of the peptidoglycan cross‐linking. The usage of QM‐cluster models is a promising technique to understand, improve, and design antibiotics to disrupt function of the Streptomyces R61 DD‐peptidase. [ABSTRACT FROM AUTHOR]