Serine peptidase catalytic machinery: Cooperative one-step mechanism

The acylation reaction of beta-lactamases by beta-lactam compounds is model ed as a one-step process. Twenty seven transition-state models are investig ated at the restricted Hartree-Fock (RHF) level within the minimal MINI-1' basis set. These transition states differ by the nature of both the substra te and the amino acids constituting the reactive nucleophile. The intrinsic reactivity of the class-A and class-C beta-lactamases are under concern. E ight transition-state models were docked in a class-A beta-lactamase, TEM1, as optimized with the benzylpenicillin at the molecular mechanics level. I n the proposed one-step acylation process, only two amino acids are directl y involved, the usual nucleophilic serine, S70 in TEM1, and a close serine or tyrosine, S130 in TEM1, Y150 in P99. The lysine close to these two resid ues, K73 in TEM1, plays only an indirect role in the process. (C) 1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 161-174, 1999.