β-Lactam synthetase: A new biosynthetic enzyme

• DOI: 10.1073/pnas.95.16.9082
• Publication Date: 2002-07-26T14:39:15Z
• Authors: Brian O. Bachmann; Rongfeng Li; Craig A. Townsend
• Keywords: Streptomyces clavuligerus; Lactam

The principal cause of bacterial resistance to penicillin and other β-lactam antibiotics is the acquisition plasmid-encoded β-lactamases, enzymes that catalyze hydrolysis bond render these inactive. Clavulanic acid a potent inhibitor β-lactamases has proven clinically effective in combating resistant infections. Although clavulanic share marked structural similarities, biosyntheses their bicyclic nuclei are wholly dissimilar. In contrast efficient iron-mediated oxidative cyclization tripeptide isopenicillin N, critical ring demonstrated form by intramolecular closure catalyzed new type ATP/Mg 2+ -dependent enzyme, synthetase (β-LS). Insertional inactivation its encoding gene wild-type Streptomyces clavuligerus resulted complete loss production accumulation N 2 -(carboxyethyl)- l -arginine (CEA). Chemical complementation this blocked mutant with authentic deoxyguanidinoproclavaminic (DGPC), expected product β-LS, restored synthesis. Finally, overexpression gave which was shown mediate conversion CEA DGPC presence . Primary amino sequence comparisons suggest mode formation could be more widely spread nature mechanistically related asparagine