title: Engineering the synthetic potential of β-lactam synthetase and the importance of catalytic loop dynamics.
abstract: The 2-azetidinone ring of the Class A and D β-lactamase inhibitor clavulanic acid (1) is synthesized by the ATP-utilizing enzyme β-lactam synthetase (βLS). A hydroxyethyl group attached to C-6 of1in the (S) configuration markedly enhances the efficacy of this compound against Class C β-lactamases. Guided by a series of X-ray structures of βLS, we have engineered this enzyme to act upon a methylated substrate analogue to give selectively the (3S)-methyl β-lactam core, which, upon closure of the second ring of the bicyclic system of1, would lead to the (6S)-methylated clavulanic acid derivative.
authors.affiliation: Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD, USA. ; Tel: 410 516 7444.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Labonte
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kudo
authors.forename: Michael F
authors.initials: MF
authors.lastname: Freeman
authors.forename: Mary L
authors.initials: ML
authors.lastname: Raber
authors.forename: Craig A
authors.initials: CA
authors.lastname: Townsend