Engineering the synthetic potential of β-lactam synthetase and the importance of catalytic loop dynamics

Jason W. Labonte, Fumitaka Kudo, Michael F. Freeman, Mary L. Raber, Craig A. Townsend

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 of 1 in 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 of 1, would lead to the (6S)-methylated clavulanic acid derivative.

Original languageEnglish (US)
Pages (from-to)960-966
Number of pages7
JournalMedChemComm
Volume3
Issue number8
DOIs
StatePublished - Aug 2012

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