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

ABSTRACT: The 2-azetidinone ring of the Class A and D ?-lactamase inhibitor clavulanic acid (1) is synthesized by the ATP-utilizing enzyme ?-lactam synthetase (?LS). A hydroxyethyl group attached to C-6 of 1 in the (S) configuration markedly enhances the efficacy of this compound against Class C ?-lactamases. Guided by a series of X-ray structures of ?LS, we have engineered this enzyme to act upon a methylated substrate analogue to give selectively the (3S)-methyl ?-lactam core, which, upon closure of the second ring of the bicyclic system of 1, would lead to the (6S)-methylated clavulanic acid derivative.

SUBMITTER: Labonte JW

PROVIDER: S-EPMC3632419 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Labonte Jason W JW Kudo Fumitaka F Freeman Michael F MF Raber Mary L ML Townsend Craig A CA

MedChemComm 20120101

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 ...[more]

PMID: 23616913

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Project description:This SuperSeries is composed of the SubSeries listed below.

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