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

The 2-azetidinone ring of the Class A and D β-lactamase inhibitor clavulanic acid ( ) is synthesized by the ATP-utilizing enzyme β-lactam synthetase (βLS). A hydroxyethyl group attached to C-6 of in the ( ) configuration markedly enhances the efficacy of this compound against Class C β-lactamases. G...

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Published inMedChemComm Vol. 3; no. 8; pp. 960 - 966
Main Authors Labonte, Jason W, Kudo, Fumitaka, Freeman, Michael F, Raber, Mary L, Townsend, Craig A
Format Journal Article
LanguageEnglish
Published England 2012
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Summary:The 2-azetidinone ring of the Class A and D β-lactamase inhibitor clavulanic acid ( ) is synthesized by the ATP-utilizing enzyme β-lactam synthetase (βLS). A hydroxyethyl group attached to C-6 of in the ( ) 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 (3 )-methyl β-lactam core, which, upon closure of the second ring of the bicyclic system of , would lead to the (6 )-methylated clavulanic acid derivative.
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ISSN:2040-2503
2040-2511
DOI:10.1039/c2md00305h