Mechanistic Basis for ATP-Dependent Inhibition of Glutamine Synthetase by Tabtoxinine-β-lactam.

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Mechanistic Basis for ATP-Dependent Inhibition of Glutamine Synthetase by Tabtoxinine-β-lactam.

Biochemistry. 2018 01 09;57(1):117-135

Authors: Patrick GJ, Fang L, Schaefer J, Singh S, Bowman GR, Wencewicz TA

Abstract
Tabtoxinine-β-lactam (TβL), also known as wildfire toxin, is a time- and ATP-dependent inhibitor of glutamine synthetase produced by plant pathogenic strains of Pseudomonas syringae. Here we demonstrate that recombinant glutamine synthetase from Escherichia coli phosphorylates the C3-hydroxyl group of the TβL 3-(S)-hydroxy-β-lactam (3-HβL) warhead. Phosphorylation of TβL generates a stable, noncovalent enzyme-ADP-inhibitor complex that resembles the glutamine synthetase tetrahedral transition state. The TβL β-lactam ring remains intact during enzyme inhibition, making TβL mechanistically distinct from traditional β-lactam antibiotics such as penicillin. Our findings could enable the design of new 3-HβL transition state inhibitors targeting enzymes in the ATP-dependent carboxylate-amine ligase superfamily with broad therapeutic potential in many disease areas.

PMID: 29039929 [PubMed – indexed for MEDLINE]