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Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors

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GlnA4 catalyses ATP-dependent glutamylation of ethanolamine and is essential for ethanolamine metabolization in Streptomyces coelicolor. We rationally developed a GlnA4-specific inhibitor derived from methionine sulfoximine, the gold standard inhibitor for glutamine synthetase. The novel inhibitor shows no inhibition of glutamine synthetase but blocks GlnA4 activity in vitro and intracellularly.


Abstract

γ-Glutamylamine synthetases are an important class of enzymes that play a key role in glutamate-based metabolism. Methionine sulfoximine (MSO) is a well-established inhibitor for the archetypal glutamine synthetase (GS) but inhibitors for most GS-like enzymes are unknown. Assuming a conserved catalytic mechanism for GS and GS-like enzymes, we explored if subtype-selective inhibitors can be obtained by merging MSO with the cognate substrates of the respective GS-like enzymes. Using GlnA4 Sc from Streptomyces coelicolor, an enzyme recently shown to produce γ-glutamylethanolamine, we demonstrate that MSO can be reengineered in a straightforward fashion into potent and selective GlnA4 Sc inhibitors. Linkage chemistry as well as linker length between the MSO moiety and the terminal hydroxyl group derived from ethanolamine were in agreement with the postulated phosphorylated catalytic intermediate. The best GlnA4 inhibitor 7 b potently blocked S. coelicolor growth in the presence of ethanolamine as the sole nitrogen source. Our results provide the first GlnA4 Sc -specific inhibitors and suggest a general strategy to develop mechanism-based inhibitors for GS-like enzymes.

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