Mechanism-Based Design of the First GlnA4-Specific Inhibitors.

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 t

SUBMITTER: Purder PL 

PROVIDER: S-EPMC9826267 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature