The metabolic “acetate switch” connects central carbon metabolism with both natural product biosynthesis and post-translational regulation. I will first show how the acetate switch can be applied to decode the biosynthesis of polyketides in bacteria and filamentous fungi.

More importantly, I will present how the acetate switch is regulated in Bacillus subtilis. Acetyl-CoA synthetase (AcsA), a key enzyme in acetate metabolism, is controlled by reversible lysine acetylation through the acuABC operon. We identified a pausing complex between the acetyltransferase AcuA and AcsA in the absence of acetyl-CoA. Cryo-EM analysis reveals that AcuA traps the catalytic lysine of AcsA and blocks its CoA-binding pocket, thereby preventing catalysis, while physiological levels of acetyl-CoA trigger dissociation of this complex and promote acetylation. In parallel, the regulatory protein AcuB binds the alarmone Ap4A with nanomolar affinity and inhibits the deacetylase AcuC through complex formation, a process further strengthened by Ap4A. Together, these results uncover a multilayer regulatory network linking metabolic state and stress signaling to protein acetylation control, providing new mechanistic insights into the interplay between metabolism and enzyme regulation.