The Mechanism of Acetyl-CoA Synthase Through the Lens of a Nickel Model System

Given the urgent need to develop new methods of CO2/CO utilization, understanding the mechanism of acetyl-CoA synthase (ACS) – a primordial nickel enzyme that converts these gases into a source of cellular energy, is crucial; however, conflicting hypotheses and a dearth of well-characterized bioorganometallic intermediates have hindered a proper understanding of its mechanism. Herein, we report a functional model system that supports several organometallic intermediates proposed for ACS, including the long sought-after Ni(methyl)(CO) species, and promotes all key reaction steps during catalysis: methylation, carbonylation, and thiolysis. Our investigations provide key mechanistic insights that are directly relevant to ACS, suggesting that binding of a second CO molecule to the Ni center promotes migratory insertion, that one-electron oxidation of Ni drives a fast reductive elimination, that both paramagnetic and diamagnetic Ni intermediates are involved, and confirm the feasibility of a random binding order of the methyl and CO groups to the Ni center.