The mechanism of acetyl-CoA synthase through the lens of a nickel model system

Shounak Nath, Leonel Griego and Liviu M. Mirica ()
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Shounak Nath: University of Illinois Urbana-Champaign
Leonel Griego: University of Illinois Urbana-Champaign
Liviu M. Mirica: University of Illinois Urbana-Champaign

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Given the urgent need to develop new methods of CO2/CO utilization, understanding the mechanism of acetyl-CoA synthase (ACS)—a primordial nickel-containing 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 the following key mechanistic insights that are directly relevant to ACS: (i) the binding of a second CO molecule to the Ni center promotes migratory insertion, (ii) both paramagnetic and diamagnetic Ni intermediates are involved, (iii) one-electron oxidation of the NiII(acetyl)(thiolate) species drives a fast reductive elimination, and (iv) a random binding order of the methyl and CO groups to the Ni center is feasible.

Date: 2025
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DOI: 10.1038/s41467-025-60163-z

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