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

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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)

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.

Suggested Citation

  • Shounak Nath & Leonel Griego & Liviu M. Mirica, 2025. "The mechanism of acetyl-CoA synthase through the lens of a nickel model system," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60163-z
    DOI: 10.1038/s41467-025-60163-z
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