Regulation of acetyl-CoA biosynthesis via an intertwined acetyl-CoA synthetase/acetyltransferase complex

Liujuan Zheng (), Yifei Du, Wieland Steinchen, Mathias Girbig, Frank Abendroth, Ekaterina Jalomo-Khayrova, Patricia Bedrunka, Isabelle Bekeredjian-Ding, Christopher-Nils Mais, Georg K. A. Hochberg, Johannes Freitag and Gert Bange ()
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Liujuan Zheng: Max-Planck Institute for Terrestrial Microbiology
Yifei Du: MRC Laboratory of Molecular Biology
Wieland Steinchen: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Mathias Girbig: Max-Planck Institute for Terrestrial Microbiology
Frank Abendroth: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Ekaterina Jalomo-Khayrova: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Patricia Bedrunka: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Isabelle Bekeredjian-Ding: Faculty of Medicine
Christopher-Nils Mais: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Georg K. A. Hochberg: Max-Planck Institute for Terrestrial Microbiology
Johannes Freitag: Center for Synthetic Microbiology (SYNMIKRO) & Departments of Chemistry and Biology
Gert Bange: Max-Planck Institute for Terrestrial Microbiology

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Acetyl-CoA synthetase (Acs) generates acetyl-coenzyme A (Ac-CoA) but its excessive activity can deplete ATP and lead to a growth arrest. To prevent this, Acs is regulated through Ac-CoA-dependent feedback inhibition executed by Ac-CoA-dependent acetyltransferases such as AcuA in Bacillus subtilis. AcuA acetylates the catalytic lysine of AcsA turning the synthetase inactive. Here, we report that AcuA and AcsA form a tightly intertwined complex – the C-terminal domain binds to acetyltransferase domain of AcuA, while the C-terminus of AcuA occupies the CoA-binding site in the N-terminal domain of AcsA. Formation of the complex reduces AcsA activity in addition to the well-established acetylation of the catalytic lysine 549 in AcsA which we show can disrupt the complex. Thus, different modes of regulation accomplished through AcuA adjust AcsA activity to the concentrations of the different substrates of the reaction. In summary, our study provides detailed mechanistic insights into the regulatory framework underlying acetyl-CoA biosynthesis from acetate.

Date: 2025
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DOI: 10.1038/s41467-025-57842-2

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