Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule

Chuan Qin, Leonie G. Graf, Kilian Striska, Markus Janetzky, Norman Geist, Robin Specht, Sabrina Schulze, Gottfried J. Palm, Britta Girbardt, Babett Dörre, Leona Berndt, Stefan Kemnitz, Mark Doerr, Uwe T. Bornscheuer, Mihaela Delcea and Michael Lammers ()
Additional contact information
Chuan Qin: University of Greifswald
Leonie G. Graf: University of Greifswald
Kilian Striska: University of Greifswald
Markus Janetzky: University of Greifswald
Norman Geist: University of Greifswald
Robin Specht: University of Greifswald
Sabrina Schulze: University of Greifswald
Gottfried J. Palm: University of Greifswald
Britta Girbardt: University of Greifswald
Babett Dörre: University of Greifswald
Leona Berndt: University of Greifswald
Stefan Kemnitz: University of Greifswald
Mark Doerr: University of Greifswald
Uwe T. Bornscheuer: University of Greifswald
Mihaela Delcea: University of Greifswald
Michael Lammers: University of Greifswald

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract The AMP-forming acetyl-CoA synthetase is regulated by lysine acetylation both in bacteria and eukaryotes. However, the underlying mechanism is poorly understood. The Bacillus subtilis acetyltransferase AcuA and the AMP-forming acetyl-CoA synthetase AcsA form an AcuA•AcsA complex, dissociating upon lysine acetylation of AcsA by AcuA. Crystal structures of AcsA from Chloroflexota bacterium in the apo form and in complex with acetyl-adenosine-5′-monophosphate (acetyl-AMP) support the flexible C-terminal domain adopting different conformations. AlphaFold2 predictions suggest binding of AcuA stabilizes AcsA in an undescribed conformation. We show the AcuA•AcsA complex dissociates upon acetyl-coenzyme A (acetyl-CoA) dependent acetylation of AcsA by AcuA. We discover an intrinsic phosphotransacetylase activity enabling AcuA•AcsA generating acetyl-CoA from acetyl-phosphate (AcP) and coenzyme A (CoA) used by AcuA to acetylate and inactivate AcsA. Here, we provide mechanistic insights into the regulation of AMP-forming acetyl-CoA synthetases by lysine acetylation and discover an intrinsic phosphotransacetylase allowing modulation of its activity based on AcP and CoA levels.

Date: 2024
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DOI: 10.1038/s41467-024-49952-0

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