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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Mar, 2024. "Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49952-0
    DOI: 10.1038/s41467-024-49952-0
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    References listed on IDEAS

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