Distribution and diversity of classical deacylases in bacteria

Leonie G. Graf, Carlos Moreno-Yruela, Chuan Qin, Sabrina Schulze, Gottfried J. Palm, Ole Schmöker, Nancy Wang, Dianna M. Hocking, Leila Jebeli, Britta Girbardt, Leona Berndt, Babett Dörre, Daniel M. Weis, Markus Janetzky, Dirk Albrecht, Daniela Zühlke, Susanne Sievers, Richard A. Strugnell, Christian A. Olsen, Kay Hofmann and Michael Lammers ()
Additional contact information
Leonie G. Graf: University of Greifswald
Carlos Moreno-Yruela: University of Copenhagen
Chuan Qin: University of Greifswald
Sabrina Schulze: University of Greifswald
Gottfried J. Palm: University of Greifswald
Ole Schmöker: University of Greifswald
Nancy Wang: The University of Melbourne
Dianna M. Hocking: The University of Melbourne
Leila Jebeli: The University of Melbourne
Britta Girbardt: University of Greifswald
Leona Berndt: University of Greifswald
Babett Dörre: University of Greifswald
Daniel M. Weis: University of Greifswald
Markus Janetzky: University of Greifswald
Dirk Albrecht: University of Greifswald
Daniela Zühlke: University of Greifswald
Susanne Sievers: University of Greifswald
Richard A. Strugnell: The University of Melbourne
Christian A. Olsen: University of Copenhagen
Kay Hofmann: University of Cologne
Michael Lammers: University of Greifswald

Nature Communications, 2024, vol. 15, issue 1, 1-31

Abstract: Abstract Classical Zn2+-dependent deac(et)ylases play fundamental regulatory roles in life and are well characterized in eukaryotes regarding their structures, substrates and physiological roles. In bacteria, however, classical deacylases are less well understood. We construct a Generalized Profile (GP) and identify thousands of uncharacterized classical deacylases in bacteria, which are grouped into five clusters. Systematic structural and functional characterization of representative enzymes from each cluster reveal high functional diversity, including polyamine deacylases and protein deacylases with various acyl-chain type preferences. These data are supported by multiple crystal structures of enzymes from different clusters. Through this extensive analysis, we define the structural requirements of substrate selectivity, and discovered bacterial de-d-/l-lactylases and long-chain deacylases. Importantly, bacterial deacylases are inhibited by archetypal HDAC inhibitors, as supported by co-crystal structures with the inhibitors SAHA and TSA, and setting the ground for drug repurposing strategies to fight bacterial infections. Thus, we provide a systematic structure-function analysis of classical deacylases in bacteria and reveal the basis of substrate specificity, acyl-chain preference and inhibition.

Date: 2024
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DOI: 10.1038/s41467-024-53903-0

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