Distribution and diversity of classical deacylases in bacteria
Classical Zn<sup>2+</sup>-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.
Authors
- Richard A. Strugnell (ORCID: https://orcid.org/0000-0003-0614-5641)
- Leona Berndt (ORCID: https://orcid.org/0000-0002-2864-6386)
- Michael Lammers (ORCID: https://orcid.org/0000-0003-4168-4640)
- Christian Adam Olsen (ORCID: https://orcid.org/0000-0002-2953-8942)
- Susanne Sievers (ORCID: https://orcid.org/0000-0002-5457-2552)
- Leila Jebeli (ORCID: https://orcid.org/0000-0003-4240-9528)
- Sabrina Schulze (ORCID: https://orcid.org/0000-0002-0122-5688)
- Britta Girbardt
- Carlos Moreno–Yruela (ORCID: https://orcid.org/0000-0003-2450-6519)
- Gottfried J. Palm (ORCID: https://orcid.org/0000-0003-0329-0413)
- Daniela Zühlke (ORCID: https://orcid.org/0000-0002-6751-9654)
- Dianna M. Hocking (ORCID: https://orcid.org/0000-0002-3485-0586)
- Chuan Qin (ORCID: https://orcid.org/0000-0002-6261-1232)
- Leonie G. Graf (ORCID: https://orcid.org/0009-0007-7269-1743)
- Daniel Weis
- Babett Dörre
- Nancy Wang (ORCID: https://orcid.org/0000-0001-7623-1858)
- Dirk Albrecht (ORCID: https://orcid.org/0009-0003-6633-2761)
- Kay Hofmann (ORCID: https://orcid.org/0000-0002-2289-9083)
- Markus Janetzky
- Ole Schmöker (ORCID: https://orcid.org/0009-0005-4754-8246)
Institutions
- University of Copenhagen (DK)
- The University of Melbourne (AU)
- University of Cologne (DE)
- Universitätsmedizin Greifswald (DE)
- Universität Greifswald (DE)
- Peter Doherty Institute (AU)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-03
- DOI
- https://doi.org/10.1038/s41467-024-53903-0
- Citations
- 2
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.57
Funders
- Deutsche Forschungsgemeinschaft
- Universität zu Köln
- LEO Fondet
- Deutsches Elektronen-Synchrotron