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. 2024 Nov 3;15:9496. doi: 10.1038/s41467-024-53903-0

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 8 — a The cluster 3 enzymes LcApaH (3) and LpApaH (3) are bacterial virulence factors. Structurally the cluster 3 enzymes contain two distinct features. The eight-stranded parallel β-sheet is extended by two antiparallel β-strands (LcApaH (3): brown; LpApaH (3): red) and there are two additional α-helices in the catalytic core domain. b Heatmap of the pre-screening of selected bacterial deacylases by the hydroxamate inhibitors SAHA and trichostatin A (TSA), the benzamide inhibitor entinostat (MS-275), and the cyclic peptides apicidin A and trapoxin A. The color code represents the residual activity after 1 h incubation at 37 °C. The experiments were performed in two independent replicates (n = 2). Shown are the means. Source data are provided as Source Data file. c Dose-response curves obtained for inhibition of bacterial deacylases with the hydroxamate inhibitors SAHA, TSA, and the cyclic peptides apicidin A and trapoxin A. The experiments were performed in two independent replicates (n = 2). Shown are the means. Source data are provided as Source Data file. d The hydroxamate inhibitors SAHA and/or TSA use an identical inhibitory mechanism for bacterial deacylases and for mammalian HDACs. For BsAcuC (2c) an AlphaFold2 model was created to show interaction with trapoxin A by superposition with the structure of HsHDAC8 (2a)•trapoxin A (PDB: 5VI6). For binding of the cyclic inhibitors formation of hydrogen bonds between the main-chain amide of the cyclic peptides and the side chain of a conserved Asp (BsAcuC (2c): Asp91; HsHDAC2 (2a): Asp100; HsHDAC8 (2a): Asp101) is important. e Model of the molecular mechanisms underlying the observed substrate and acyl-chain type preferences of bacterial deacylases. Bacterial deacylases apply three major mechanisms for their activity and for the determination of substrate specificity. Left: Oligomerisation determines the accessibility of substrates to the active site. Middle: The architecture of the foot pocket determines acyl-chain preference. Right: Differences in the sequences and presence of additional structural features determine substrate promiscuity, acyl-chain preference, and the inhibitory potency by different classes of inhibitors.