Functional Divergence and Structural Changes of class IV Histone Deacetylases (HDACs) Across the Tree of Life
Abstract Class IV histone deacetylases (HDACs) are the least understood branch of the classical zinc-dependent HDAC family with HDAC11 standing out as the sole member of class IV HDACs. Using a broad phylogenetic dataset spanning bacteria, archaea, and eukaryotes, we identified two deeply conserved HDAC11 lineages, clades A and B, that differ in evolutionary origin, predicted subcellular localization, and enzymatic properties. Clade A is enriched in phototrophic eukaryotes and targeted to mitochondria or plastids, whereas clade B predominates in heterotrophs and localizes mainly to the cytoplasm or nucleus. High-resolution crystal structures of selected representatives from each clade revealed a conserved catalytic core but distinct structural features—including electrostatic surface profiles, loop architectures, and foot-pocket geometries—that clearly separate the two lineages and act as sequential “selectivity filters” shaping substrate specificity. Biochemical assays show robust long-chain fatty-acid deacylase activity in clade B enzymes, but no detectable activity for any of clade A representatives against peptide substrates, suggesting adaptation to alternative, non-peptidic targets. Together, these findings define a revised evolutionary framework for HDAC11 and provide structural and functional insights into the diversification of this ancient enzyme family.
Authors
- Natan Horáček
- Pavlína Jaklová
- Miroslav Obornı́k (ORCID: https://orcid.org/0000-0003-4819-7319)
- Marketa Ondrakova
- Štěpán Strnad (ORCID: https://orcid.org/0000-0002-0769-2420)
- Ansgar Gruber (ORCID: https://orcid.org/0000-0002-5876-4391)
- L. Motlova (ORCID: https://orcid.org/0000-0002-5581-8737)
- Andrea Schenkmayerová (ORCID: https://orcid.org/0000-0003-0883-9866)
- Pavla Bartošová‐Sojková (ORCID: https://orcid.org/0000-0003-2370-6981)
- Zora Nováková (ORCID: https://orcid.org/0000-0001-9804-6346)
- Vladimír Vrkoslav (ORCID: https://orcid.org/0000-0002-5126-8360)
- Josef Cvačka (ORCID: https://orcid.org/0000-0002-3590-9009)
- Mike Schutkowski (ORCID: https://orcid.org/0000-0003-0919-7076)
- Tereza Krunclová (ORCID: https://orcid.org/0000-0002-5232-8214)
- Marat Meleshin (ORCID: https://orcid.org/0000-0002-6887-0200)
- Cyril Bařinka (ORCID: https://orcid.org/0000-0003-2751-3060)
- Zsófia Kutil (ORCID: https://orcid.org/0000-0001-9936-9518)
- Barbora Havlínová (ORCID: https://orcid.org/0009-0007-1391-5284)
- Julia Kudlacova (ORCID: https://orcid.org/0000-0001-7100-4162)
- Ruzena Tuckova
- Sebastian Kroll
- Petr Žáček
- Wolfgang Sippl
- Fady Baselious
Institutions
- Sewanee: The University of the South (US)
- Luther University (KR)
- University of South Bohemia in České Budějovice (CZ)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Institute of Parasitology of the Slovak Academy of Sciences (SK)
- IONICS Mass Spectrometry (Canada) (CA)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Martin Luther University Halle-Wittenberg (DE)
Publication Details
- Journal
- Molecular Biology and Evolution
- Published
- 2026-06-16
- DOI
- https://doi.org/10.1093/molbev/msag150
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00