Functional Classification of Zn2+-Dependent Histone Deacetylase Homologs and Variants Using Chemical Profiling
- 1Department of Chemical Engineering and Biotechnology, Darmstadt University of Applied Sciences, Haardtring 100, 64295 Darmstadt, Germany
- 2European University of Technology, European Union, 64290 Darmstadt, Germany
Abstract
Zinc-dependent histone deacetylases (HDACs) are found in all species, ranging from bacteria to eukaryotes. They catalyze the removal of acetyl groups or various organic acid residues, including fatty acids, from proteins or polyamines. These enzymes are located in various cellular compartments, and their function is modulated by their ability to form different protein complexes. HDACs are prominent targets in the study of human diseases and infections, but they have also recently been considered as targets for fungicides. The active sites of HDACs are highly conserved, both structurally and sequentially. Therefore, the development of isoenzyme-selective inhibitors poses an exceptionally great challenge. In this study, a chemical profiling approach was used to classify human HDAC isoenzymes, bacterial homologs, and mutant variants by function and to identify specific ligand-binding patterns. While the recognition profiles generally reflected established HDAC classes, HDAC8 exhibited significant differences from HDAC1–3. In contrast, HDAC6 demonstrated substantial similarity with HDAC1–3 despite their low sequence identity, distinguishing itself from the sequentially closely related HDAC10. These findings demonstrate that sequence similarity alone is not a reliable predictor of ligand recognition and underscore the importance of local active-site architecture and physicochemical properties. Zebrafish HDAC10 closely resembles human HDAC10, supporting its use as a functional surrogate, while bacterial homologs display distinct profiles that suggest opportunities for species-selective inhibitor development. A single active-site substitution in class IIa HDAC4 (H976Y) shifted its recognition profile from HDAC class IIa toward class I. Engineered HDAC11 variants showed substantially improved recombinant expression and comparable stability while retaining wild-type-like ligand recognition. This supports their use in screening, biophysical, and structural studies. Together, these results establish ligand recognition profiling as a practical approach for functionally classifying HDACs and guiding the development of selective inhibitors.
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BibTeX
@article{kopranovic2026functional,
title = {{Functional Classification of Zn2+-Dependent Histone Deacetylase Homologs and Variants Using Chemical Profiling}},
author = {Aleksandra Kopranovic and Hannah Münster and Aaron Rosowski and Louis Groll and Florian Almstätter and Eva Attenhauser and Franz-Josef Meyer-Almes},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219595},
url = {https://www.mdpi.com/1422-0067/27/21/9595},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Functional Classification of Zn2+-Dependent Histone Deacetylase Homologs and Variants Using Chemical Profiling
AU - Aleksandra Kopranovic
AU - Hannah Münster
AU - Aaron Rosowski
AU - Louis Groll
AU - Florian Almstätter
AU - Eva Attenhauser
AU - Franz-Josef Meyer-Almes
PY - 2026
DA - 2026/10/27
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219595
UR - https://www.mdpi.com/1422-0067/27/21/9595
AB - Zinc-dependent histone deacetylases (HDACs) are found in all species, ranging from bacteria to eukaryotes. They catalyze the removal of acetyl groups or various organic acid residues, including fatty acids, from proteins or polyamines. These enzymes are located in various cellular compartments, and their function is modulated by their ability to form different protein complexes. HDACs are prominent targets in the study of human diseases and infections, but they have also recently been considered as targets for fungicides. The active sites of HDACs are highly conserved, both structurally and sequentially. Therefore, the development of isoenzyme-selective inhibitors poses an exceptionally great challenge. In this study, a chemical profiling approach was used to classify human HDAC isoenzymes, bacterial homologs, and mutant variants by function and to identify specific ligand-binding patterns. While the recognition profiles generally reflected established HDAC classes, HDAC8 exhibited significant differences from HDAC1–3. In contrast, HDAC6 demonstrated substantial similarity with HDAC1–3 despite their low sequence identity, distinguishing itself from the sequentially closely related HDAC10. These findings demonstrate that sequence similarity alone is not a reliable predictor of ligand recognition and underscore the importance of local active-site architecture and physicochemical properties. Zebrafish HDAC10 closely resembles human HDAC10, supporting its use as a functional surrogate, while bacterial homologs display distinct profiles that suggest opportunities for species-selective inhibitor development. A single active-site substitution in class IIa HDAC4 (H976Y) shifted its recognition profile from HDAC class IIa toward class I. Engineered HDAC11 variants showed substantially improved recombinant expression and comparable stability while retaining wild-type-like ligand recognition. This supports their use in screening, biophysical, and structural studies. Together, these results establish ligand recognition profiling as a practical approach for functionally classifying HDACs and guiding the development of selective inhibitors.
SN - 1422-0067
ER -