Uncovering Robust Delactoylase and Depyruvoylase Activities of HDAC Isoforms

0558797 - BTÚ 2023 RIV US eng J - Journal Article
Zessin, M. - Meleshin, M. - Praetorius, L. - Sippl, W. - Bařinka, Cyril - Schutkowski, M.
Uncovering Robust Delactoylase and Depyruvoylase Activities of HDAC Isoforms.
ACS Chemical Biology. Roč. 17, č. 6 (2022), s. 1364-1375. ISSN 1554-8929. E-ISSN 1554-8937
R&D Projects: GA ČR(CZ) GA21-31806S
Institutional support: RVO:86652036
Keywords : histone crotonylation * lysine * inhibitor * substrate
OECD category: Biochemistry and molecular biology
Impact factor: 4, year: 2022
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acschembio.1c00863

Zinc-dependent histone deacetylases (HDACs) and sirtuins (SIRT) represent two different classes of enzymes which are responsible for deacylation of modified lysine side chains. The repertoire of acyl residues on lysine side chains identified in vivo is rapidly growing, and very recently lysine lactoylation was described to be involved in metabolic reprogramming. Additionally, lysine pyruvoylation represents a marker for aging and liver cirrhosis. Here, we report a systematic analysis of acyl-specificity of human zinc-dependent HDAC and sirtuin isoforms. We identified HDAC3 as a robust delactoylase with several-thousand-fold higher activity as compared to SIRT2, which was claimed to be the major in vivo delactoylase. Additionally, we systematically searched for enzymes, capable of removing pyruvoyl residues from lysine side chains. Using model peptides, we uncovered high depyruvoylase activity for HDAC6 and HDAC8. Interestingly, such substrates have extremely low K-M values for both HDAC isoforms, pointing to possible in vivo functions.
Permanent Link: https://hdl.handle.net/11104/0332584