Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle/Saale, 06120, Germany.
Department of Enzymology, Charles Tanford Protein Center, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, 06120, Germany.
ACS Chem Biol. 2022 Jun 17;17(6):1364-1375. doi: 10.1021/acschembio.1c00863. Epub 2022 May 31.
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 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 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 values for both HDAC isoforms, pointing to possible functions.
锌依赖的组蛋白去乙酰化酶（HDACs）和沉默调节蛋白（SIRT）代表了两类负责修饰赖氨酸侧链脱酰基的酶。赖氨酸侧链上酰基残基的种类在迅速增加，最近有研究描述了赖氨酸乳酰化参与代谢重编程。此外，赖氨酸丙酮酸化是衰老和肝硬化的一个标志。在这里，我们报告了对人类锌依赖的 HDAC 和 SIRT 同工型的酰基特异性的系统分析。我们鉴定出 HDAC3 是一种强有力的脱乳酰酶，其活性比被认为是主要脱乳酰酶的 SIRT2 高几千倍。此外，我们系统地搜索了能够从赖氨酸侧链上去除丙酮酸残基的酶。使用模型肽，我们发现 HDAC6 和 HDAC8 具有很高的脱丙酮酸酶活性。有趣的是，这些底物对两种 HDAC 同工型的 值极低，这表明可能具有功能。
