Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine.

IF 3.2 Q2 GENETICS & HEREDITY Epigenetics Insights Pub Date : 2021-12-10 eCollection Date: 2021-01-01 DOI:10.1177/25168657211065685

Harrison Yoo, Gregory A Polsinelli

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Abstract

Histone deacetylases (HDACs) catalyze the removal of Ɛ-acetyl-lysine residues of histones via hydrolysis. Removal of acetyl groups results in condensation of chromatin structure and alteration of gene expression by repression. HDACs are considered targets for the treatment of cancer due to their role in regulating transcription. HDAC8 inhibition may be an important anti-proliferative factor for histone deacetylase inhibitors on cancer cells and may give rise to the progression of apoptosis. HDAC8 activity was analyzed with various peptides where the target lysine is modified with medium-chain fatty acyl group. Kinetic data were determined for each p53 peptide substrate. The results suggest that there was HDAC8 deacetylase activity on peptide substrate as well as deacylase activity with acylated peptide substrate variants. HDAC8 inhibition by hexanoic and decanoic acid was also examined. The K_i for hexanoic and decanoic acid were determined to be 2.35 ± 0.341 and 4.48 ± 0.221 mM, respectively.

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中链脂肪酰基赖氨酸对人组蛋白脱乙酰酶8的动力学表征

组蛋白去乙酰化酶(HDACs)通过水解催化去除组蛋白Ɛ-acetyl-lysine残基。乙酰基的去除导致染色质结构的凝聚和基因表达的改变。由于hdac在调节转录方面的作用，它被认为是治疗癌症的靶点。抑制HDAC8可能是组蛋白去乙酰化酶抑制剂作用于癌细胞的重要抗增殖因子，并可能导致细胞凋亡的进展。用不同的多肽分析了HDAC8的活性，其中目标赖氨酸被中链脂肪酰基修饰。测定了每种p53肽底物的动力学数据。结果表明，在肽底物上存在HDAC8脱乙酰酶活性，在酰化肽底物变异体上也存在HDAC8脱乙酰酶活性。同时考察了己酸和癸酸对HDAC8的抑制作用。己酸和癸酸的Ki值分别为2.35±0.341和4.48±0.221 mM。

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