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首页> 外文期刊>Biochemistry >Substrate Specificity and Kinetic Mechanism of the Sir2 Family of NAD~+-Dependent Histone/Protein Deacetylases
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Substrate Specificity and Kinetic Mechanism of the Sir2 Family of NAD~+-Dependent Histone/Protein Deacetylases

机译：NAD〜+依赖的组蛋白/蛋白质脱乙酰基酶Sir2家族的底物特异性和动力学机制

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摘要

The Silent information regulator 2 (Sir2) family of enzymes consists of NAD~+-dependent histone/protein deacetylases that tightly couple the hydrolysis of NAD~+ and the deacetylation of an acetylated substrate to form nicotinamide,the deacetylated product,and the novel metabolite O-acetyl-ADP-ribose (OAADPR).In this paper,we analyzed the substrate specificity of the yeast Sir2 (ySir2),the yeast HST2,and the human SIRT2 homologues toward various monoacetylated histone H3 and H4 peptides,determined the basic kinetic mechanism,and resolved individual chemical steps of the Sir2 reaction.Using steady-state kinetic analysis,we have shown that ySir2,HST2,and SIRT2 exhibit varying catalytic efficiencies and display a preference among the monoacetylated peptide substrates.Bisubstrate kinetic analysis indicates that Sir2 enzymes follow a sequential mechanism,where both the acetylated substrate and NAD~+ must bind to form a ternary complex,prior to any catalytic step.Using rapid-kinetic analysis,we have shown that after ternary complex formation,nicotinamide cleavage occurs first,followed by the transfer of the acetyl group from the donor substrate to the ADP-ribose portion of NAD~+ to form OAADPr and the deacetylated product.Product and dead-end inhibition analyses revealed that nicotinamide is the first product released followed by random release of OAADPr and the deacetylated product.
机译：沉默信息调节剂2（Sir2）酶家族由NAD〜+依赖的组蛋白/蛋白质脱乙酰基酶组成，它们与NAD〜+的水解作用和乙酰化底物的脱乙酰作用紧密结合，从而形成烟酰胺，脱乙酰化产物和新型代谢物本文分析了酵母Sir2（ySir2），酵母HST2和人类SIRT2同源物对各种单乙酰化组蛋白H3和H4肽的底物特异性，确定了基本动力学通过稳态动力学分析，我们发现ySir2，HST2和SIRT2表现出不同的催化效率，并且在单乙酰化肽底物中表现出偏爱性。双底物动力学分析表明Sir2酶遵循顺序机制，其中乙酰化底物和NAD〜+必须在任何催化步骤之前结合形成三元络合物。使用快速动力学分析，我们发现三元复合物形成后，首先发生烟酰胺裂解，随后乙酰基从供体底物转移到NAD〜+的ADP-核糖部分以形成OAADPr和脱乙酰化产物。分析表明，烟酰胺是首先释放的产物，随后是随机释放的OAADPr和脱乙酰基产物。

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