Sauve Anthony A, Schramm Vern L
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave F304, Bronx, NY 10461, USA.
Curr Med Chem. 2004 Apr;11(7):807-26. doi: 10.2174/0929867043455675.
The Sir2 family of enzymes is a recently described class of NAD(+)-dependent protein deacetylases that use NAD+ as a reactant to deacetylate acetyllysine residues of protein substrates to form the aminolysine sidechain and a novel product 2'-O-acetyl-ADP-ribose. The founding member of the Sir2 proteins, the yeast Sir2p, has been identified as a key member of SIR complexes responsible for the long-term silencing of genes in the yeast Saccharomyces cerevisiae. Increase of Sir2 activity by caloric restriction or osmotic stress increases genome stability and lifespan in this organism. The Sir2 reaction mechanism couples ADP-ribosyltransfer and hydrolysis reactions via the formation of a stabilized ADPR-peptidyl intermediate. Principles of the chemistry of stabilized ADPR intermediates are examined for Sir2 and the mechanistically related ADP-ribosylcyclase CD38. An examination of the crystal structures of Sir2 family members is presented with a view to the chemical requirements of the Sir2 reaction. The present review describes the current knowledge of the Sir2 reaction, the reaction mechanism and the regulation of Sir2.
Sir2 酶家族是最近描述的一类依赖 NAD⁺ 的蛋白质脱乙酰酶，它利用 NAD⁺ 作为反应物，使蛋白质底物的乙酰赖氨酸残基脱乙酰化，形成氨基赖氨酸侧链和一种新产物 2'-O-乙酰基-ADP-核糖。Sir2 蛋白的创始成员，即酵母 Sir2p，已被确定为 SIR 复合物的关键成员，该复合物负责酿酒酵母中基因的长期沉默。通过热量限制或渗透胁迫提高 Sir2 活性可增加该生物体的基因组稳定性和寿命。Sir2 反应机制通过形成稳定的 ADPR-肽基中间体将 ADP-核糖基转移和水解反应耦合在一起。针对 Sir2 和机制相关的 ADP-核糖基环化酶 CD38，研究了稳定的 ADPR 中间体的化学原理。对 Sir2 家族成员的晶体结构进行了研究，以了解 Sir2 反应的化学要求。本综述描述了目前关于 Sir2 反应、反应机制和 Sir2 调控的知识。
