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线粒体 Sirtuin 3 和天然化合物的作用:翻译后修饰对细胞代谢的影响。

Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism.

发表日期:2024 Jul 11
作者: Francesca Oppedisano, Salvatore Nesci, Anna Spagnoletta
来源: Crit Rev Biochem Mol

摘要:

Sirtuins (SIRT) 是具有酶活性的蛋白质家族。特别地,它们是III类NAD依赖性组蛋白脱乙酰酶和ADP-核糖基转移酶的家族。由sirtuin催化的NAD依赖性脱酰化酶活性包括酰化、丙酰化、丁酰化、巴豆酰化、多酰化和琥珀酰化。具体来说,人类 SIRT3 是一种 399 个氨基酸的蛋白质,具有两个功能域:一个大的罗斯曼折叠基序和 NAD 结合,以及一个小的复杂螺旋和锌结合基序。 SIRT3 在富含线粒体的组织中广泛表达,参与维持线粒体完整性、稳态和功能。此外,SIRT3还调节相关疾病,如衰老、肝脏、肾脏、神经退行性和心血管疾病、代谢疾病和癌症发展。特别是,最重要和最具破坏性的翻译后修饰之一是不可逆的蛋白质氧化,即羰基化。这一过程是由线粒体功能障碍导致的 ROS 产生增加明确诱导的。 SIRT3 在 Cys280 水平被 4-羟基壬烯醛羰基化。羰基化会诱导活性位点的构象变化,导致 SIRT3 活性的变构抑制,并丧失脱乙酰化和调节抗氧化酶活性的能力。植物化学物质,特别是多酚,由于其强大的抗氧化活性,是对各种病理中的 SIRT3 具有积极调节作用的天然化合物。事实上,SIRT3 酶活性可以通过不同的天然多酚类(包括白藜芦醇和佛手柑多酚部分)进行调节。因此,本综述旨在阐明植物化学物质与 SIRT3 相互作用的机制,从而产生调节细胞代谢的翻译后修饰。
Sirtuins (SIRTs) are a family of proteins with enzymatic activity. In particular, they are a family of class III NAD+-dependent histone deacetylases and ADP-ribosyltransferases. NAD+-dependent deac(et)ylase activities catalyzed by sirtuin include ac(et)ylation, propionylation, butyrylation, crotonylation, manylation, and succinylation. Specifically, human SIRT3 is a 399 amino acid protein with two functional domains: a large Rossmann folding motif and NAD+ binding, and a small complex helix and zinc-binding motif. SIRT3 is widely expressed in mitochondria-rich tissues and is involved in maintaining mitochondrial integrity, homeostasis, and function. Moreover, SIRT3 regulates related diseases, such as aging, hepatic, kidney, neurodegenerative and cardiovascular disease, metabolic diseases, and cancer development. In particular, one of the most significant and damaging post-translational modifications is irreversible protein oxidation, i.e. carbonylation. This process is induced explicitly by increased ROS production due to mitochondrial dysfunction. SIRT3 is carbonylated by 4-hydroxynonenal at the level of Cys280. The carbonylation induces conformational changes in the active site, resulting in allosteric inhibition of SIRT3 activity and loss of the ability to deacetylate and regulate antioxidant enzyme activity. Phytochemicals and, in particular, polyphenols, thanks to their strong antioxidant activity, are natural compounds with a positive regulatory action on SIRT3 in various pathologies. Indeed, the enzymatic SIRT3 activity is modulated, for example, by different natural polyphenol classes, including resveratrol and the bergamot polyphenolic fraction. Thus, this review aims to elucidate the mechanisms by which phytochemicals can interact with SIRT3, resulting in post-translational modifications that regulate cellular metabolism.