去酰化酶SIRT5的研究进展

[摘要] 长寿因子5（Sirtuin 5），也叫SIRT5，是长寿因子（Sirtuins）家族成员之一。除具有去乙酰化酶活性外，还具有很强的去琥珀酰化、去丙二酰基化及去戊二酰基化活性。现已明确的SIRT5的底物仅有十余种，通过对不同底物发挥相同的酶活性，或对同一底物发挥不同的酶活性，参与调控葡萄糖氧化、脂肪酸氧化、氨解毒等物质代谢和活性氧自由基（ROS）清除、抗凋亡、炎性反应等多种生命活动。SIRT5表达异常与肿瘤的发生及发展密切相关，但其作用尚无定论。SIRT5可促进肿瘤增殖、转移、耐药及代谢重编程，发挥促癌基因作用；也可抑制肿瘤细胞生长和凋亡，发挥抑癌基因作用。此外，SIRT5异常还与肥厚性心肌病和心肌梗塞等心血管疾病，及帕金森病和阿尔兹海默症等神经代谢性疾病密切相关。本文将从SIRT5的结构与调控、酶活性与生物学功能、及SIRT5与疾病的关系等方面进行综述，以全面了解SIRT5的研究现状。

[关键词] SIRT5；去乙酰化；去琥珀酰化；去丙二酰基化；去戊二酰基化；肿瘤

[中图分类号] R979.1 [文献标识码] A [文章编号] 1673-7210（2018）04（a）-0042-04

[Abstract] Sirtuin 5， also called SIRT5， is a member of Sirtuins family. Besides its deacetylation activity， SIRT5 also has strong desuccinylation， demalonylation and deglutarylation activities. Therefore， SIRT5 has been attracted much attention in recent years. Currently， about more than tenproteins were identified as substrates of SIRT5. SIRT5 is involved in the regulation of glucose oxidation， ROS metabolism and fatty acid oxidation， ammonia removal， detoxification， anti apoptosis， inflammation and so on， by playing the same enzymatic activity on different substrates， or playing different enzymatic activity on the same substrate. The abnormal expression of SIRT5 is closely related to the occurrence and development of tumor， though its function is not clarified yet. SIRT5 can play the role of oncogene to promote tumor proliferation， metastasis， drug resistance and metabolic reprogramming. On the other hand， SIRT5 also play the role of tumor suppressor gene to inhibit tumor cell growth and apoptosis. In addition， SIRT5 abnormalities are also closely related to hypertrophic cardiomyopathy， myocardial infarction and other cardiovascular diseases， such as Parkinson′s disease and Alzheimer′s disease. In order to have a good comprehensive on the research progress of SIRT5， this paper reviews the structure and regulation， enzyme activity and biological function of SIRT5， and the relationship between SIRT5 and desease in details here.

[Key words] SIRT5； Deacetylation； Desuccinylation； Demalonylation； Deglutarylation； Tumor

Sirtuins家族屬于烟酰胺腺嘌呤二核苷酸（NAD+）依赖性的Ⅲ类去乙酰化酶，包含SIRT1-SIRT7七个成员。与Sirtuins家族其他成员相比，SIRT5因其具有更大的赖氨酸酰基结合口袋的结构特点，使其除有较弱的去乙酰化酶活性外，还有很强的去琥珀酰化、去丙二酰化和去戊二酰基化酶活性，近年来备受关注。琥珀酰化、丙二酰化、去戊二酰化修饰是比乙酰化更普遍的蛋白翻译后修饰，但相关研究刚刚起步。现已发现的SIRT5底物蛋白仅有十余种，通过调节底物蛋白的去酰化修饰，改变其活性和功能，参与多种物质代谢和生命活动。SIRT5异常表达与肿瘤、心血管疾病和神经系统疾病等的发生发展密切相关。本文将全面综述SIRT5的研究现状，并提出尚待解决的问题，以期为肿瘤等疾病的发生发展机制提供新的理论依据，为疾病治疗及新药的研发提供新的思路。

1 SIRT5定位、结构与调控

人类SIRT5基因位于6p23，可编码310和299个氨基酸的两种蛋白亚型[1]。SIRT5蛋白主要定位于线粒体，也存在于细胞质中，由14个α环和9条β链构成Zn2+结构域和Rossman折叠域，形成底物和NAD+结合位点。在底物结合位点，Phe223、Leu227和Val254三个疏水残基构成酰化赖氨酸基团底物的入口，两个非疏水性残基Tyr102和Arg105特异性识别带负电荷的酰基赖氨酸结构，此外，Ala86残基结构使SIRT5具有更大的赖氨酸酰基结合口袋[2]。这种结构特征决定了SIRT5优先结合丙二酰基、琥珀酰基和戊二酰基等短链羧基，而非乙酰基[3]。因此，SIRT5的去琥珀酰化酶、去丙二酰化酶和去戊二酰化酶催化效率约比去乙酰化酶高1000倍[4]。