Tomaselli Daniela, Steegborn Clemens, Mai Antonello, Rotili Dante
Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Rome, Italy.
Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
Front Oncol. 2020 Apr 15;10:474. doi: 10.3389/fonc.2020.00474. eCollection 2020.
Sirtuins are NAD-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.
沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD）的去酰基酶，在细胞代谢调节中发挥关键作用，因此与多种疾病有关。线粒体沉默调节蛋白Sirt4长期以来主要被认为是一种单ADP核糖基转移酶，最近除了已被认可的依赖底物的硫辛酰胺酶和脱乙酰酶特性外，还显示出强大的去酰基酶活性。通过这些以及可能的其他酶促和非酶促活性，Sirt4密切控制各种代谢事件，其失调与各种与衰老相关的疾病有关，包括2型糖尿病、心脏肥大、非酒精性脂肪性肝病、肥胖症和癌症。由于其抑制谷氨酰胺分解代谢的能力以及在不同DNA损伤条件下对癌细胞基因组稳定性的调节作用，Sirt4被认为在不同背景下既是线粒体肿瘤抑制因子，又是肿瘤促进蛋白。除了已知Sirt4在不同生物学环境中的作用外，为了验证这种酶作为各种衰老疾病的新潜在靶点，肯定仍需要进一步研究。
