二氢硫辛酰转乙酰基酶通过乙酰化磷酸葡糖酸脱氢酶促进核酸合成  

Dihydrolipoamide Acetyltransferase Promotes Nucleic Acid Synthesis by Controlling Phosphogluconate Dehydrogenase Acetylation

作　　者：孙明明 乔亚亚 李垒垒 山长亮 张帅 SUN Ming-Ming;QIAO Ya-Ya;LI Lei-Lei;SHAN Chang-Liang;ZHANG Shuai(Department of Pharmacology,College of Pharmacy,Nankai University,Tianjin 300350,China;Department of Physiology,School of Integrative Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China)

机构地区：[1]南开大学药学院药理系,天津300350 [2]天津中医药大学中西医结合学院生理教研室,天津301617

出　　处：《中国生物化学与分子生物学报》2021年第3期339-346,共8页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.81902826和No.81973356)资助。

摘　　要：丙酮酸脱氢酶复合物(pyruvate dehydrogenase complex,PDC)是位于线粒体内的多酶复合物,催化丙酮酸不可逆地氧化脱羧转为乙酰辅酶A,二氢硫辛酰转乙酰基酶(dihydrolipoyl acetyltransferase,DLAT)是PDC的1个亚基。PDC在细胞线粒体呼吸中发挥关键作用。但是DLAT在核酸合成中的作用仍不清楚。在本研究中,首先利用GEO数据库、Oncomine数据库和人类蛋白质图谱数据库分析发现,DLAT在肺癌组织中的表达明显高于癌旁组织(P=0.0002),并且高表达DLAT的病人有较短的生存期(HR=1.47,logrank P=4e-09)。因此推测,DLAT在肿瘤生长中发挥关键作用。进而本文构建了敲低DLAT的肺癌细胞系,并用免疫印迹结果验证了DLAT敲低效果。进一步的研究发现,敲低DLAT将降低戊糖磷酸途径第3个酶磷酸葡糖酸脱氢酶(6-phosphogluconate dehydrogenase,6PGD)的乙酰化水平,进而降低6PGD酶活性,从而导致核酸合成受阻(P<0.01),最终抑制肺癌细胞增殖(P<0.01)。机制研究发现,DLAT通过乙酰化6PGD而使其酶活性增强,进而提高核酸合成,从而达到促进肺癌细胞增殖的作用。综上所述,本研究为DLAT作为潜在的靶点,为药物开发和临床肺癌的治疗提供了新的思路。Mitochondrial pyruvate dehydrogenase complex(PDC)is crucial for glucose homeostasis in mammalian cells,decarboxylation of glycolytic intermediate pyruvate to acetyl coenzyme A(acetyl-CoA)in mitochondria.Dihydrolipoyl acetyltransferase(DLAT)is a subunit of the pyruvate dehydrogenase complex.Here,we reported that DLAT was commonly increased in lung cancer and its expression was associated with worse clinical outcomes.We found that suppression of DLAT in lung cancer cells resulted in reduced nucleic acid biosynthesis and attenuated cancer cell proliferation through controlling acetylation level of 6-phosphogluconate dehydrogenase(6 PGD),the third enzyme in the oxidative pentose phosphate pathway(PPP),in which ribulose-5-phosphate(Ru-5-P)is produced for nucleic acid biosynthesis.Together,our study contributes to recent interest and discussion cross talk in cancer metabolism,which contributes to tumor growth.Future mechanistic studies should lead to the elucidation of the mode of action of DLAT in human lung cancer and establish DLAT as a viable drug target.

关 键 词：线粒体 二氢硫辛酰转乙酰基酶 磷酸葡糖酸脱氢酶 戊糖磷酸途径 

分 类 号：Q2[生物学—细胞生物学] Q7