Yao Pengbo, Sun Huishan, Xu Chang, Chen Taiqi, Zou Bing, Jiang Peng, Du Wenjing
From the School of Life Sciences, Tsinghua University, Beijing 100084, China and.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
J Biol Chem. 2017 Oct 13;292(41):17113-17120. doi: 10.1074/jbc.M117.810309. Epub 2017 Aug 28.
Recent studies have revealed that the oxidative entose hosphate athway (PPP), malic enzyme (ME), and folate metabolism are the three major routes for generating cellular NADPH, a key cofactor involved in redox control and reductive biosynthesis. Many tumor cells exhibit altered NADPH metabolism to fuel their rapid proliferation. However, little is known about how NADPH metabolism is coordinated in tumor cells. Here we report that ME1 increases the PPP flux by forming physiological complexes with 6-phosphogluconate dehydrogenase (6PGD). We found that ME1 and 6PGD form a hetero-oligomer that increases the capability of 6PGD to bind its substrate 6-phosphogluconate. Through activating 6PGD, ME1 enhances NADPH generation, PPP flux, and tumor cell growth. Interestingly, although ME1 could bind either the dimer-defect mutant 6PGD (K294R) or the NADP-binding defect 6PGD mutants, only 6PGD (K294R) activity was induced by ME1. Thus, ME1/6PGD hetero-complexes may mimic the active oligomer form of 6PGD. Together, these findings uncover a direct cross-talk mechanism between ME1 and PPP, may reveal an alternative model for signaling transduction via protein conformational simulation, and pave the way for better understanding how metabolic pathways are coordinated in cancer.
最近的研究表明，氧化戊糖磷酸途径（PPP）、苹果酸酶（ME）和叶酸代谢是细胞内产生烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的三条主要途径，NADPH是参与氧化还原控制和还原性生物合成的关键辅助因子。许多肿瘤细胞表现出NADPH代谢改变以满足其快速增殖的需求。然而，关于肿瘤细胞中NADPH代谢是如何协调的，我们所知甚少。在此我们报告，ME1通过与6-磷酸葡萄糖酸脱氢酶（6PGD）形成生理复合物来增加PPP通量。我们发现ME1和6PGD形成一种异源寡聚体，增强了6PGD结合其底物6-磷酸葡萄糖酸的能力。通过激活6PGD，ME1增强了NADPH的生成、PPP通量和肿瘤细胞生长。有趣的是，尽管ME1可以与二聚体缺陷突变体6PGD（K294R）或NADP结合缺陷的6PGD突变体结合，但只有6PGD（K294R）的活性受到ME1的诱导。因此，ME1/6PGD异源复合物可能模拟了6PGD的活性寡聚体形式。这些发现共同揭示了ME1与PPP之间直接的相互作用机制，可能揭示了一种通过蛋白质构象模拟进行信号转导的替代模型，并为更好地理解癌症中代谢途径的协调方式铺平了道路。
