Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions
Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions
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苹果酸酶和磷酸戊糖途径之间通过结构相互作用直接相互作用的证据
DOI：
10.1074/jbc.m117.810309
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发表时间：
2017-10-13
影响因子：
4.8
通讯作者：
Du, Wenjing
中科院分区：
文献类型：
--
作者：
Yao, Pengbo;Sun, Huishan;Du, Wenjing
最近的研究表明，氧化戊糖磷酸途径（PPP）、苹果酸酶（ME）和叶酸代谢是产生细胞NADPH的三个主要途径，NADPH是参与氧化还原控制和还原生物合成的关键辅助因子。许多肿瘤细胞表现出 NADPH 代谢的改变，以促进其快速增殖。然而，人们对 NADPH 代谢在肿瘤细胞中如何协调知之甚少。在这里，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 形成异源寡聚物，提高 6PGD 结合其底物 6-磷酸葡萄糖酸的能力。通过激活 6PGD，ME1 增强 NADPH 生成、PPP 通量和肿瘤细胞生长。有趣的是，虽然ME1可以结合二聚体缺陷突变体6PGD（K294R）或NADP+结合缺陷6PGD突变体，但ME1仅诱导6PGD（K294R）活性。因此，ME1/6PGD 杂合物可以模拟 6PGD 的活性寡聚物形式。总之，这些发现揭示了 ME1 和 PPP 之间的直接串扰机制，可能揭示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如何协调铺平道路。
Recent studies have revealed that the oxidative pentose phosphate pathway (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.