The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells.
The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells.
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线粒体NADPH依赖性异位酸脱氢酶在癌细胞中的作用。
DOI：
10.1155/2012/273947
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发表时间：
2012
影响因子：
--
通讯作者：
Ježek P
中科院分区：
文献类型：
--
作者：
Smolková K;Ježek P
异柠檬酸脱氢酶2（IDH 2）位于线粒体基质中。IDH 2在正向克雷布斯循环中作为NADP+消耗酶起作用，提供NADPH以维持还原型谷胱甘肽和过氧化物氧还蛋白系统，并通过谷氧还蛋白2再活化胱氨酸失活的IDH 2进行自我维持。在高度呼吸的细胞中，所产生的NAD+积累然后诱导沉默调节蛋白-3介导的激活IDH 2脱乙酰化，从而增加其保护功能。2-酮戊二酸被IDH 2还原羧化（在逆Krebs循环方向上），其消耗NADPH，可能在癌细胞中谷氨酰胺氨解为2-酮戊二酸之后。当逆顺乌头酸酶反应和柠檬酸盐流出增加时，这种整体“缺氧”的氨解模式可能有助于高度恶性肿瘤在缺氧期间的无糖血症中存活。假设需要间歇性糖酵解来提供ATP。当氧化磷酸化处于休眠状态时，这种模式会导致严重的氧化应激。人IDH 2的Arg 172突变体--在2级和3级胶质瘤、继发性胶质母细胞瘤和急性髓性白血病中经常与胞质IDH 1的类似突变体一起发现--催化2-酮戊二酸的还原羧化并还原为D-2-羟基戊二酸，其通过竞争性抑制组蛋白去甲基化和5-甲基胞嘧啶羟基化来增强肿瘤表型，导致全基因组蛋白和DNA甲基化改变。D-2-羟基戊二酸还干扰脯氨酸羟基化，因此可能稳定缺氧诱导因子α。
Isocitrate dehydrogenase 2 (IDH2) is located in the mitochondrial matrix. IDH2 acts in the forward Krebs cycle as an NADP+-consuming enzyme, providing NADPH for maintenance of the reduced glutathione and peroxiredoxin systems and for self-maintenance by reactivation of cystine-inactivated IDH2 by glutaredoxin 2. In highly respiring cells, the resulting NAD+ accumulation then induces sirtuin-3-mediated activating IDH2 deacetylation, thus increasing its protective function. Reductive carboxylation of 2-oxoglutarate by IDH2 (in the reverse Krebs cycle direction), which consumes NADPH, may follow glutaminolysis of glutamine to 2-oxoglutarate in cancer cells. When the reverse aconitase reaction and citrate efflux are added, this overall “anoxic” glutaminolysis mode may help highly malignant tumors survive aglycemia during hypoxia. Intermittent glycolysis would hypothetically be required to provide ATP. When oxidative phosphorylation is dormant, this mode causes substantial oxidative stress. Arg172 mutants of human IDH2—frequently found with similar mutants of cytosolic IDH1 in grade 2 and 3 gliomas, secondary glioblastomas, and acute myeloid leukemia—catalyze reductive carboxylation of 2-oxoglutarate and reduction to D-2-hydroxyglutarate, which strengthens the neoplastic phenotype by competitive inhibition of histone demethylation and 5-methylcytosine hydroxylation, leading to genome-wide histone and DNA methylation alternations. D-2-hydroxyglutarate also interferes with proline hydroxylation and thus may stabilize hypoxia-induced factor α.