Hypoxia Induces Production of L-2-Hydroxyglutarate.
Hypoxia Induces Production of L-2-Hydroxyglutarate.
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DOI：
10.1016/j.cmet.2015.06.023
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发表时间：
2015-08-04
期刊：
影响因子：
29
通讯作者：
Thompson CB
中科院分区：
文献类型：
--
作者：
Intlekofer AM;Dematteo RG;Venneti S;Finley LW;Lu C;Judkins AR;Rustenburg AS;Grinaway PB;Chodera JD;Cross JR;Thompson CB
异柠檬酸脱氢酶1或2(IDH1/2)的体细胞突变通过产生肿瘤代谢产物D-2-羟基戊二酸(D-2HG)参与癌症的发生。升高的D-2HG可以作为α-酮戊二酸(α-KG)依赖酶的竞争性抑制物，包括Jumonji家族组蛋白赖氨酸脱甲基酶，从而阻断肿瘤细胞的分化。2HG是一种手性分子，既可以存在于D-对映体中，也可以存在于L对映体中。虽然与癌症相关的IDH1/2突变会产生D-2HG，但生化研究表明，L-2HG也是α-KG依赖酶的有效抑制因子。在此，我们报道了在缺氧条件下，哺乳动物细胞通过酶促还原α-KG选择性地产生L-2HG。低氧诱导的L-2HG不是由IDH1或IDH2介导的，而是主要由乳酸脱氢酶A(LDHA)介导的底物错配使用的结果。在低氧条件下，L-2HG的增加是诱导组蛋白抑制标志，包括组蛋白3赖氨酸9(H3K9me3)甲基化的必要条件和充分条件。
Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of alpha-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although cancer-associated IDH1/2 mutations produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).