College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul, Korea.
J Neurochem. 2015 Jan;132(2):183-93. doi: 10.1111/jnc.12950. Epub 2014 Nov 2.
The R132H and R172K mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have neomorphic activity of generating 2-hydroxyglutarate (2-HG) which has been implicated in the oncogenesis. Although similarities in structure and enzyme activity for the two isotypic mutations have been suggested, the difference in their cellular localization and biochemical properties suggests differential effects on the metabolic oncogenesis. Using U87 cells transfected with either wild-type (WT) and mutant (MT) IDH genes, the MT-IDH1 and MT-IDH2 cells were compared with NMR-based metabolomics. When normalized with the respective WT-IDH cells, the general metabolic shifts of MT-IDH1 and IDH2 were almost opposite. Subsequent analysis with LC-MS and metabolic pathway mapping showed that key metabolites in pentose phosphate pathway and tricarboxylic acid cycle are disproportionately altered in the two mutants, suggesting different activities in the key metabolic pathways. Notably, lactate level was lower in MT-IDH2 cells which produced more 2-HG than MT-IDH1 cells, indicating that the Warburg effects can be overridden by the production of 2-HG. We also found that the effect of a mutant enzyme inhibitor is mainly reduction of the 2-HG level rather than general metabolic normalization. Overall, the metabolic alterations in the MT-IDH1 and 2 can be different and seem to be commensurate with the degree of 2-HG production. The R132H and R172K mutations of isocitrate dehydrogenase 1 and 2, respectively, (IDH1 and IDH2) have neomorphic activity of generating 2-hydroxyglutarate (2-HG) which has been implicated in oncogenesis. The mutant cell's metabolic shifts from the respective wild type cells were almost opposite, with lactate level being lower in the IDH2 mutant only, implicating an overridden Warburg effect. The metabolic effect of an IDH1 mutant inhibitor was limited to 2-HG lowering.
IDH1 和 IDH2 的 R132H 和 R172K 突变具有生成 2-羟基戊二酸（2-HG）的新功能，该物质与肿瘤发生有关。尽管两种同型突变在结构和酶活性上具有相似性，但细胞定位和生化特性的差异表明它们对代谢致癌作用有不同的影响。使用转染野生型（WT）和突变型（MT）IDH 基因的 U87 细胞，用 NMR 基于代谢组学比较 MT-IDH1 和 MT-IDH2 细胞。当与相应的 WT-IDH 细胞归一化时，MT-IDH1 和 IDH2 的一般代谢变化几乎相反。随后的 LC-MS 和代谢途径映射分析表明，两个突变体中戊糖磷酸途径和三羧酸循环中的关键代谢物不成比例地改变，表明关键代谢途径的活性不同。值得注意的是，MT-IDH2 细胞中的乳酸水平较低，而 MT-IDH2 细胞产生的 2-HG 多于 MT-IDH1 细胞，表明 2-HG 的产生可以取代沃伯格效应。我们还发现，突变酶抑制剂的作用主要是降低 2-HG 水平，而不是一般的代谢正常化。总的来说，MT-IDH1 和 2 的代谢改变可能不同，似乎与 2-HG 产生的程度成正比。IDH1 和 IDH2 的 R132H 和 R172K 突变分别具有生成 2-羟基戊二酸（2-HG）的新功能，该物质与肿瘤发生有关。突变细胞的代谢变化与各自的野生型细胞几乎相反，只有 IDH2 突变体的乳酸水平较低，暗示沃伯格效应被取代。IDH1 突变抑制剂的代谢作用仅限于降低 2-HG。
