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    • 3. 发明申请
    • EFFECTS OF IDH1 AND IDH2 MUTATIONS ON THE CELLULAR METABOLOME
    • IDH1和IDH2突变对细胞代谢物的影响
    • US20120202883A1
    • 2012-08-09
    • US13355129
    • 2012-01-20
    • Yan HaiDarell BignerYiping HeGenglin JinZachary Reitman
    • Yan HaiDarell BignerYiping HeGenglin JinZachary Reitman
    • A61K31/191A61K31/197A61P35/02C12Q1/68A61P35/00
    • A61K31/194A61K31/198A61K38/05G01N33/6812G01N2570/00
    • Point mutations of the NADP+-dependent isocitrate dehydrogenases (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. Here, we profiled >200 metabolites in human oligodendroglioma cell line (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in both mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG was also significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations.
    • NADP +依赖性异柠檬酸脱氢酶(IDH1和IDH2)的点突变发生在胶质瘤发病早期。 当突变时,IDH1和IDH2获得产生代谢物(R)-2-羟基戊二酸(2HG)的能力,但突变体IDH1和IDH2蛋白质或2HG对细胞代谢的下游作用是未知的。 在这里,我们在人类少突神经胶质瘤细胞系(HOG)细胞中分析了200种代谢物,以确定IDH1和IDH2突变体的表达效应。 氨基酸,谷胱甘肽代谢物,胆碱衍生物和三羧酸(TCA)循环中间体的水平在突变体IDH1和IDH2表达细胞中都被改变。 这些变化与用2HG处理细胞后鉴定的变化相似。 值得注意的是,脑中常见的二肽N-乙酰天冬氨酰谷氨酸(NAAG)在表达IDH1突变体的细胞中减少了50倍,表达IDH2突变体的细胞减少了8.3倍。 NAAG在含有IDH突变的人胶质瘤组织中也明显低于没有这种突变的胶质瘤。