Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target.
Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target.
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DOI：
10.1097/wco.0b013e32834cd415
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发表时间：
2011-12
影响因子：
4.8
通讯作者：
Yan H
中科院分区：
文献类型：
--
作者：
Guo C;Pirozzi CJ;Lopez GY;Yan H
异柠檬酸脱氢酶IDH 1和IDH 2将异柠檬酸脱羧为α-酮戊二酸（α-KG），并将NADP还原为NADPH。IDH 1和IDH 2的点突变已在胶质瘤中发现。IDH突变导致天然酶活性丧失，并赋予将α-KG转化为2-羟基戊二酸（2-HG）的新活性。IDH突变在胶质瘤发生中的作用机制及其作为诊断、预后指标和治疗靶点的价值已得到广泛研究。本文就这些研究的结果进行综述。晶体结构研究揭示了突变IDHs的构象变化，这可能解释了突变IDHs的功能获得。IDH突变体的产物2-HG是α-KG依赖性双加氧酶的抑制剂，其可能导致人类胶质瘤的全基因组表观遗传改变。IDH突变是一个有利的预后因子，可作为鉴别诊断和亚类分类的生物标志物，而不是治疗反应的预测因子。初步数据表明，抑制突变IDH酶的底物的产生导致神经胶质瘤细胞生长减慢。IDH突变体作为胶质瘤诊断和预后的重要标志物，其生物学功能尚不清楚，这使得IDH在胶质瘤中的靶向治疗变得困难和不安全。
Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG), and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.