The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute, Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Curr Opin Neurol. 2011 Dec;24(6):648-52. doi: 10.1097/WCO.0b013e32834cd415.
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, and 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.
异柠檬酸脱氢酶（IDH）1 和 IDH2 将异柠檬酸脱羧为 α-酮戊二酸（α-KG）并将 NADP 还原为 NADPH。在神经胶质瘤中发现 IDH1 和 IDH2 的点突变。IDH 突变导致失去天然酶活性，并赋予将 α-KG 转化为 2-羟基戊二酸（2-HG）的新活性。IDH 突变在神经胶质瘤发生中的机制及其作为诊断、预后标志物和治疗靶点的价值已得到广泛研究。本文旨在总结这些研究的结果。
晶体结构研究揭示了突变 IDH 的构象变化，这可能解释了突变 IDH 的获得性功能。突变 IDH 的产物 2-HG 是 α-KG 依赖性双加氧酶的抑制剂，这可能导致人类神经胶质瘤中的全基因组表观遗传改变。IDH 突变是人类神经胶质瘤的有利预后因素，可作为鉴别诊断和亚分类的生物标志物，而不是治疗反应的预测因子。初步数据表明，抑制突变 IDH 酶底物的产生可减缓神经胶质瘤细胞的生长。
作为人类神经胶质瘤有价值的诊断和预后标志物，突变 IDH 的生物学功能仍知之甚少，这使得靶向神经胶质瘤中的 IDH 既困难又不安全。
