Isocitrate dehydrogenases 1 and 2 (IDH1/2) are enzymes that play a major role in the Krebs cycle. Mutations in these enzymes are found in the majority of lower gliomas and secondary glioblastomas, but also in myeloid malignancies and other cancers. IDH1 and IDH2 mutations are restricted to specific arginine residues in the active site of the enzymes and are gain-of-function, i.e. they confer a neomorphic enzyme activity resulting in the accumulation of D-2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite causing profound metabolic dysregulation which, among others, results in methylator phenotypes and in defects in homologous recombination repair. In this review, we summarize current knowledge regarding the function of normal and mutated IDH, explain the possible mechanisms through which these mutations might drive malignant transformation of progenitor cells in the central nervous system, and provide a comprehensive review of potential treatment strategies for IDH-mutated malignancies, focusing on gliomas.

中文翻译：

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将癌症生物学与诊所联系起来：理解和利用胶质瘤中的 IDH 基因突变。

异柠檬酸脱氢酶 1 和 2 (IDH1/2) 是在克雷布斯循环中起主要作用的酶。这些酶的突变存在于大多数低位胶质瘤和继发性胶质母细胞瘤中，但也存在于髓系恶性肿瘤和其他癌症中。IDH1 和 IDH2 突变仅限于酶活性位点中的特定精氨酸残基，并且是功能获得性的，即它们赋予新形态的酶活性，导致 D-2-羟基戊二酸 (2-HG) 的积累。2-HG 是一种致癌代谢物，可导致严重的代谢失调，除其他外，会导致甲基化表型和同源重组修复缺陷。在这篇综述中，我们总结了当前关于正常和突变 IDH 功能的知识，