Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Genes Dev. 2013 Apr 15;27(8):836-52. doi: 10.1101/gad.217406.113.
Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.
在癌症中，代谢酶（包括异柠檬酸脱氢酶 1（IDH1）和 IDH2）的突变强烈暗示代谢改变在肿瘤发生中的作用。IDH1 和 IDH2 催化异柠檬酸和 2-氧戊二酸（2OG）的相互转化。2OG 是三羧酸循环（TCA）的中间产物，也是许多酶的必需辅因子，包括 JmjC 结构域包含的组蛋白去甲基酶、TET 5-甲基胞嘧啶羟化酶和 EglN 脯氨酰-4-羟化酶。与癌症相关的 IDH 突变改变了这些酶，使它们将 2OG 还原为结构类似的代谢物（R）-2-羟基戊二酸[（R）-2HG]。在这里，我们回顾了突变 IDH 转化的分子机制，并讨论了它们对开发针对 IDH 突变恶性肿瘤的靶向治疗的意义。
