Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
复制标题
DOI：
10.1093/jnci/djq187
复制
发表时间：
2010-07-07
影响因子：
10.3
通讯作者：
Yan, Hai
中科院分区：
文献类型：
--
作者：
Reitman, Zachary J.;Yan, Hai
代谢失调是癌细胞的普遍现象。NADP（+）依赖性异柠檬酸脱氢酶1和2 （IDH1和IDH2）在脂质合成、细胞防御氧化应激、氧化呼吸和氧传感信号转导等细胞代谢的十字路口发挥作用。我们回顾了编码酶的正常功能，最近在人类癌症中发现的IDH1和IDH2的频繁突变，以及突变酶在人类疾病中的可能作用。IDH1和IDH2突变经常发生在世界卫生组织分级为2-4级的胶质瘤和核型正常的急性髓性白血病中。IDH1和IDH2突变对编码每种酶活性部位的保守功能重要精氨酸的密码子具有显著的特异性。迄今为止，所有的IDH1突变都在Arg132密码子上被鉴定出来。IDH2中的Arg140密码子以及与IDH1中的Arg132一致的Arg172密码子已被鉴定出突变。IDH1和IDH2突变在癌症中通常是杂合的，它们似乎赋予酶一种新形态的酶活性，以催化d -2-羟戊二酸的产生。研究这些代谢酶的变化可能为了解癌细胞的代谢提供新的见解，并为开发抗癌治疗方法提供新的途径。
Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.