Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
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胞质异柠檬酸脱氢酶1 （IDH1）的突变是原发性人类脑癌的一个主要亚群的共同特征。这些突变发生在IDH1活性位点的单个氨基酸残基上，导致酶催化异柠檬酸盐转化为α-酮戊二酸盐的能力丧失。然而，在肿瘤中只有一个基因拷贝发生突变，这增加了突变不会导致简单的功能丧失的可能性。在这里，我们发现癌症相关的IDH1突变导致酶具有新的能力，可以催化nadph依赖的α-酮戊二酸还原为R(−)-2-羟基戊二酸（2HG）。结构研究表明，当R132突变为组氨酸时，活性位点的残基发生移位，产生与异柠檬酸氧化脱羧减少和α-酮戊二酸转化为2HG的能力相一致的结构变化。2HG的过量积累已被证明会导致先天性2HG代谢错误患者患恶性脑肿瘤的风险增加。同样，在IDH1突变的人类恶性胶质瘤中，我们发现2HG水平显著升高。这些数据表明，IDH1突变导致肿瘤代谢物2HG的产生，并表明体内积累的过量2HG有助于胶质瘤的形成和恶性进展。
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site resulting in loss of the enzyme’s ability to catalyze conversion of isocitrate to α-ketoglutarate. However, only a single copy of the gene is mutated in tumors, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when R132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert α-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harboring IDH1 mutations, we find dramatically elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and suggest that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
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DOI：
10.1126/science.1170944
发表时间：
2009-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zhao S;Lin Y;Xu W;Jiang W;Zha Z;Wang P;Yu W;Li Z;Gong L;Peng Y;Ding J;Lei Q;Guan KL;Xiong Y
通讯作者：
Xiong Y
影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.4
作者：
Kölker, S;Pawlak, V;Köhr, G
通讯作者：
Köhr, G
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW