Cancer-associated IDH1 mutations produce 2-hydroxyglutarate跟癌症相关的异柠檬酸脱氢酶1突变会产生2-羟基戊二酸Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. 胞质中异柠檬酸脱氢酶1的突变是原发性人脑癌的一个常见主要特征。These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme’s ability to catalyse conversion of isocitrate to α-ketoglutarate. 异柠檬酸脱氢酶1的作用是催化异柠檬酸转变为酮戊二酸;当突变发生在异柠檬酸脱氢酶1活性基团的一个单一的氨基酸上,将导致这个酶活性的丧失。However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. 然而,在肿瘤中只有一个基因的单一复制出现突变,那就会增加突变的可能性而不仅仅是导致一个简单功能的丢失。Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 这里我们介绍与癌症相关的异柠檬酸脱氢酶1发生突变时,该酶出现一种新的能力,就是催化NADPH依赖性的还原反应,把α-酮戊二酸还原成2-羟基戊二酸。Structural studies demonstrate that when arginine 132 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. 结构鉴定结果表明,当精氨酸132突变成组氨酸,活性基团的残基将发生结构改变,这与异柠檬酸氧化脱羧反应的减少是一致的,从而获得新能力去转化α-酮戊二酸成2-羟基戊二酸。Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. 2-羟基戊二酸的过度累积将在那些出生时2-羟基戊二酸代谢异常患者增加患脑部恶性肿瘤的风险。Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG.类似地,在人恶性神经胶质瘤固有的异柠檬酸脱氢酶1突变中,我们发现2-羟基戊二酸也是明显性地上升。 These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.这些数据表明异柠檬酸脱氢酶1突变导致肿瘤代谢物2-羟基戊二酸的产生,并且2-羟基戊二酸在体内的过度累积也是神经胶质瘤的形成与恶性变化的标记。
yukilsh 2010-01-05