Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617.
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 catalyse conversion of isocitrate to alpha-ketoglutarate. 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. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 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 alpha-ketoglutarate to 2HG. 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. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. 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.
突变的酶胞质异柠檬酸脱氢酶 1 (IDH1) 是一个常见的特征主要子集的原发性脑肿瘤。这些突变发生在 IDH1 活性部位的一个单一的氨基酸残基，导致失去酶的能力，催化异柠檬酸转化为α-酮戊二酸。然而，只有一个基因的拷贝在肿瘤中发生突变，这就提出了这样一种可能性，即突变不会导致简单的功能丧失。在这里，我们表明，癌症相关的 IDH1 突变导致了新的酶的能力，以催化 NADPH 依赖的还原的α-酮戊二酸到 R(-)-2-羟基戊二酸 (2HG)。结构研究表明，当精氨酸 132 突变为组氨酸时，活性部位的残基发生移位，产生与异柠檬酸的氧化脱羧作用降低和获得将α-酮戊二酸转化为 2HG 的能力相一致的结构变化。已经表明，2HG 的过量积累会导致患有 2HG 代谢先天性错误的患者恶性脑肿瘤的风险增加。同样，在携带 IDH1 突变的人类恶性胶质瘤中，我们发现 2HG 的水平显著升高。这些数据表明，IDH1 突变导致致癌代谢物 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。
