PDF(Pubmed)
Abstract：
The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.
摘要：
使用下一代测序（NGS）的全面基因组分析的出现揭示了丰富的潜在可操作的遗传畸变，这些畸变塑造了我们对癌症生物学格局的理解。异柠檬酸脱氢酶(IDH)是存在于细胞质(IDH1)和线粒体(IDH2和IDH3)中的酶。在线粒体中，它催化异柠檬酸酯的不可逆氧化脱羧，产生α-酮戊二酸和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）以及二氧化碳（CO2）的生产。在细胞质中，IDH催化异柠檬酸脱羧为α-酮戊二酸以及α-酮戊二酸反向还原羧化为异柠檬酸。三羧酸循环中的这些限速步骤，以及细胞质对氧化应激的反应，在基因调控中起关键作用，细胞分化，和组织稳态。编码IDH1和IDH2的基因突变，不太常见，IDH3已在多种癌症中发现，最常见的是神经胶质瘤，急性髓系白血病(AML),软骨肉瘤,和肝内胆管癌。在本文中,我们打算阐明IDH异构体突变背后的理论病理生理学，它在癌症表现中的含义，并讨论有关新型IDH抑制剂的使用及其在治疗中的作用的一些可用临床数据。
