Abstract：
2-Hydroxyglutarate (2HG) is an oncometabolite that can contribute to tumor progression. Two enantiomer forms, L-2HG and D-2HG, arise from independent pathways starting from the precursor α-ketoglutarate (αKG). L-2HG production occurs through the promiscuous activities of malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) under acidic and/or hypoxic conditions. D-2HG frequently accumulates by gain-of-function mutations in the genes encoding two isoforms of isocitrate dehydrogenase (IDH1 and IDH2). Cognate metabolite repair enzymes, L- and D-2-hydroxyglutarate dehydrogenases, oxidize the enantiomers and cause abnormally high 2HG accumulation and disease when mutated. Elevated levels of either oncometabolite affect redox homeostasis, metabolism, and immune system functioning. Moreover, the oncometabolites inhibit several α-ketoglutarate-dependent dioxygenases resulting in epigenetic changes such as DNA and histone hypermethylation as well as deficiencies in DNA repair. L-2HG, and D-2HG in some cases, inhibit degradation of hypoxia-inducible factor (HIF1α), a transcription factor that alters gene expression to adapt to hypoxic conditions, favoring tumorigenesis. Patients with the rare disease 2-hydroxyglutaric aciduria (2HGA) have exceedingly high levels of 2HG, which is neurotoxic, causing developmental delays and brain abnormalities. D-2HG also has specific effects on collagen production and NADPH pools. Recently, D-2HG has been targeted in new chemotherapies aimed at disrupting the gain-of-function IDH1 and IDH2 mutants, resulting in successful clinical trials for several cancers.
摘要：
2-羟基戊二酸（2HG）是一种可促进肿瘤进展的代谢产物。两种对映异构体形式，L-2HG和D-2HG,从前体α-酮戊二酸（αKG）开始的独立途径产生。在酸性和/或低氧条件下,通过苹果酸脱氢酶(MDH)和乳酸脱氢酶(LDH)的混杂活性产生L-2HG。D-2HG经常通过编码异柠檬酸脱氢酶的两种同工型（IDH1和IDH2）的基因中的功能获得性突变而积累。同源代谢物修复酶，L-和D-2-羟基戊二酸脱氢酶，氧化对映异构体，并在突变时引起异常高的2HG积累和疾病。两种代谢物水平的升高都会影响氧化还原稳态，新陈代谢，和免疫系统功能。此外，代谢产物抑制几种α-酮戊二酸依赖性双加氧酶，导致表观遗传变化，如DNA和组蛋白超甲基化以及DNA修复缺陷。L-2HG,和D-2HG在某些情况下，抑制缺氧诱导因子（HIF1α）的降解，改变基因表达以适应缺氧条件的转录因子，有利于肿瘤发生。罕见疾病2-羟基戊二酸尿症（2HGA）患者的2HG水平极高，有神经毒性，导致发育迟缓和大脑异常。D-2HG还对胶原蛋白产生和NADPH池具有特定作用。最近,D-2HG已成为新的化疗药物的目标，旨在破坏IDH1和IDH2突变体的功能获得。导致几种癌症的成功临床试验。
