产品号 #100-0514_C
抑制α-酮戊二酸依赖性双加氧酶
总览
（2R）-辛烷基-α-羟戊二酸酯是α-羟戊二酸酯（2-HG）的细胞渗透性衍生物。D-和l -2-羟基戊二酸脱氢酶将2-HG转化为α-酮戊二酸（αKG或2-氧戊二酸），与氧一起，是αKG依赖性双加氧酶大家族的共底物。2-HG本身通过与αKG竞争与该酶家族的结合来抑制αKG依赖性双加氧酶（Xu et al.）。异柠檬酸脱氢酶1 （IDH1）和IDH2突变与某些癌症有关(Reitman et al.；Sulkowski et al.)。这些酶将异柠檬酸转化为2-HG而不是αKG，这导致癌细胞中积累的高水平2-HG。（2R）-辛基-α-羟戊二酸酯可用于研究癌症中IDH突变的线粒体氧化过程。
癌症研究
·抑制αKG依赖性双加氧酶(Sulkowski et al.；Xu et al.)。
别名
2‑羟基戊二酸2-辛基酯
研究领域
癌症
CAS 编号
1391194-67-4
化学式
C13H24O5
分子量
260.3 克/摩尔
纯度
≥ 95 %
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (3)
Publications (3)
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science translational medicine 2017
Abstract
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on $\alpha$-ketoglutarate ($\alpha$KG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme and conversely it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH rather than attempting to block 2HG production by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore our results uncover an unexpected link between oncometabolites altered DNA repair and genetic instability."
Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. The Journal of biological chemistry 2014 aug
Abstract
Mutations in the cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers.
Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of $\alpha$-ketoglutarate-dependent dioxygenases. Cancer cell 2011 jan
Abstract
IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of $\alpha$-ketoglutarate ($\alpha$-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple $\alpha$-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as $\alpha$-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce $\alpha$-KG and accumulate an $\alpha$-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.
更多信息
| Molecular Weight | 260.3 g/mol |
|---|---|
| Alternative Names | (2R)-Octyl-2-HG |
| Cas Number | 1391194-67-4 |
| Chemical Formula | C13H24O5 |
| Purity | ≥ 95% |
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