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文章简介NADP~+-IDH突变产生的代谢物2-hydroxyglutarate(2-HG)是三羧酸循环代谢物琥珀酸的机构类似物,其累积抑制了琥珀酸脱氢酶(sDH)的酶活力并导致其上游代谢物Succinyl-CoA的累积。Succinyl-CoA是已知的赖氨酸自发修饰底物,在细胞中广泛修饰蛋白并改变多种生理性状。但是,由于Succinyl-CoA在线粒体内产生,所以NADP~+-IDH突变以及SDH及富马酸水化酶(FH)突变疾病都导致线粒体内蛋白的异常高琥珀酰化。高琥珀酰化导致线粒体包括氧化磷酸化、膜电位的异常,促进Warburg效应同时诱导凋
Introduction The 2-hydroxyglutarate (2-HG), a metabolite of the NADP ~ + -IDH mutation, is an analogue of the succinic acid, a cyclic metabolite of the tricarboxylic acid, which cumulatively inhibits the enzyme activity of succinate dehydrogenase (sDH) Leading to the accumulation of its upstream metabolite Succinyl-CoA. Succinyl-CoA is a well-known lysine-modified substrate that widely modifies proteins in cells and alters many physiological traits. However, due to the production of Succinyl-CoA in the mitochondria, mutations in NADP ~ + -IDH and mutations in SDH and fumarate hydratase (FH) result in abnormally high succinylation of mitochondrial proteins. High succinate acylation leads to oxidative phosphorylation of mitochondria, abnormal membrane potential, and promotion of Warburg effect while inducing apoptosis