期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 41, 页码 43035-43045出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M402759200
关键词
-
Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD(+) and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria pre-incubated with sulfite failed to reduce NAD(+). Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the K-m ( glutamate) and a decrease in V-max resulting in an attenuation in V-max/K-m ( glutamate) at 100 muM sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both K-m (NAD(+)) and V-max, whereas V-max/K-m (NAD(+)) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in alpha-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据