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首页> 外文期刊>Biochemistry >Arsenic(III) Species Inhibit Oxidative Protein Folding in Vitro
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Arsenic(III) Species Inhibit Oxidative Protein Folding in Vitro

机译：砷（III）物种抑制体外氧化蛋白折叠。

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The success of arsenic trioxide in the treatment of acute promyelocytic leukemia has renewedninterest in the cellular targets of As(III) species. The effects of arsenicals are usually attributed to theirnability to bind vicinal thiols or thiol selenols in prefolded proteins thereby compromising cellular function.nThe present studies suggest an additional, more pleiotropic, contribution to the biological effects ofnarsenicals. As(III) species, by avid coordination to the cysteine residues of unfolded reduced proteins,ncan compromise protein folding pathways. Three representative As(III) compounds (arsenite, mono-nmethylarsenous acid (MMA), and an aryl arsenical (PSAO)) have been tested with three reduced secretednproteins (lysozyme, ribonuclease A, and riboflavin binding protein (RfBP)). Using absorbance, fluorescence,nand pre-steady-state methods, we show that arsenicals bind tightly to low micromolar concentrations ofnthese unfolded proteins with stoichiometries of 1 As(III) per 2 thiols for MMA and PSAO and 1 As(III)nfor every 3 thiols with arsenite. Arsenicals, at 10 µM, strongly disrupt the oxidative folding of RfBP evennin the presence of 5 mM reduced glutathione, a competing ligand for As(III) species. MMA catalyzes thenformation of amyloid-like monodisperse fibrils using reduced RNase. These in itro data show that As(III)nspecies can slow, or even derail, protein folding pathways. In i o, the propensity of As(III) species tonbind to unfolded cysteine-containing proteins may contribute to oxidative and protein folding stressesnthat are prominent features of the cellular response to arsenic exposure.
机译：三氧化二砷治疗急性早幼粒细胞白血病的成功已经引起人们对As（III）物种细胞靶标的兴趣。砷的作用通常归因于它们无法结合预折叠蛋白质中的邻位硫醇或硫醇硒醇，从而损害细胞功能。n本研究表明，对麻醉药的生物学作用还有其他的多效性。作为（III）物种，通过与未折叠的还原蛋白的半胱氨酸残基进行强烈配位，可以破坏蛋白折叠途径。用三种还原的分泌蛋白（溶菌酶，核糖核酸酶A和核糖核酸结合蛋白（RfBP））测试了三种代表性的As（III）化合物（亚砷酸盐，单正甲基亚砷酸（MMA）和芳基砷酸（PSAO））。使用吸收，荧光和非稳态方法，我们显示砷与低摩尔浓度的这些未折叠蛋白紧密结合，化学计量比为MMA和PSAO每2个硫醇为1 As（III），每3个为1 As（III）n硫醇与亚砷酸盐。即使存在5 mM还原型谷胱甘肽（As（III）的竞争配体），砷中的10 µM也会强烈破坏RfBP的氧化折叠。 MMA使用还原的RNase催化淀粉样样单分散纤维的形成。这些数据表明，As（III）n种可以减缓甚至破坏蛋白质折叠途径。在这种情况下，砷（III）物种对未折叠的含半胱氨酸蛋白的倾向可能有助于氧化和蛋白折叠应力，这是细胞对砷暴露的显着特征。

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