Major targets of iron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins
Major targets of iron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins
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DOI：
10.1016/j.freeradbiomed.2008.01.014
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发表时间：
2008-05-01
影响因子：
7.4
通讯作者：
Tamarit, Jordi
中科院分区：
文献类型：
--
作者：
Irazusta, Veronica;Moreno-Cermeno, Armando;Tamarit, Jordi
铁积累与多种病理状况有关，例如弗里德赖希共济失调。这种人类疾病是由 frataxin 表达减少引起的。铁过量会引发氧化应激，但这种应激的主要目标尚不清楚。在缺乏 frataxin 直系同源物 YFH1 的酵母细胞中，我们鉴定了一组 14 种羰基化蛋白，其中包括线粒体 ATP 合酶、磷酸甘油酸激酶、丙酮酸激酶和分子伴侣。有趣的是，大多数靶蛋白是镁和/或核苷酸结合蛋白。这一关键特征使我们推测，当铁积累时，可螯合铁在相应的金属结合位点取代镁，从而促进对这些蛋白质的选择性损伤。与这一假设一致，使用纯丙酮酸激酶和磷酸甘油酸激酶进行的体外实验表明，镁可以防止这些蛋白质的氧化，并且 ATP 的存在可以增加这些蛋白质的氧化。此外，与核苷酸形成复合物的可螯合铁在 Delta yfh1 细胞中增加了七倍。此外，通过去铁胺降低 Delta yfh1 细胞中的螯合铁，可以防止酶失活。作为一般性结论，我们提出，当这种金属积累时，与蛋白质结合的镁会被可螯合铁取代。这种机制解释了选择性蛋白质氧化，并为更好地理解铁超载病理学提供了线索。 (c) 2008 Elsevier Inc. 保留所有权利。
Iron accumulation has been associated with several pathological conditions such as Friedreich ataxia. This human disorder is caused by decreased expression of frataxin. Iron-overload triggers oxidative stress, but the main targets of such stress are not known. In yeast cells lacking the frataxin ortholog YFH1, we have identified a set of 14 carbonylated proteins, which include mitochondrial ATP synthase, phosphoglycerate kinase, pyruvate kinase, and molecular chaperones. Interestingly, most of the target proteins are magnesium- and/or nucleotide-binding proteins. This key feature leads us to postulate that when iron accumulates, chelatable iron replaces magnesium at the corresponding metal-binding site, promoting selective damage to these proteins. Consistent with this hypothesis, in vitro experiments performed with pure pyruvate kinase and phosphoglycerate kinase showed that oxidation of these proteins can be prevented by magnesium and increased by the presence of ATP. Also, chelatable iron, which forms complexes with nucleotides, showed a sevenfold increase in Delta yfh1 cells. Moreover, lowering chelatable iron in Delta yfh1 cells by desferrioxamine prevented enzyme inactivation. As a general conclusion, we propose that magnesium bound to proteins is replaced by chelatable iron when this metal accumulates. This mechanism explains selective protein oxidation and provides clues for better understanding of iron-overloading pathologies. (c) 2008 Elsevier Inc. All rights reserved.