人类拥有两种线粒体铁氧还蛋白 Fdx1 和 Fdx2，在类固醇生成、血红素和 Fe/S 簇生物合成中具有不同的作用。,Proceedings of the National Academy of Sciences of the United States of America

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人类拥有两种线粒体铁氧还蛋白 Fdx1 和 Fdx2，在类固醇生成、血红素和 Fe/S 簇生物合成中具有不同的作用。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2010 Jun 29 , DOI: 10.1073/pnas.1004250107
Alex D Sheftel ₁ , Oliver Stehling , Antonio J Pierik , Hans-Peter Elsässer , Ulrich Mühlenhoff , Holger Webert , Anna Hobler , Frank Hannemann , Rita Bernhardt , Roland Lill

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哺乳动物肾上腺素氧还蛋白（铁氧还蛋白 1；Fdx1）对于肾上腺中各种类固醇激素的合成至关重要。作为含 [2Fe-2S] 簇的铁氧还蛋白家族的成员，Fdx1 减少线粒体细胞色素 P450 酶，然后催化；例如，胆固醇转化为孕烯醇酮、醛固酮和皮质醇。Fdx1 与其酵母肾上腺素氧还蛋白同源物 (Yah1) 之间的高蛋白质序列相似性表明，Fdx1 与 Yah1 一样，可能参与血红素 A 和 Fe/S 簇的生物合成，这两种多功能且必不可少的蛋白质辅助因子。我们的研究采用 RNAi 技术来消耗人类 Fdx1，并未证实这一预期。相反，我们鉴定了一种 Fdx1 相关线粒体蛋白，命名为铁氧还蛋白 2 (Fdx2)，并发现它对血红素 A 和 Fe/S 蛋白生物合成至关重要。与 Fdx1 不同的是，Fdx2 无法有效地减少线粒体细胞色素 P450 并转化类固醇，这表明两种铁氧还蛋白同种型对其在不同生化途径中的底物具有高度特异性。此外，Fdx2 缺乏通过受损的 Fe/S 蛋白生物合成对细胞铁稳态产生严重影响，导致细胞铁摄取和线粒体铁积累增加。我们得出的结论是，哺乳动物依赖两种不同的线粒体铁氧还蛋白来特异性产生类固醇激素或血红素 A 和 Fe/S 蛋白。细胞铁稳态，导致线粒体中细胞铁摄取和铁积累增加。我们得出的结论是，哺乳动物依赖两种不同的线粒体铁氧还蛋白来特异性产生类固醇激素或血红素 A 和 Fe/S 蛋白。细胞铁稳态，导致线粒体中细胞铁摄取和铁积累增加。我们得出的结论是，哺乳动物依赖两种不同的线粒体铁氧还蛋白来特异性产生类固醇激素或血红素 A 和 Fe/S 蛋白。

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Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis.

Mammalian adrenodoxin (ferredoxin 1; Fdx1) is essential for the synthesis of various steroid hormones in adrenal glands. As a member of the [2Fe-2S] cluster-containing ferredoxin family, Fdx1 reduces mitochondrial cytochrome P450 enzymes, which then catalyze; e.g., the conversion of cholesterol to pregnenolone, aldosterone, and cortisol. The high protein sequence similarity between Fdx1 and its yeast adrenodoxin homologue (Yah1) suggested that Fdx1, like Yah1, may be involved in the biosynthesis of heme A and Fe/S clusters, two versatile and essential protein cofactors. Our study, employing RNAi technology to deplete human Fdx1, did not confirm this expectation. Instead, we identified a Fdx1-related mitochondrial protein, designated ferredoxin 2 (Fdx2) and found it to be essential for heme A and Fe/S protein biosynthesis. Unlike Fdx1, Fdx2 was unable to efficiently reduce mitochondrial cytochromes P450 and convert steroids, indicating that the two ferredoxin isoforms are highly specific for their substrates in distinct biochemical pathways. Moreover, Fdx2 deficiency had a severe impact, via impaired Fe/S protein biogenesis, on cellular iron homeostasis, leading to increased cellular iron uptake and iron accumulation in mitochondria. We conclude that mammals depend on two distinct mitochondrial ferredoxins for the specific production of either steroid hormones or heme A and Fe/S proteins.

更新日期：2017-01-31

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