铁氧还蛋白包含一大类铁硫 (Fe–S) 蛋白，它们在不同的生物过程中穿梭电子。人线粒体含有两种 [2Fe-2S] 铁氧还蛋白同种型 FDX1（又名肾上腺素）和 FDX2，在细胞色素 P450 依赖性类固醇转化和 Fe-S 蛋白生物合成中具有已知功能。在这里，我们表明只有 FDX2，而不是 FDX1，参与 Fe-S 蛋白的成熟。反之亦然，FDX1 不仅对类固醇生成有特异性，而且对血红素a也有特异性和硫辛酰辅因子生物合成。在后一种途径中，FDX1 提供电子以启动由硫辛酰合酶催化的自由基链反应。我们还将脂酰化确定为有毒抗肿瘤铜离子载体 elesclomol 的靶标。最后，每个铁氧还蛋白的显着目标特异性被分配给小的保守序列基序。交换这些图案改变了这些电子供体的目标特异性。总之，我们的研究结果确定了线粒体铁氧还蛋白的新生化任务，并提供了对其功能特异性的结构见解。

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Ferredoxins comprise a large family of iron–sulfur (Fe–S) proteins that shuttle electrons in diverse biological processes. Human mitochondria contain two isoforms of [2Fe-2S] ferredoxins, FDX1 (aka adrenodoxin) and FDX2, with known functions in cytochrome P450-dependent steroid transformations and Fe–S protein biogenesis. Here, we show that only FDX2, but not FDX1, is involved in Fe–S protein maturation. Vice versa, FDX1 is specific not only for steroidogenesis, but also for heme a and lipoyl cofactor biosyntheses. In the latter pathway, FDX1 provides electrons to kickstart the radical chain reaction catalyzed by lipoyl synthase. We also identified lipoylation as a target of the toxic antitumor copper ionophore elesclomol. Finally, the striking target specificity of each ferredoxin was assigned to small conserved sequence motifs. Swapping these motifs changed the target specificity of these electron donors. Together, our findings identify new biochemical tasks of mitochondrial ferredoxins and provide structural insights into their functional specificity.