Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H2SePO3−), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.

中文翻译：

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PRDX6 有助于硒代半胱氨酸代谢和铁死亡抵抗


硒代半胱氨酸 （Sec） 代谢对于细胞功能和铁死亡预防至关重要，从摄取 Sec 载体硒蛋白 P （SELENOP） 开始。摄取后，从 SELENOP 释放的 Sec 通过硒代半胱氨酸裂解酶 （SCLY） 代谢，产生硒化物，硒磷酸盐合成酶 2 （SEPHS2） 的底物，它提供必需的硒供体硒磷酸盐 （H2SePO3−），用于 Sec-tRNA 的生物合成。在这里，我们发现了由过氧化物还原蛋白 6 （PRDX6） 介导的 Sec 代谢的另一种途径，独立于 SCLY。从机制上讲，我们证明 PRDX6 可以很容易地与硒反应并与 SEPHS2 相互作用，可能充当硒递送系统。此外，我们证明了这种替代途径在人癌细胞中的功能意义，揭示了 PRDX6 表达升高与人 MYCN 扩增的神经母细胞瘤亚型之间的显着关联。我们的研究揭示了 Sec 代谢以前未被认识的方面及其在铁死亡中的影响，为治疗开发提供了更多的可能性。