Covalent inhibition of Plasmodium falciparum Ubc13 impairs global protein synthesis

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-28 DOI:10.1016/j.isci.2025.112545

Anna Truong , Ruitian Hu , Baiyi Quan , Morgan A. Bailey , Erin A. Schroeder , Kayla Sylvester , Gaëlle Neveu , Björn F.C. Kafsack , Michael C. Fitzgerald , Emily R. Derbyshire

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引用次数: 0

Abstract

The ubiquitin-conjugating enzyme 13 (Ubc13) has an essential function and putative role in artemisinin activity against Plasmodium falciparum. Ubc13 conjugates lysine 63-linked ubiquitin (K63-Ub) to proteins, but the role of this modification in Plasmodium remains largely unknown. Herein, we characterize and deploy NSC697923 to interrogate PfUbc13 function. We demonstrate that NSC697923 covalently targets the PfUbc13 catalytic cysteine and exhibits nanomolar inhibitory potency. NSC697923 inhibits multiple life stages and synergizes with the malaria drug dihydroartemisinin. NSC697923 specifically reduces K63-Ub in blood stage parasites, and subsequent chemoproteomic studies identified 31 putative PfUbc13 substrates. These proteins were enriched in transcription, translation, and proteasome processes, and 90% overlapped with previous Plasmodium ubiquitinome studies. Nascent protein synthesis was reduced following NSC697923 exposure, supporting a role for PfUbc13 and K63-Ub in mediating protein translation. These findings expand our knowledge of PfUbc13-dependent processes in these pathogenic parasites and highlight this enzyme as a potential antimalarial drug target.

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恶性疟原虫Ubc13共价抑制损害了全球蛋白合成

泛素偶联酶13 （Ubc13）在青蒿素抗恶性疟原虫活性中起重要作用。Ubc13将赖氨酸63连接的泛素（K63-Ub）偶联到蛋白质上，但这种修饰在疟原虫中的作用仍然很大程度上未知。在这里，我们对NSC697923进行了表征和部署，以询问PfUbc13的功能。我们证明了NSC697923共价靶向PfUbc13催化半胱氨酸，并表现出纳摩尔抑制效力。NSC697923抑制多个生命阶段，并与疟疾药物双氢青蒿素协同作用。NSC697923在血期寄生虫中特异性降低K63-Ub，随后的化学蛋白质组学研究鉴定了31个推测的PfUbc13底物。这些蛋白在转录、翻译和蛋白酶体过程中富集，90%与先前的疟原虫泛素研究重叠。NSC697923暴露后，新生蛋白合成减少，支持PfUbc13和K63-Ub介导蛋白质翻译的作用。这些发现扩大了我们对这些致病性寄生虫中pfubc13依赖过程的认识，并强调了这种酶是一种潜在的抗疟疾药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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