Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A.

IF 15.6 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of the American Chemical Society Pub Date : 2025-06-16 DOI:10.1021/jacs.5c03802

Danielle A Yee,Ross D Overacker,Michelle F Grau,Amber Cornelius,Adrianne Pigula,Daniel Mummau,Thomas Pavey,Cynthia Bailey,Clarence Hue Lok Yeung,Lawrence S Hon,Joseph E Spraker,Sheena Li,Bruno Perlatti,Samuel K Oteng-Pabi,Henry H Le,Colin J B Harvey

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引用次数: 0

Abstract

The ribosome is essential for protein synthesis and targeting its function serves as a platform for many therapies. Resistance gene-guided genome mining for a priori target identification has emerged as a useful workflow in natural product drug discovery, allowing for identification of a compound's target before the time-consuming work of isolation and characterization is performed. In this work, we identify the previously unknown lig biosynthetic gene cluster (BGC) which contains a predicted resistance gene that shares sequence identity with the gene for human ribosomal protein RPL10. Through both heterologous expression and in situ BGC engineering, we identify ligustrone A (1) as this BGC's product. Utilizing chemical genetics and chemoproteomics, we validate that 1 engages RPL10. Taken together, via resistance gene-guided mining we both discover a new target for a known natural product and elucidate its biosynthesis.

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耐药基因引导的基因组挖掘揭示了RPL10是川芎酮A的靶点。

核糖体对蛋白质合成至关重要，靶向其功能是许多治疗的平台。抗性基因引导的基因组挖掘用于先验靶点鉴定已经成为天然产物药物发现的一个有用的工作流程，允许在耗时的分离和表征工作之前鉴定化合物的靶点。在这项工作中，我们鉴定了以前未知的轻生物合成基因簇（BGC），其中包含与人类核糖体蛋白RPL10基因序列相同的预测抗性基因。通过异种表达和原位BGC工程，我们确定了该BGC的产物为川芎酮A(1)。利用化学遗传学和化学蛋白质组学，我们验证了1参与RPL10。总之，通过抗性基因引导挖掘，我们都发现了已知天然产物的新靶点，并阐明了其生物合成。

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

Journal of the American Chemical Society 化学-化学综合

CiteScore

24.40

自引率

6.00%

发文量

2398

审稿时长

1.6 months

期刊介绍： The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.