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
{"title":"耐药基因引导的基因组挖掘揭示了RPL10是川芎酮A的靶点。","authors":"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","doi":"10.1021/jacs.5c03802","DOIUrl":null,"url":null,"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.","PeriodicalId":49,"journal":{"name":"Journal of the American Chemical Society","volume":"65 1","pages":""},"PeriodicalIF":15.6000,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A.\",\"authors\":\"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\",\"doi\":\"10.1021/jacs.5c03802\",\"DOIUrl\":null,\"url\":null,\"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.\",\"PeriodicalId\":49,\"journal\":{\"name\":\"Journal of the American Chemical Society\",\"volume\":\"65 1\",\"pages\":\"\"},\"PeriodicalIF\":15.6000,\"publicationDate\":\"2025-06-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of the American Chemical Society\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/jacs.5c03802\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the American Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/jacs.5c03802","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A.
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.
期刊介绍:
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