一种启动生物素合成的细菌甲基转移酶,一种有吸引力的抗eskape药物途径

IF 12.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Zhi Su, Weizhen Zhang, Yu Shi, Tao Cui, Yongchang Xu, Runshi Yang, Man Huang, Chun Zhou, Huimin Zhang, Ting Lu, Jiuxin Qu, Zheng-Guo He, Jianhua Gan, Youjun Feng
{"title":"一种启动生物素合成的细菌甲基转移酶,一种有吸引力的抗eskape药物途径","authors":"Zhi Su,&nbsp;Weizhen Zhang,&nbsp;Yu Shi,&nbsp;Tao Cui,&nbsp;Yongchang Xu,&nbsp;Runshi Yang,&nbsp;Man Huang,&nbsp;Chun Zhou,&nbsp;Huimin Zhang,&nbsp;Ting Lu,&nbsp;Jiuxin Qu,&nbsp;Zheng-Guo He,&nbsp;Jianhua Gan,&nbsp;Youjun Feng","doi":"10.1126/sciadv.adp3954","DOIUrl":null,"url":null,"abstract":"<div >The covalently attached cofactor biotin plays pivotal roles in central metabolism. The top-priority ESKAPE-type pathogens, <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i>, constitute a public health challenge of global concern. Despite the fact that the late step of biotin synthesis is a validated anti-ESKAPE drug target, the primary stage remains fragmentarily understood. We report the functional definition of two BioC isoenzymes (AbBioC for <i>A. baumannii</i> and KpBioC for <i>K. pneumoniae</i>) that act as malonyl-ACP methyltransferase and initiate biotin synthesis. The physiological requirement of biotin is diverse within ESKAPE pathogens. CRISPR-Cas9–based inactivation of <i>bioC</i> rendered <i>A. baumannii</i> and <i>K. pneumoniae</i> biotin auxotrophic. The availability of soluble AbBioC enabled the in vitro reconstitution of DTB/biotin synthesis. We solved two crystal structures of AbBioC bound to SAM cofactor (2.54 angstroms) and sinefungin (SIN) inhibitor (1.72 angstroms). Structural and functional study provided molecular basis for SIN inhibition of BioC. We demonstrated that BioC methyltransferase plays dual roles in <i>K. pneumoniae</i> infection and <i>A. baumannii</i> colistin resistance.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 51","pages":""},"PeriodicalIF":12.5000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp3954","citationCount":"0","resultStr":"{\"title\":\"A bacterial methyltransferase that initiates biotin synthesis, an attractive anti-ESKAPE druggable pathway\",\"authors\":\"Zhi Su,&nbsp;Weizhen Zhang,&nbsp;Yu Shi,&nbsp;Tao Cui,&nbsp;Yongchang Xu,&nbsp;Runshi Yang,&nbsp;Man Huang,&nbsp;Chun Zhou,&nbsp;Huimin Zhang,&nbsp;Ting Lu,&nbsp;Jiuxin Qu,&nbsp;Zheng-Guo He,&nbsp;Jianhua Gan,&nbsp;Youjun Feng\",\"doi\":\"10.1126/sciadv.adp3954\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >The covalently attached cofactor biotin plays pivotal roles in central metabolism. The top-priority ESKAPE-type pathogens, <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i>, constitute a public health challenge of global concern. Despite the fact that the late step of biotin synthesis is a validated anti-ESKAPE drug target, the primary stage remains fragmentarily understood. We report the functional definition of two BioC isoenzymes (AbBioC for <i>A. baumannii</i> and KpBioC for <i>K. pneumoniae</i>) that act as malonyl-ACP methyltransferase and initiate biotin synthesis. The physiological requirement of biotin is diverse within ESKAPE pathogens. CRISPR-Cas9–based inactivation of <i>bioC</i> rendered <i>A. baumannii</i> and <i>K. pneumoniae</i> biotin auxotrophic. The availability of soluble AbBioC enabled the in vitro reconstitution of DTB/biotin synthesis. We solved two crystal structures of AbBioC bound to SAM cofactor (2.54 angstroms) and sinefungin (SIN) inhibitor (1.72 angstroms). Structural and functional study provided molecular basis for SIN inhibition of BioC. We demonstrated that BioC methyltransferase plays dual roles in <i>K. pneumoniae</i> infection and <i>A. baumannii</i> colistin resistance.</div>\",\"PeriodicalId\":21609,\"journal\":{\"name\":\"Science Advances\",\"volume\":\"10 51\",\"pages\":\"\"},\"PeriodicalIF\":12.5000,\"publicationDate\":\"2024-12-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/sciadv.adp3954\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Advances\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciadv.adp3954\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/sciadv.adp3954","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

摘要

共价附着的辅因子生物素在中枢代谢中起关键作用。最优先的eskape型病原体鲍曼不动杆菌和肺炎克雷伯菌构成了全球关注的公共卫生挑战。尽管生物素合成的后期阶段是一个经过验证的抗eskape药物靶点,但其初级阶段仍然知之甚少。我们报道了两个BioC同工酶的功能定义(鲍曼不动杆菌的AbBioC和肺炎克雷伯菌的KpBioC),它们作为丙二酰acp甲基转移酶并启动生物素合成。ESKAPE病原菌对生物素的生理需求是多种多样的。基于crispr - cas9的生物素失活使鲍曼不动杆菌和肺炎克雷伯菌生物素营养不良。可溶性AbBioC的可用性使DTB/生物素合成的体外重构成为可能。我们解出了AbBioC与SAM辅助因子(2.54埃)和sininefungin (SIN)抑制剂(1.72埃)结合的两种晶体结构。结构和功能研究为BioC抑制SIN提供了分子基础。我们证明了BioC甲基转移酶在肺炎克雷伯菌感染和鲍曼假杆菌粘菌素耐药性中起双重作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A bacterial methyltransferase that initiates biotin synthesis, an attractive anti-ESKAPE druggable pathway

A bacterial methyltransferase that initiates biotin synthesis, an attractive anti-ESKAPE druggable pathway
The covalently attached cofactor biotin plays pivotal roles in central metabolism. The top-priority ESKAPE-type pathogens, Acinetobacter baumannii and Klebsiella pneumoniae, constitute a public health challenge of global concern. Despite the fact that the late step of biotin synthesis is a validated anti-ESKAPE drug target, the primary stage remains fragmentarily understood. We report the functional definition of two BioC isoenzymes (AbBioC for A. baumannii and KpBioC for K. pneumoniae) that act as malonyl-ACP methyltransferase and initiate biotin synthesis. The physiological requirement of biotin is diverse within ESKAPE pathogens. CRISPR-Cas9–based inactivation of bioC rendered A. baumannii and K. pneumoniae biotin auxotrophic. The availability of soluble AbBioC enabled the in vitro reconstitution of DTB/biotin synthesis. We solved two crystal structures of AbBioC bound to SAM cofactor (2.54 angstroms) and sinefungin (SIN) inhibitor (1.72 angstroms). Structural and functional study provided molecular basis for SIN inhibition of BioC. We demonstrated that BioC methyltransferase plays dual roles in K. pneumoniae infection and A. baumannii colistin resistance.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
期刊介绍: Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信