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

IF 11.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Advances Pub Date : 2024-12-20 DOI:10.1126/sciadv.adp3954
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":"A bacterial methyltransferase that initiates biotin synthesis, an attractive anti-ESKAPE druggable pathway","authors":"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","doi":"10.1126/sciadv.adp3954","DOIUrl":null,"url":null,"abstract":"The covalently attached cofactor biotin plays pivotal roles in central metabolism. The top-priority ESKAPE-type pathogens, <jats:italic>Acinetobacter baumannii</jats:italic> and <jats:italic>Klebsiella pneumoniae</jats:italic> , 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 <jats:italic>A. baumannii</jats:italic> and KpBioC for <jats:italic>K. pneumoniae</jats:italic> ) 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 <jats:italic>bioC</jats:italic> rendered <jats:italic>A. baumannii</jats:italic> and <jats:italic>K. pneumoniae</jats:italic> 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 <jats:italic>K. pneumoniae</jats:italic> infection and <jats:italic>A. baumannii</jats:italic> colistin resistance.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 1","pages":""},"PeriodicalIF":11.7000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://doi.org/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

Abstract

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.
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
求助全文
约1分钟内获得全文 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.
期刊最新文献
Ain't no stoppin' us now…. Meeting metformin again for the first time. The human auditory cortex concurrently tracks syllabic and phonemic timescales via acoustic spectral flux Evolutionary engineering of Saccharomyces cerevisiae : Crafting a synthetic methylotroph via self-reprogramming Approaching the standard quantum limit of a Rydberg-atom microwave electrometer
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1