Advancing Genetically Encoded Lysine (GEK) Chemistry: From Precision Modulation to Therapeutic Innovation

IF 17.7 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2025-09-26 DOI:10.1021/acs.accounts.5c00401

Guoqing Jin, Yifan Shi, Shivangi Sharma, Wenshe Ray Liu

{"title":"Advancing Genetically Encoded Lysine (GEK) Chemistry: From Precision Modulation to Therapeutic Innovation","authors":"Guoqing Jin, Yifan Shi, Shivangi Sharma, Wenshe Ray Liu","doi":"10.1021/acs.accounts.5c00401","DOIUrl":null,"url":null,"abstract":"Genetically encoded lysine (GEK) chemistry has transformed protein engineering by enabling precise and site-specific modifications, which expand lysine’s functional landscape beyond its native post-translational modifications (PTMs). Our work has systematically advanced GEK chemistry by developing engineered pyrrolysyl-tRNA synthetase (PylRS) variants that efficiently incorporate diverse lysine (Lys) derivatives with tailored chemical reactivity. By integrating bioorthogonal handles, acyl and electrophilic warheads, photo-cross-linking groups, and PTM mimics, we have established a set of powerful toolkits for protein labeling, functional studies, and Lys-directed drug design. These advances provide precise control over protein structure and function, facilitating the study of epigenetic modifications, enzyme–substrate interactions, and Lys-guided inhibitor development. As GEK chemistry continues to evolve, its integration with structural/synthetic biology and therapeutic innovation will further expand its impact, unlocking new frontiers in chemical biology and precision therapeutics.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"155 1","pages":""},"PeriodicalIF":17.7000,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.accounts.5c00401","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

Genetically encoded lysine (GEK) chemistry has transformed protein engineering by enabling precise and site-specific modifications, which expand lysine’s functional landscape beyond its native post-translational modifications (PTMs). Our work has systematically advanced GEK chemistry by developing engineered pyrrolysyl-tRNA synthetase (PylRS) variants that efficiently incorporate diverse lysine (Lys) derivatives with tailored chemical reactivity. By integrating bioorthogonal handles, acyl and electrophilic warheads, photo-cross-linking groups, and PTM mimics, we have established a set of powerful toolkits for protein labeling, functional studies, and Lys-directed drug design. These advances provide precise control over protein structure and function, facilitating the study of epigenetic modifications, enzyme–substrate interactions, and Lys-guided inhibitor development. As GEK chemistry continues to evolve, its integration with structural/synthetic biology and therapeutic innovation will further expand its impact, unlocking new frontiers in chemical biology and precision therapeutics.

Abstract Image

查看原文本刊更多论文

推进遗传编码赖氨酸（GEK）化学：从精确调制到治疗创新

遗传编码赖氨酸（GEK）化学通过实现精确和位点特异性修饰改变了蛋白质工程，这扩展了赖氨酸的功能景观，超出了其天然的翻译后修饰（PTMs）。我们的工作通过开发工程的pyrlyyl - trna合成酶（PylRS）变体，系统地推进了GEK化学，这些变体有效地结合了具有定制化学反应性的各种赖氨酸（Lys）衍生物。通过整合生物正交处理、酰基和亲电弹头、光交联基团和PTM模拟物，我们已经建立了一套强大的蛋白质标记、功能研究和lys定向药物设计工具包。这些进展提供了对蛋白质结构和功能的精确控制，促进了表观遗传修饰、酶-底物相互作用和赖氨酸引导抑制剂开发的研究。随着GEK化学的不断发展，其与结构/合成生物学和治疗创新的整合将进一步扩大其影响，为化学生物学和精确治疗开辟新的领域。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.