Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques.

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Critical Reviews in Biochemistry and Molecular Biology Pub Date : 2024-02-01 Epub Date: 2024-03-07 DOI:10.1080/10409238.2024.2318547
Philipp Schnee, Jürgen Pleiss, Albert Jeltsch
{"title":"Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques.","authors":"Philipp Schnee, Jürgen Pleiss, Albert Jeltsch","doi":"10.1080/10409238.2024.2318547","DOIUrl":null,"url":null,"abstract":"<p><p>Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2. Biochemical experiments have unraveled many mechanistic features of PKMTs concerning their substrate and product specificity, processivity and the effects of somatic mutations observed in PKMTs in cancer cells. Structural data additionally provided information about the substrate recognition, enzyme-substrate complex formation, and allowed for simulations of the substrate peptide interaction and mechanism of PKMTs with atomistic resolution by molecular dynamics and hybrid quantum mechanics/molecular mechanics methods. These simulation technologies uncovered important mechanistic details of the PKMT reaction mechanism including the processes responsible for the deprotonation of the target lysine residue, essential conformational changes of the PKMT upon substrate binding, but also rationalized regulatory principles like PKMT autoinhibition. Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.</p>","PeriodicalId":10794,"journal":{"name":"Critical Reviews in Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":6.2000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Critical Reviews in Biochemistry and Molecular Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/10409238.2024.2318547","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2. Biochemical experiments have unraveled many mechanistic features of PKMTs concerning their substrate and product specificity, processivity and the effects of somatic mutations observed in PKMTs in cancer cells. Structural data additionally provided information about the substrate recognition, enzyme-substrate complex formation, and allowed for simulations of the substrate peptide interaction and mechanism of PKMTs with atomistic resolution by molecular dynamics and hybrid quantum mechanics/molecular mechanics methods. These simulation technologies uncovered important mechanistic details of the PKMT reaction mechanism including the processes responsible for the deprotonation of the target lysine residue, essential conformational changes of the PKMT upon substrate binding, but also rationalized regulatory principles like PKMT autoinhibition. Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.

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
利用生化和模拟技术探究蛋白质赖氨酸甲基转移酶的催化机理。
蛋白质赖氨酸甲基转移酶(PKMTs)可将多达三个甲基转移到蛋白质中赖氨酸残基的侧链上,并通过控制蛋白质的稳定性、定位和蛋白质/蛋白质相互作用来实现重要的调控功能。甲基化反应受到高度调控,蛋白质的异常甲基化与多种疾病有关,包括神经系统疾病、心血管疾病和各种癌症。这篇综述介绍了过去几年中通过生化实验和模拟方法的综合应用对各种 PKMT 催化机制的新见解,重点是与临床相关且研究较多的该组酶,如 DOT1L、SMYD1-3、SET7/9、G9a/GLP、SETD2、SUV420H2、NSD1/2、不同的 MLL 和 EZH2。生化实验揭示了 PKMTs 在底物和产物特异性、过程性以及体细胞突变对癌细胞的影响等方面的许多机理特征。结构数据还提供了有关底物识别、酶-底物复合物形成的信息,并通过分子动力学和量子力学/分子力学混合方法,以原子分辨率模拟了 PKMTs 的底物肽相互作用和机理。这些模拟技术揭示了 PKMT 反应机制的重要机理细节,包括目标赖氨酸残基的去质子化过程、PKMT 与底物结合后的基本构象变化,以及 PKMT 自动抑制等调控原理的合理性。本文讨论了进一步的研究进展,这些进展可能会在不久的将来使我们更接近于从机理上理解这一类重要酶的催化作用。本文描述的结果说明了通过生化实验和模拟技术的结合应用来研究酶机理的威力。
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 去求助
来源期刊
CiteScore
14.90
自引率
0.00%
发文量
6
期刊介绍: As the discipline of biochemistry and molecular biology have greatly advanced in the last quarter century, significant contributions have been made towards the advancement of general medicine, genetics, immunology, developmental biology, and biophysics. Investigators in a wide range of disciplines increasingly require an appreciation of the significance of current biochemical and molecular biology advances while, members of the biochemical and molecular biology community itself seek concise information on advances in areas remote from their own specialties. Critical Reviews in Biochemistry and Molecular Biology believes that well-written review articles prove an effective device for the integration and meaningful comprehension of vast, often contradictory, literature. Review articles also provide an opportunity for creative scholarship by synthesizing known facts, fruitful hypotheses, and new concepts. Accordingly, Critical Reviews in Biochemistry and Molecular Biology publishes high-quality reviews that organize, evaluate, and present the current status of high-impact, current issues in the area of biochemistry and molecular biology. Topics are selected on the advice of an advisory board of outstanding scientists, who also suggest authors of special competence. The topics chosen are sufficiently broad to interest a wide audience of readers, yet focused enough to be within the competence of a single author. Authors are chosen based on their activity in the field and their proven ability to produce a well-written publication.
期刊最新文献
The general transcription factors (GTFs) of RNA polymerase II and their roles in plant development and stress responses. Mechanisms of immune evasion by Mycobacterium tuberculosis: the impact of T7SS and cell wall lipids on host defenses. Evolution, classification, and mechanisms of transport, activity regulation, and substrate specificity of ZIP metal transporters. Methanogens and what they tell us about how life might survive on Mars. Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".
×
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