Rational Engineering of Self-Sufficient P450s to Boost Catalytic Efficiency of Carbene-Mediated C–S Bond Formation

IF 11.3 1区化学 Q1 CHEMISTRY, PHYSICAL

ACS Catalysis Pub Date : 2025-03-27 DOI:10.1021/acscatal.5c01569

Binhao Wang, Tai-Ping Zhou, Yu Shen, Jie Hu, Jieyu Zhou, Jin Tang, Ruizhi Han, Guochao Xu, Ulrich Schwaneberg, Binju Wang, Ye Ni

{"title":"Rational Engineering of Self-Sufficient P450s to Boost Catalytic Efficiency of Carbene-Mediated C–S Bond Formation","authors":"Binhao Wang, Tai-Ping Zhou, Yu Shen, Jie Hu, Jieyu Zhou, Jin Tang, Ruizhi Han, Guochao Xu, Ulrich Schwaneberg, Binju Wang, Ye Ni","doi":"10.1021/acscatal.5c01569","DOIUrl":null,"url":null,"abstract":"Intermolecular C–S bond formation is a key step in the construction of sulfur-containing compounds in organic chemistry. As versatile biocatalysts, P450-catalyzed radical reactions are compatible with a diverse range of functional groups. Here, to boost the catalytic efficiency of carbene-mediated C–S bond formation, self-sufficient P450TT was rationally engineered using multiple AI models (SaProt, ProSST, EVmutation). Employing purified enzymes, a triple variant P450TT-M3 (V118A/C385H/F424P) demonstrated a significantly higher TOF of 6.1 min–1 than that of P450TT-M1(C385H) (1.5) in 1 h. Furthermore, with remarkable adaptability to a diverse range of aryl mercaptans, it exhibits high versatility in catalyzing the formation of intermolecular C–S bonds. Computational studies have shown that C–S bond formation involved H atom transfer from the thiol group of thiophenol to Fe-carbene, which differs from P450-catalyzed N–H insertion reactions. In addition, QM/MM simulations suggested that the variant enables a further approach of ethyl diazoacetate to the iron center, thereby enhancing the catalytic efficiency.","PeriodicalId":9,"journal":{"name":"ACS Catalysis ","volume":"36 1","pages":""},"PeriodicalIF":11.3000,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Catalysis ","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acscatal.5c01569","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}

引用次数: 0

Abstract

Intermolecular C–S bond formation is a key step in the construction of sulfur-containing compounds in organic chemistry. As versatile biocatalysts, P450-catalyzed radical reactions are compatible with a diverse range of functional groups. Here, to boost the catalytic efficiency of carbene-mediated C–S bond formation, self-sufficient P450_TT was rationally engineered using multiple AI models (SaProt, ProSST, EVmutation). Employing purified enzymes, a triple variant P450_TT-M3 (V118A/C385H/F424P) demonstrated a significantly higher TOF of 6.1 min^–1 than that of P450_TT-M1(C385H) (1.5) in 1 h. Furthermore, with remarkable adaptability to a diverse range of aryl mercaptans, it exhibits high versatility in catalyzing the formation of intermolecular C–S bonds. Computational studies have shown that C–S bond formation involved H atom transfer from the thiol group of thiophenol to Fe-carbene, which differs from P450-catalyzed N–H insertion reactions. In addition, QM/MM simulations suggested that the variant enables a further approach of ethyl diazoacetate to the iron center, thereby enhancing the catalytic efficiency.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Catalysis CHEMISTRY, PHYSICAL-

CiteScore

20.80

自引率

6.20%

发文量

1253

审稿时长

1.5 months

期刊介绍： ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels. The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.