Pimvisuth Chunkrua, Mirjam A. Kabel, Jean-Paul Vincken, Willem J.H. van Berkel, Wouter J.C. de Bruijn
{"title":"Prenylation of diverse indole derivatives by the fungal aromatic prenyltransferase RePT","authors":"Pimvisuth Chunkrua, Mirjam A. Kabel, Jean-Paul Vincken, Willem J.H. van Berkel, Wouter J.C. de Bruijn","doi":"10.1016/j.nbt.2025.09.002","DOIUrl":null,"url":null,"abstract":"<div><div>Prenylation is a widespread natural modification of compounds that serves to functionalize and often enhance the bioactivity of plant and microbial secondary metabolites, including indole derivatives. In this study, we aimed to expand the library of prenylated indoles using RePT, a fungal (i.e. <em>Rasamsonia emersonii</em>) aromatic prenyltransferase from the dimethylallyl tryptophan synthase (DMATS) family. Previous work showed that RePT readily <em>C</em>7- and <em>N</em>1-prenylated <span>l</span>-tryptophan, and <em>O</em>-prenylated <span>l</span>-tyrosine and a number of phenolic stilbenes. Here, we investigated its regioselectivity further with 23 indole substrates, including tryptophan derivatives with varying <em>C</em>4-<em>C</em>7 substituents and several <em>C</em>3-substituted indoles. High conversion was observed primarily with fluorinated tryptophans and unsubstituted indole. Product analysis by UHPLC-PDA-ESI-MS<sup>n</sup> and NMR revealed that RePT mainly catalyzed either normal prenylation at <em>C</em>7 or reverse prenylation at <em>N</em>1 on a series of halogenated tryptophans. The regioselectivity observed for several substrates was strongly influenced by the position of the halogen substituent, particularly fluorine, which displayed its characteristic <em>ortho-</em>/<em>para-</em>directing effect. In the absence of the amino acid moiety, RePT’s regioselectivity in some cases shifted from its typical preference, leading to prenylation at alternative positions such as <em>C</em>3 and <em>C</em>6. These findings showcase the versatility of RePT for modifying diverse indole derivatives and demonstrate, for the first time, halogen-induced steering of the regioselectivity of DMATS to facilitate synthesis of bioactive prenylated compounds and intermediates.</div></div>","PeriodicalId":19190,"journal":{"name":"New biotechnology","volume":"90 ","pages":"Pages 88-96"},"PeriodicalIF":4.9000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"New biotechnology","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1871678425000858","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
Abstract
Prenylation is a widespread natural modification of compounds that serves to functionalize and often enhance the bioactivity of plant and microbial secondary metabolites, including indole derivatives. In this study, we aimed to expand the library of prenylated indoles using RePT, a fungal (i.e. Rasamsonia emersonii) aromatic prenyltransferase from the dimethylallyl tryptophan synthase (DMATS) family. Previous work showed that RePT readily C7- and N1-prenylated l-tryptophan, and O-prenylated l-tyrosine and a number of phenolic stilbenes. Here, we investigated its regioselectivity further with 23 indole substrates, including tryptophan derivatives with varying C4-C7 substituents and several C3-substituted indoles. High conversion was observed primarily with fluorinated tryptophans and unsubstituted indole. Product analysis by UHPLC-PDA-ESI-MSn and NMR revealed that RePT mainly catalyzed either normal prenylation at C7 or reverse prenylation at N1 on a series of halogenated tryptophans. The regioselectivity observed for several substrates was strongly influenced by the position of the halogen substituent, particularly fluorine, which displayed its characteristic ortho-/para-directing effect. In the absence of the amino acid moiety, RePT’s regioselectivity in some cases shifted from its typical preference, leading to prenylation at alternative positions such as C3 and C6. These findings showcase the versatility of RePT for modifying diverse indole derivatives and demonstrate, for the first time, halogen-induced steering of the regioselectivity of DMATS to facilitate synthesis of bioactive prenylated compounds and intermediates.
期刊介绍:
New Biotechnology is the official journal of the European Federation of Biotechnology (EFB) and is published bimonthly. It covers both the science of biotechnology and its surrounding political, business and financial milieu. The journal publishes peer-reviewed basic research papers, authoritative reviews, feature articles and opinions in all areas of biotechnology. It reflects the full diversity of current biotechnology science, particularly those advances in research and practice that open opportunities for exploitation of knowledge, commercially or otherwise, together with news, discussion and comment on broader issues of general interest and concern. The outlook is fully international.
The scope of the journal includes the research, industrial and commercial aspects of biotechnology, in areas such as: Healthcare and Pharmaceuticals; Food and Agriculture; Biofuels; Genetic Engineering and Molecular Biology; Genomics and Synthetic Biology; Nanotechnology; Environment and Biodiversity; Biocatalysis; Bioremediation; Process engineering.