Site-selective Chlorination of Pyrrolic Heterocycles by Flavin
Dependent Enzyme PrnC

Guangrong Peh; Terence Tay; Lee Ling Tan; Elaine Tiong; Yi Ling Goh; Suming Ye; Fu Lin; Cheryl Jia Xin Tan; Yong Zi Tan; Joel Wong; Huimin Zhao; Fong Tian Wong; Ee Lui Ang; Yee Hwee Lim

doi:10.26434/chemrxiv-2022-t1mrn

Catalysis

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Site-selective Chlorination of Pyrrolic Heterocycles by Flavin Dependent Enzyme PrnC

Working Paper

Guangrong Peh Institute of Sustainability for Chemicals, Energy and Environment, A*STAR ,
Terence Tay Singapore Institute of Food and Biotechnology Innovation, A*STAR ,
Lee Ling Tan Institute of Molecular and Cell Biology, A*STAR ,
Elaine Tiong Institute of Molecular and Cell Biology, A*STAR ,
Yi Ling Goh Institute of Sustainability for Chemicals, Energy and Environment, A*STAR ,
Suming Ye Institute of Sustainability for Chemicals, Energy and Environment, A*STAR ,
Fu Lin Singapore Institute of Food and Biotechnology Innovation, A*STAR ,
Cheryl Jia Xin Tan National University of Singapore ,
Yong Zi Tan National University of Singapore & Disease Intervention Technology Laboratory, Institute of Molecular and Cell Biology, A*STAR ,
Joel Wong Institute of Sustainability for Chemicals, Energy and Environment, A*STAR ,
Huimin Zhao Singapore Institute of Food and Biotechnology Innovation, A*STAR & University of Illinois at Urbana-Champaign, Urbana, IL, USA ,
Fong Tian Wong Institute of Molecular and Cell Biology, A*STAR ,
Ee Lui Ang Singapore Institute of Food and Biotechnology Innovation, A*STAR ,
Yee Hwee Lim Institute of Sustainability for Chemicals, Energy and Environment, A*STAR

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Abstract

Halogenation of pyrrole requires strong electrophilic reagents and often leads to undesired polyhalogenated products. Biocatalytic halogenation is a highly attractive approach given its chemoselectivity and benign reaction conditions. Whilst there are several reports of enzymatic phenol and indole halogenation in organic synthesis, corresponding reports on enzymatic pyrrole halogenation has been lacking. Here we describe the first in vitro functional and structural characterization of PrnC, a flavin-dependent halogenase that can act on free-standing pyrroles. Computational modelling and site mutagenesis studies identified three key residues in the catalytic pocket. Moderate resolution map using single-particle cryogenic electron microscopy (CryoEM) reveals PrnC to be a dimer. This native PrnC can halogenate a library of structurally diverse pyrrolic heterocycles in a site-selective manner and was applied in the chemoenzymatic synthesis of a chlorinated analog of the agrochemical fungicide, Fludioxonil.