Structure function and engineering of multifunctional non-heme iron dependent oxygenases in fungal meroterpenoid biosynthesis

Nature Communications
Yu NakashimaIkuro Abe

Abstract

Non-heme iron and α-ketoglutarate (αKG) oxygenases catalyze remarkably diverse reactions using a single ferrous ion cofactor. A major challenge in studying this versatile family of enzymes is to understand their structure-function relationship. AusE from Aspergillus nidulans and PrhA from Penicillium brasilianum are two highly homologous Fe(II)/αKG oxygenases in fungal meroterpenoid biosynthetic pathways that use preaustinoid A1 as a common substrate to catalyze divergent rearrangement reactions to form the spiro-lactone in austinol and cycloheptadiene moiety in paraherquonin, respectively. Herein, we report the comparative structural study of AusE and PrhA, which led to the identification of three key active site residues that control their reactivity. Structure-guided mutagenesis of these residues results in successful interconversion of AusE and PrhA functions as well as generation of the PrhA double and triple mutants with expanded catalytic repertoire. Manipulation of the multifunctional Fe(II)/αKG oxygenases thus provides an excellent platform for the future development of biocatalysts.

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Citations

Mar 8, 2018·Natural Product Reports·Hitomi NakamuraIkuro Abe
Jul 17, 2018·Natural Product Reports·Katherine S Ryan, Catherine L Drennan
Nov 7, 2019·The FEBS Journal·David P Fewer, Mikko Metsä-Ketelä
Mar 20, 2020·Chembiochem : a European Journal of Chemical Biology·Maria Agustina VilaRudi Fasan
Mar 20, 2019·Nature Chemical Biology·Yi-Ming ShiHelge B Bode
Jan 14, 2021·Acta Crystallographica. Section F, Structural Biology Communications·Ryuichi KatoToshiya Senda
Jul 5, 2018·Journal of the American Chemical Society·Yu NakashimaIkuro Abe
Sep 24, 2020·ACS Chemical Biology·Asfandyar SikandarJesko Koehnke
Dec 10, 2021·Journal of the American Chemical Society·Xinyang LiIkuro Abe

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Methods Mentioned

BETA
X-ray
dynamic light-scattering
NMR
PCR
gel filtration

Software Mentioned

AutoBuild
Phenix
AutoSol
ArealMol
PyMOL
CCP4
XDS
Chem3D Ultra
AIMLESS
GraphPad Prism

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