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Issue 3, 2016
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The molecular steps of citrinin biosynthesis in fungi

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Abstract

The individual steps of citrinin 1 biosynthesis in Monascus ruber M7 were determined by a combination of targeted gene knockout and heterologous gene expression in Aspergillus oryzae. The pathway involves the synthesis of an unreduced trimethylated pentaketide 10 by a non-reducing polyketide synthase (nrPKS) known as CitS. Reductive release yields the keto-aldehyde 2 as the first enzyme-free intermediate. The nrPKS appears to be assisted by an as-yet cryptic hydrolysis step catalysed by CitA which was previously wrongly annotated as an oxidase. CitB is a non-heme iron oxidase which oxidises the 12-methyl of 2 to an alcohol. Subsequent steps are catalysed by CitC which oxidises the 12-alcohol to an aldehyde and CitD which converts the 12-aldehyde to a carboxylic acid. Final reduction of C-3 by CitE yields citrinin. The pathway rules out alternatives involving intramolecular rearrangements, and fully defines the molecular steps for the first time and corrects previous errors in the literature. The activity of CitB links the pathway to fungal tropolone biosynthesis and the observation of aminated shunt products links the pathway to azaphilone biosynthesis. Production of citrinin by coordinated production of CitS + CitA–CitE in the heterologous host A. oryzae, in which each gene was driven by a constitutive promoter, was achieved in high yield.

Graphical abstract: The molecular steps of citrinin biosynthesis in fungi

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Supplementary files

Article information


Submitted
23 Oct 2015
Accepted
14 Dec 2015
First published
17 Dec 2015

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 2119-2127
Article type
Edge Article
Author version available

The molecular steps of citrinin biosynthesis in fungi

Y. He and R. J. Cox, Chem. Sci., 2016, 7, 2119
DOI: 10.1039/C5SC04027B

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