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Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system

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Abstract

Perylenequinones are a class of aromatic polyketides characterised by a highly conjugated pentacyclic core, which confers them with potent light-induced bioactivities and unique photophysical properties. Despite the biosynthetic gene clusters for the perylenequinones elsinochrome A (1), cercosporin (4) and hypocrellin A (6) being recently identified, key biosynthetic aspects remain elusive. Here, we first expressed the intact elc gene cluster encoding 1 from the wheat pathogen Parastagonospora nodorum heterologously in Aspergillus nidulans on a yeast-fungal artificial chromosome (YFAC). This led to the identification of a novel flavin-dependent monooxygenase, ElcH, responsible for oxidative enolate coupling of a perylenequinone intermediate to the hexacyclic dihydrobenzo(ghi)perylenequinone in 1. In the absence of ElcH, the perylenequione intermediate formed a hexacyclic cyclohepta(ghi)perylenequinone system via an intramolecular aldol reaction resulting in 6 and a novel hypocrellin 12 with opposite helicity to 1. Theoretical calculations supported that 6 and 12 resulted from atropisomerisation upon formation of the 7-membered ring. Using a bottom-up pathway reconstruction approach on a tripartite YFAC system developed in this study, we uncovered that both a berberine bridge enzyme-like oxidase ElcE and a laccase-like multicopper oxidase ElcG are involved in the double coupling of two naphthol intermediates to form the perylenequinone core. Gene swapping with the homologs from the biosynthetic pathway of 4 showed that cognate pairing of the two classes of oxidases is required for the formation of the perylenequinone core, suggesting the involvement of protein–protein interactions.

Graphical abstract: Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system

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Publication details

The article was received on 29 Jun 2018, accepted on 21 Nov 2018 and first published on 22 Nov 2018


Article type: Edge Article
DOI: 10.1039/C8SC02870B
Citation: Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system

    J. Hu, F. Sarrami, H. Li, G. Zhang, K. A. Stubbs, E. Lacey, S. G. Stewart, A. Karton, Andrew M. Piggott and Y. Chooi, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C8SC02870B

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