Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi

ABSTRACT Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monas...

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Autores principales:	Mu Li, Lijing Kang, Xiaoli Ding, Jiao Liu, Qingpei Liu, Yanchun Shao, István Molnár, Fusheng Chen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Monascus spp. naphthoquinone nested biosynthetic pathway supercluster resistance mechanism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ded7001b3d364908abd3d199b4e7e152
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spelling	oai:doaj.org-article:ded7001b3d364908abd3d199b4e7e1522021-11-15T15:56:57ZMonasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi10.1128/mBio.02676-192150-7511https://doaj.org/article/ded7001b3d364908abd3d199b4e7e1522020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02676-19https://doaj.org/toc/2150-7511ABSTRACT Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monasones) reside within the gene cluster for Monascus azaphilone pigments (MonAzPs). We elucidate the biosynthetic pathway of monasones by a combination of comparative genome analysis, gene knockouts, heterologous coexpression, and in vivo and in vitro enzymatic reactions to show that this pathway branches from the first polyketide intermediate of MonAzPs. Furthermore, we propose that the monasone subset of biosynthetic genes also encodes a two-tiered resistance strategy in which an inducible monasone-specific exporter expels monasones from the mycelia, while residual intracellular monasones may be rendered nontoxic through a multistep reduction cascade. IMPORTANCE The genes for Monascus naphthoquinone (monasone) biosynthesis are embedded in and form a composite supercluster with the Monascus azaphilone pigment biosynthetic gene cluster. Early biosynthetic intermediates are shared by the two pathways. Some enzymes encoded by the supercluster play double duty in contributing to both pathways, while others are specific for one or the other pathway. The monasone subcluster is independently regulated and inducible by elicitation with competing microorganisms. This study illustrates genomic and biosynthetic parsimony in fungi and proposes a potential path for the evolution of the mosaic-like azaphilone-naphthoquinone supercluster. The monasone subcluster also encodes a two-tiered self-resistance mechanism that models resistance determinants that may transfer to target microorganisms or emerge in cancer cells in case of naphthoquinone-type cytotoxic agents.Mu LiLijing KangXiaoli DingJiao LiuQingpei LiuYanchun ShaoIstván MolnárFusheng ChenAmerican Society for MicrobiologyarticleMonascus spp.naphthoquinonenested biosynthetic pathwaysuperclusterresistance mechanismMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Monascus spp. naphthoquinone nested biosynthetic pathway supercluster resistance mechanism Microbiology QR1-502
spellingShingle	Monascus spp. naphthoquinone nested biosynthetic pathway supercluster resistance mechanism Microbiology QR1-502 Mu Li Lijing Kang Xiaoli Ding Jiao Liu Qingpei Liu Yanchun Shao István Molnár Fusheng Chen Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
description	ABSTRACT Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monasones) reside within the gene cluster for Monascus azaphilone pigments (MonAzPs). We elucidate the biosynthetic pathway of monasones by a combination of comparative genome analysis, gene knockouts, heterologous coexpression, and in vivo and in vitro enzymatic reactions to show that this pathway branches from the first polyketide intermediate of MonAzPs. Furthermore, we propose that the monasone subset of biosynthetic genes also encodes a two-tiered resistance strategy in which an inducible monasone-specific exporter expels monasones from the mycelia, while residual intracellular monasones may be rendered nontoxic through a multistep reduction cascade. IMPORTANCE The genes for Monascus naphthoquinone (monasone) biosynthesis are embedded in and form a composite supercluster with the Monascus azaphilone pigment biosynthetic gene cluster. Early biosynthetic intermediates are shared by the two pathways. Some enzymes encoded by the supercluster play double duty in contributing to both pathways, while others are specific for one or the other pathway. The monasone subcluster is independently regulated and inducible by elicitation with competing microorganisms. This study illustrates genomic and biosynthetic parsimony in fungi and proposes a potential path for the evolution of the mosaic-like azaphilone-naphthoquinone supercluster. The monasone subcluster also encodes a two-tiered self-resistance mechanism that models resistance determinants that may transfer to target microorganisms or emerge in cancer cells in case of naphthoquinone-type cytotoxic agents.
format	article
author	Mu Li Lijing Kang Xiaoli Ding Jiao Liu Qingpei Liu Yanchun Shao István Molnár Fusheng Chen
author_facet	Mu Li Lijing Kang Xiaoli Ding Jiao Liu Qingpei Liu Yanchun Shao István Molnár Fusheng Chen
author_sort	Mu Li
title	Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
title_short	Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
title_full	Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
title_fullStr	Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
title_full_unstemmed	Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi
title_sort	monasone naphthoquinone biosynthesis and resistance in <italic toggle="yes">monascus</italic> fungi
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ded7001b3d364908abd3d199b4e7e152
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Monasone Naphthoquinone Biosynthesis and Resistance in <italic toggle="yes">Monascus</italic> Fungi

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