Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1

ABSTRACT Total biosynthesis or whole-cell biocatalytic production of sulfated small molecules relies on the discovery and implementation of appropriate sulfotransferase enzymes. Although fungi are prominent biocatalysts and have been used to sulfate drug-like phenolics, no gene encoding a sulfotrans...

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Autores principales:	Linan Xie, Dongliang Xiao, Xiaojing Wang, Chen Wang, Jing Bai, Qun Yue, Haitao Yue, Ye Li, István Molnár, Yuquan Xu, Liwen Zhang
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Fusarium combinatorial biosynthesis phenolic sulfotransferase Microbiology QR1-502
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spelling	oai:doaj.org-article:e1cfc2e976144483ae7c2f995219c8272021-11-15T15:31:12ZCombinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-110.1128/mSphere.00949-202379-5042https://doaj.org/article/e1cfc2e976144483ae7c2f995219c8272020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00949-20https://doaj.org/toc/2379-5042ABSTRACT Total biosynthesis or whole-cell biocatalytic production of sulfated small molecules relies on the discovery and implementation of appropriate sulfotransferase enzymes. Although fungi are prominent biocatalysts and have been used to sulfate drug-like phenolics, no gene encoding a sulfotransferase enzyme has been functionally characterized from these organisms. Here, we identify a phenolic sulfotransferase, FgSULT1, by genome mining from the plant-pathogenic fungus Fusarium graminearum PH-1. We expressed FgSULT1 in a Saccharomyces cerevisiae chassis to modify a broad range of benzenediol lactones and their nonmacrocyclic congeners, together with an anthraquinone, with the resulting unnatural natural product (uNP) sulfates displaying increased solubility. FgSULT1 shares low similarity with known animal and plant sulfotransferases. Instead, it forms a sulfotransferase family with putative bacterial and fungal enzymes for phase II detoxification of xenobiotics and allelochemicals. Among fungi, putative FgSULT1 homologues are encoded in the genomes of Fusarium spp. and a few other genera in nonsyntenic regions, some of which may be related to catabolic sulfur recycling. Computational structure modeling combined with site-directed mutagenesis revealed that FgSULT1 retains the key catalytic residues and the typical fold of characterized animal and plant sulfotransferases. Our work opens the way for the discovery of hitherto unknown fungal sulfotransferases and provides a synthetic biological and enzymatic platform that can be adapted to produce bioactive sulfates, together with sulfate ester standards and probes for masked mycotoxins, precarcinogenic toxins, and xenobiotics. IMPORTANCE Sulfation is an expedient strategy to increase the solubility, bioavailability, and bioactivity of nutraceuticals and clinically important drugs. However, chemical or biological synthesis of sulfoconjugates is challenging. Genome mining, heterologous expression, homology structural modeling, and site-directed mutagenesis identified FgSULT1 of Fusarium graminearum PH-1 as a cytosolic sulfotransferase with the typical fold and active site architecture of characterized animal and plant sulfotransferases, despite low sequence similarity. FgSULT1 homologues are sparse in fungi but form a distinct clade with bacterial sulfotransferases. This study extends the functionally characterized sulfotransferase superfamily to the kingdom Fungi and demonstrates total biosynthetic and biocatalytic synthetic biological platforms to produce unnatural natural product (uNP) sulfoconjugates. Such uNP sulfates may be utilized for drug discovery in human and veterinary medicine and crop protection. Our synthetic biological methods may also be adapted to generate masked mycotoxin standards for food safety and environmental monitoring applications and to expose precarcinogenic xenobiotics.Linan XieDongliang XiaoXiaojing WangChen WangJing BaiQun YueHaitao YueYe LiIstván MolnárYuquan XuLiwen ZhangAmerican Society for MicrobiologyarticleFusariumcombinatorial biosynthesisphenolic sulfotransferaseMicrobiologyQR1-502ENmSphere, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fusarium combinatorial biosynthesis phenolic sulfotransferase Microbiology QR1-502
spellingShingle	Fusarium combinatorial biosynthesis phenolic sulfotransferase Microbiology QR1-502 Linan Xie Dongliang Xiao Xiaojing Wang Chen Wang Jing Bai Qun Yue Haitao Yue Ye Li István Molnár Yuquan Xu Liwen Zhang Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
description	ABSTRACT Total biosynthesis or whole-cell biocatalytic production of sulfated small molecules relies on the discovery and implementation of appropriate sulfotransferase enzymes. Although fungi are prominent biocatalysts and have been used to sulfate drug-like phenolics, no gene encoding a sulfotransferase enzyme has been functionally characterized from these organisms. Here, we identify a phenolic sulfotransferase, FgSULT1, by genome mining from the plant-pathogenic fungus Fusarium graminearum PH-1. We expressed FgSULT1 in a Saccharomyces cerevisiae chassis to modify a broad range of benzenediol lactones and their nonmacrocyclic congeners, together with an anthraquinone, with the resulting unnatural natural product (uNP) sulfates displaying increased solubility. FgSULT1 shares low similarity with known animal and plant sulfotransferases. Instead, it forms a sulfotransferase family with putative bacterial and fungal enzymes for phase II detoxification of xenobiotics and allelochemicals. Among fungi, putative FgSULT1 homologues are encoded in the genomes of Fusarium spp. and a few other genera in nonsyntenic regions, some of which may be related to catabolic sulfur recycling. Computational structure modeling combined with site-directed mutagenesis revealed that FgSULT1 retains the key catalytic residues and the typical fold of characterized animal and plant sulfotransferases. Our work opens the way for the discovery of hitherto unknown fungal sulfotransferases and provides a synthetic biological and enzymatic platform that can be adapted to produce bioactive sulfates, together with sulfate ester standards and probes for masked mycotoxins, precarcinogenic toxins, and xenobiotics. IMPORTANCE Sulfation is an expedient strategy to increase the solubility, bioavailability, and bioactivity of nutraceuticals and clinically important drugs. However, chemical or biological synthesis of sulfoconjugates is challenging. Genome mining, heterologous expression, homology structural modeling, and site-directed mutagenesis identified FgSULT1 of Fusarium graminearum PH-1 as a cytosolic sulfotransferase with the typical fold and active site architecture of characterized animal and plant sulfotransferases, despite low sequence similarity. FgSULT1 homologues are sparse in fungi but form a distinct clade with bacterial sulfotransferases. This study extends the functionally characterized sulfotransferase superfamily to the kingdom Fungi and demonstrates total biosynthetic and biocatalytic synthetic biological platforms to produce unnatural natural product (uNP) sulfoconjugates. Such uNP sulfates may be utilized for drug discovery in human and veterinary medicine and crop protection. Our synthetic biological methods may also be adapted to generate masked mycotoxin standards for food safety and environmental monitoring applications and to expose precarcinogenic xenobiotics.
format	article
author	Linan Xie Dongliang Xiao Xiaojing Wang Chen Wang Jing Bai Qun Yue Haitao Yue Ye Li István Molnár Yuquan Xu Liwen Zhang
author_facet	Linan Xie Dongliang Xiao Xiaojing Wang Chen Wang Jing Bai Qun Yue Haitao Yue Ye Li István Molnár Yuquan Xu Liwen Zhang
author_sort	Linan Xie
title	Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
title_short	Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
title_full	Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
title_fullStr	Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
title_full_unstemmed	Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1
title_sort	combinatorial biosynthesis of sulfated benzenediol lactones with a phenolic sulfotransferase from <named-content content-type="genus-species">fusarium graminearum</named-content> ph-1
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e1cfc2e976144483ae7c2f995219c827
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Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from <named-content content-type="genus-species">Fusarium graminearum</named-content> PH-1

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