Monasone Naphthoquinone Biosynthesis and Resistance in Monascus Fungi
Monasone Naphthoquinone Biosynthesis and Resistance in Monascus Fungi
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红曲霉中莫奈酮萘醌的生物合成和抗性
DOI：
10.1128/mbio.02676-19
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发表时间：
2020-01-01
期刊：
影响因子：
6.4
通讯作者：
Chen, Fusheng
中科院分区：
文献类型：
--
作者：
Li, Mu;Kang, Lijing;Chen, Fusheng
Monoclonal naphthoquinone（monasone）生物合成基因嵌入Monoclonal azaphilone色素生物合成基因簇中并与Monoclonal azaphilone色素生物合成基因簇形成复合超簇。这两种途径共享早期生物合成中间产物。由超簇编码的一些酶在促进两种途径中发挥双重作用，而另一些酶则对一种或另一种途径具有特异性。莫那松亚群是独立调节和诱导的诱导与竞争微生物的启发。这项研究说明了真菌基因组和生物合成的简约性，并提出了一个潜在的路径的马赛克般的azaphilone萘醌超集群的演变。莫那松亚群还编码一种双层自耐机制，该机制模拟了可能转移到靶微生物或在萘醌型细胞毒性剂的情况下出现在癌细胞中的耐药决定因素。摘要尽管天然产物萘醌具有重要的生物活性，但真菌对这类化合物的生物合成途径和抗性机制仍知之甚少。在这里，我们报告说，基因负责的生物合成Monopolysanthaphinoquinones（monasones）驻留在基因簇Monopolysazaphilone色素（MonAzPs）。我们阐明的monasones的生物合成途径相结合的比较基因组分析，基因敲除，异源共表达，并在体内和体外的酶促反应表明，这条途径的分支从第一聚酮中间体的MonAzPs。此外，我们建议，monasone的生物合成基因的子集也编码一个两层的电阻策略，其中诱导monasone特定的出口商从菌丝体中排出monasone，而残留的细胞内monasone可能会通过多步还原级联呈现无毒。重要信息Monoclonal naphthoquinone（monasone）生物合成基因嵌入Monoclonal azaphilone色素生物合成基因簇中并与之形成复合超簇。早期的生物合成中间体由两条途径共享。由超簇编码的一些酶在促进两种途径中发挥双重作用，而另一些酶则对一种或另一种途径具有特异性。莫那松亚群是独立调节和诱导的诱导与竞争微生物的启发。这项研究说明了真菌基因组和生物合成的简约性，并提出了一个潜在的路径的马赛克般的azaphilone萘醌超集群的演变。莫那松亚群还编码一种双层自耐机制，该机制模拟了可能转移到靶微生物或在萘醌型细胞毒性剂的情况下出现在癌细胞中的耐药决定因素。
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. 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.