Filamentous fungi produce numerous high-value natural products (NPs). The biosynthetic genes for NPs are normally clustered in the genome. A valuable NP class is represented by the insecticidal austinoids. We previously determined their biosynthesis in the fungus Aspergillus calidoustus. After further computational analysis looking into the austinoid gene clusters in two additional distantly related fungi, Aspergillus nidulans and Penicillium brasilianum, a rearrangement of the genes was observed that corresponded to the diverse austinoid derivatives produced by each strain. By advanced targeted combinatorial engineering using polycistronic expression of selected genes, we rewired the austinoid pathway in the fungus A. nidulans, which then produced certain compounds of interest under industrially favored conditions. This was possible by exploiting the presence of genes previously thought to be irrelevant. Our work shows that comparative analysis of genomes can be used to not only discover new gene clusters but unearth the hidden potential of known metabolic pathways.

中文翻译：

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丝状真菌中类固醇生物合成途径的重新布线

丝状真菌可产生许多高价值的天然产物（NP）。NP的生物合成基因通常聚集在基因组中。有价值的NP类以杀虫性类奥斯汀为代表。我们以前确定了它们在木霉曲霉中的生物合成。在进一步的计算分析中，研究了另外两个远缘相关真菌曲霉曲霉和巴西青霉中的类固醇类基因簇，观察到这些基因的重排与每种菌株产生的各种类固醇类衍生物相对应。通过使用选定基因的多顺反子表达进行先进的靶向组合工程，我们重新构建了真菌A. nidulans中的奥斯汀类途径，然后在工业上有利的条件下产生了某些目标化合物。这可以通过利用以前认为不相关的基因的存在来实现。我们的工作表明，基因组的比较分析不仅可以用来发现新的基因簇，而且可以发掘已知代谢途径的潜在潜力。