Terpenoids represent the largest class of natural products, some of which are resources for pharmaceuticals, fragrances, and fuels. Generally, mass production of valuable terpenoid compounds is hampered by their low production levels in organisms and difficulty of chemical synthesis. Therefore, the development of microbial biosynthetic platforms represents an alternative approach. Although microbial terpenoid-production platforms have been established in Escherichia coli and yeast, an optimal platform has not been developed for Streptomyces species, despite the large capacity to produce secondary metabolites, such as polyketide compounds. To explore this potential, we constructed a terpenoid-biosynthetic platform in Streptomyces reveromyceticus SN-593. This strain is unique in that it harbors the mevalonate gene cluster enabling the production of furaquinocin, which can be controlled by the pathway specific regulator Fur22. We simultaneously expressed the mevalonate gene cluster and subsequent terpenoid-biosynthetic genes under the control of Fur22. To achieve improved fur22 gene expression, we screened promoters from S. reveromyceticus SN-593. Our results showed that the promoter associated with rvr2030 gene enabled production of 212 ± 20 mg/L botryococcene to levels comparable to those previously reported for other microbial hosts. Given that the rvr2030 gene encodes for an enzyme involved in the primary metabolism, these results suggest that optimized expression of terpenoid-biosynthetic genes with primary and secondary metabolism might be as important for high yields of terpenoid compounds as is the absolute expression level of a target gene(s).

中文翻译：

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reveromyceticus SN-593中萜类化合物生产平台的开发

萜类化合物代表最大种类的天然产物，其中一些是药品，香料和燃料的资源。通常，有价值的萜类化合物的大量生产因其在生物体中的低生产水平和化学合成的困难而受到阻碍。因此，微生物生物合成平台的发展代表了另一种方法。尽管已经在大肠杆菌和酵母菌中建立了微生物类萜产生平台，但是尽管链霉菌具有产生次级代谢产物（例如聚酮化合物）的强大能力，但尚未开发出针对链霉菌属物种的最佳平台。为了探索这种潜力，我们在链霉菌中构建了萜类生物合成平台。SN-593。该菌株的独特之处在于它具有甲羟戊酸基因簇，能够产生呋喃喹啉，而呋喃喹辛可以由途径特异性调节剂Fur22控制。我们在Fur22的控制下同时表达了甲羟戊酸基因簇和随后的萜类生物合成基因。为了实现改善的fur22基因表达，我们从reveromyceticus SN-593筛选了启动子。我们的结果表明，与rvr2030基因相关的启动子能够产生212±20 mg / L的葡萄球菌，其水平与以前报道的其他微生物宿主相当。鉴于rvr2030 基因编码参与初级代谢的酶，这些结果表明，具有初级和次级代谢的萜类生物合成基因的优化表达对于高产率的萜类化合物可能与目标基因的绝对表达水平一样重要。