Streptomyces are producers of medically and industrially important secondary metabolites. The genome of Streptomyces encodes biosynthesis of more than 20 different secondary metabolites. However, most of the secondary metabolites encoded by the corresponding biosynthetic gene clusters (BGCs) cannot be detected under standard laboratory conditions. Therefore, expression of these “silent” BGCs in a heterologous host seems an attractive approach to solve this problem. Several Streptomyces hosts already exists, but they do not achieve sufficient concentrations of the target product. Streptomyces rimosus is a producer of important antibiotic oxytetracycline (OTC) and is known to achieve high titers of it. Our goal was to evaluate ability of S. rimosus as a host to produce heterologous products. First, we successfully removed two BGCs encoding OTC and isorenieratene, reducing competition between native and heterologously expressed BGCs. We developed integrative vectors containing BGCs encoding tetracycline chelocardin (CHD), isoprenoids cyclooctatin and β-carotene, and polyunsaturated fatty acids (PUFA), all of which consume malonyl-CoA as a main building block. In addition to native CHD BGC, we also reconstituted synthetic BGC. In addition to the isoprenoid BGC, we also cloned the mevalonate pathway and introduced it into S. rimosus, which could ensure better availability of isoprenoid substrate. To increase yield of PUFA, the gene encoding phosphopantetheinyl-transferase was introduced into S. rimosus. Cyclooctatin, β-carotene and PUFA BGCs were successfully expressed in S. rimosus, whereas neither native nor synthetic chelocardin BGC resulted in the production of the target product.
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