Journal
ACS SYNTHETIC BIOLOGY
Volume 12, Issue 4, Pages 971-977Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.2c00610
Keywords
heterologous expression; polyketide; disorazol; PKS engineering
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Engineering the biosynthetic pathways of complex natural products is a significant approach to obtain derivatives with improved properties. Here, we constructed a streamlined engineered biosynthesis system of myxobacterium-derived complex polyketide disorazol in a heterologous host. The inactivation of dehydratase domains led to the production of hydroxylated derivatives, while module deletion allowed the generation of an unnatural derivative with a truncated macrolactone ring. These disorazol derivatives showed different activities against human cancer cell lines, indicating a structure-activity relationship. The PKS engineering enables structural derivatization of disorazol, facilitating the in-depth engineered biosynthesis of polyketides.
Engineering the biosynthetic pathways of complex natural products is a significant approach to obtain derivatives with improved properties. Here, we constructed a streamlined engineered biosynthesis system of myxobacterium-derived complex polyketide disorazol in a heterologous host, Burkholderia thailandensis E264. Inactivation of dehydratase domains in the disorazol biosynthetic pathway led to the production of two hydroxylated derivatives. Module deletion allowed the generation of an unnatural derivative with a truncated macrolactone ring, and the ACP-KS linker was the optimal fusion region for module deletion in this trans-AT polyketide synthase. These disorazol derivatives showed different activities against human cancer cell lines ranging from the nanomolar to micromolar level, suggesting the primary structure-activity relationship. The PKS engineering enables structural derivatization of disorazol, facilitating the in-depth engineered biosynthesis of polyketides.
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