Helmholtz International Lab for Anti-infectives, Shandong University-Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, 266237 Qingdao, China.
CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055 Shenzhen, China.
ACS Synth Biol. 2023 Apr 21;12(4):971-977. doi: 10.1021/acssynbio.2c00610. Epub 2023 Mar 29.
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, 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 -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.
工程化复杂天然产物的生物合成途径是获得具有改善性质的衍生物的重要方法。在这里，我们在异源宿主 E264 中构建了一个简化的粘细菌衍生的复杂聚酮化合物 disorazol 的工程生物合成系统。在 disorazol 生物合成途径中失活脱水酶结构域导致产生两种羟基化衍生物。模块缺失允许生成具有截断大环内酯环的非天然衍生物，并且 ACP-KS 接头是在该 -AT 聚酮合酶中进行模块缺失的最佳融合区域。这些 disorazol 衍生物对人癌细胞系的活性范围从纳摩尔到微摩尔，表明了主要的结构-活性关系。PKS 工程化使得 disorazol 能够进行结构衍生化，促进了聚酮化合物的深入工程生物合成。
