工程化复杂天然产物生物合成途径是获得改良特性衍生物的重要方法。在这里，我们构建了一个简化的工程化生物合成系统，用于异源宿主Burkholderia thailandensis E264中产生源于单孢菌的复杂多酮类抗癌素disorazol。去除disorazol生物合成途径中的脱水酶结构域导致产生两种羟基衍生物。模块删除使得生成了一种带有缩短大环内酯环的非自然衍生物，并且ACP-KS连接器是这种转座型AT型多酮合酶模块删除的最佳融合区域。这些disorazol衍生物对人类癌细胞系表现出不同的活性，范围从纳摩尔级到微摩尔级，提示了原始物质的结构活性关系。PKS工程使得可对disorazol进行结构衍生，促进了多酮类化合物的深入工程化生物合成。

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.