Li Zhi-Feng, Nguimbi Etienne, Li Yue-Zhong, Liu Wei-Feng
State Key Laboratory of Microbial Technology, College of Life Science, Shandong University, Jinan 250100, China.
Sheng Wu Gong Cheng Xue Bao. 2003 Sep;19(5):511-5.
Novel macrolides epothilones, produced by cellulolytic myxobacterium Sorangium cellulosum, have the activity to promote microtubule assembly, and are considered to be a potential successor to the famous antitumor drug taxol. The biosynthetic genes leading to the epothilones are clustered into a large operon. The multi-enzyme complex is a hetero-gene cluster of polyketide synthase (PKS) and non-ribosomal peptide synthetases (NRPS) and contains several functional modules, i.e. a loading module, one NRPS module, eight PKS modules, and a P450 epoxidase. The former ten modules biosynthesize desoxyepothilone (epothilones C and D), which is then epoxidized at C12 and C13 and converted into epothilones (epothilones A and B) by the P450 epoxidase. The NRPS module is responsible for the formation of the thiazole side chain from cysteine. The biosynthesis procedure of epothilones can be divided into 5 stages, i.e. formation of holo-ACP/PCP, chain initiation and thiazole ring formation, chain elongation, termination and epoxidation, and post-modification. The analysis of the gene cluster and the biosynthetic pathway reveals that novel epothilone analogs could not only be produced by chemical synthesis/modification, tranditional microbial technologies, but also can be genetically manipulated through combinatiorial biosynthesis approaches.
由纤维素分解黏细菌纤维堆囊菌产生的新型大环内酯类埃坡霉素具有促进微管组装的活性，被认为是著名抗肿瘤药物紫杉醇的潜在替代品。负责合成埃坡霉素的生物合成基因聚集在一个大操纵子中。多酶复合体是聚酮合酶（PKS）和非核糖体肽合成酶（NRPS）的异源基因簇，包含几个功能模块，即一个装载模块、一个NRPS模块、八个PKS模块和一个P450环氧化酶。前十个模块生物合成脱氧埃坡霉素（埃坡霉素C和D），然后在C12和C13处环氧化，并通过P450环氧化酶转化为埃坡霉素（埃坡霉素A和B）。NRPS模块负责由半胱氨酸形成噻唑侧链。埃坡霉素的生物合成过程可分为五个阶段，即全酶型酰基载体蛋白/磷酸泛酰巯基乙胺的形成、链起始和噻唑环形成、链延伸、终止和环氧化以及后期修饰。对基因簇和生物合成途径的分析表明，新型埃坡霉素类似物不仅可以通过化学合成/修饰、传统微生物技术生产，还可以通过组合生物合成方法进行基因操作。
