埃博霉素(Epothilones)的PKS/NRPS杂合基因簇  

The PKS/NRPS Hetero-gene Cluster of Epothilones

作　　者：黎志凤[1] Etienne Nguimbi 李越中[1] 刘巍峰[1] 

机构地区：[1]山东大学生命科学院微生物技术国家重点实验室,济南250100

出　　处：《生物工程学报》2003年第5期511-515,共5页Chinese Journal of Biotechnology

基　　金：国家自然科学基金 (No.3 0 0 70 0 0 8);863青年基金 (No.2 0 0 1AA62 8160 );教育部重点基金资助~~

摘　　要：埃博霉素是由粘细菌纤维堆囊菌产生的一类具有促微管聚合活性的大环内酯类化合物。埃博霉素生物合成的多酶复合体是一个由多个功能模块组成 ,同时含有多聚酮合酶 (PKS)和非核糖体肽合成酶 (NRPS)的大操纵子。根据同位素标记试验结果和合成酶全基因簇功能的推测 ,埃博霉素的生物合成包括聚酮链的引发、链合成的起始和噻唑环的形成、链的延伸和转移、链合成的终止释放和环化、及产物的后修饰 5个阶段。埃博霉素的PKS NRPS杂合基因簇是开展组合生物合成研究的良好材料。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.

关 键 词：埃博霉素 多聚酮合酶 非核糖体肽合成酶 基因簇 组合生物合成 抗癌药 

分 类 号：Q933[生物学—微生物学]