The PKS/NRPS Hetero-gene Cluster of Epothilones
埃博霉素（Epothilones）的PKS/NRPS杂合基因簇

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.