[The PKS/NRPS hetero-gene cluster of epothilones].
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.
Li
Zhi-Feng
ZF
State Key Laboratory of Microbial Technology, College of Life Science, Shandong University, Jinan 250100, China.
Nguimbi
Etienne
E
Li
Yue-Zhong
YZ
Liu
Wei-Feng
WF
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D034261:Epothilones / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics / Q000502:physiology*; D009231:Myxococcales / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*
D001426:Bacterial Proteins; D034261:Epothilones; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase