title: Heterologous production of epothilones B and D in Streptomyces venezuelae.
abstract: Epothilones, produced from the myxobacterium Sorangium cellulosum, are potential anticancer agents that stabilize microtubules in a similar manner to paclitaxel. The entire epothilone biosynthetic gene cluster was heterologously expressed in an engineered strain of Streptomyces venezuelae bearing a deletion of pikromycin polyketide synthase gene cluster. The resulting strains produced approximately 0.1 microg/l of epothilone B as a sole product after 4 days cultivation. Deletion of an epoF encoding the cytochrome P450 epoxidase gave rise to a mutant that selectively produces 0.4 microg/l of epothilone D. To increase the production level of epothilones B and D, an additional copy of the positive regulatory gene pikD was introduced into the chromosome of both S. venezuleae mutant strains. The resulting strains showed enhanced production of corresponding compounds (approximately 2-fold). However, deletion of putative transport genes, orf3 and orf14 in the epothilone D producing S. venezuelae mutant strain, led to an approximately 3-fold reduction in epothilone D production. These results introduce S. venezuelae as an alternative heterologous host for the production of these valuable anticancer agents and demonstrate the possibility of engineering this strain as a generic heterologous host for the production of polyketides and hybrid polyketide-nonribosomal peptides.
authors.affiliation: Department of Chemistry and Nano Science, Ewha Womans University, Seoul, 120-750, Republic of Korea.
authors.forename: Sung Ryeol
authors.initials: SR
authors.lastname: Park
authors.forename: Je Won
authors.initials: JW
authors.lastname: Park
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Jung
authors.forename: Ah Reum
authors.initials: AR
authors.lastname: Han
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Ban
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Sohng
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Sim
authors.forename: Yeo Joon
authors.initials: YJ
authors.lastname: Yoon