Heterologous production of epothilones B and D in Streptomyces venezuelae.
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.
Park
Sung Ryeol
SR
Department of Chemistry and Nano Science, Ewha Womans University, Seoul, 120-750, Republic of Korea.
Park
Je Won
JW
Jung
Won Seok
WS
Han
Ah Reum
AR
Ban
Yeon-Hee
YH
Kim
Eun Ji
EJ
Sohng
Jae Kyung
JK
Sim
Sang Jun
SJ
Yoon
Yeo Joon
YJ