Cloning and heterologous expression of the epothilone gene cluster.
The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading module, one nonribosomal peptide synthetase module, eight polyketide synthase modules, and a P450 epoxidase that converts desoxyepothilone into epothilone. Concomitant expression of these genes in the actinomycete Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent.
Tang
L
L
KOSAN Biosciences, 3832 Bay Center Place, Hayward, CA 94545, USA.
Shah
S
S
Chung
L
L
Carney
J
J
Katz
L
L
Khosla
C
C
Julien
B
B
D001426:Bacterial Proteins; D003001:Cloning, Molecular; D003360:Cosmids; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D034261:Epothilones; D004852:Epoxy Compounds / Q000378:metabolism*; D005285:Fermentation; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D009231:Myxococcales / Q000235:genetics; D009876:Operon; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism*; D014170:Transformation, Genetic
D001426:Bacterial Proteins; D034261:Epothilones; D004852:Epoxy Compounds; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D013844:Thiazoles; C093787:epothilone A; D003577:Cytochrome P-450 Enzyme System; C403885:EpoK protein, Polyangium cellulosum; D010088:Oxidoreductases; C023111:epoxidase; C093788:epothilone B