Biosynthesis of the antitumor chromomycin A3 in Streptomyces griseus: analysis of the gene cluster and rational design of novel chromomycin analogs.
The biosynthetic gene cluster of the aureolic acid type antitumor drug chromomycin A3 from S. griseus subsp. griseus has been identified and characterized. It spans 43 kb and contains 36 genes involved in polyketide biosynthesis and modification, deoxysugar biosynthesis and sugar transfer, pathway regulation and resistance. The organization of the cluster clearly differs from that of the closely related mithramycin. Involvement of the cluster in chromomycin A3 biosynthesis was demonstrated by disrupting the cmmWI gene encoding a polyketide reductase involved in side chain reduction. Three novel chromomycin derivatives were obtained, named chromomycin SK, chromomycin SA, and chromomycin SDK, which show antitumor activity and differ with respect to their 3-side chains. A pathway for the biosynthesis of chromomycin A3 and its deoxysugars is proposed.
Menéndez
Nuria
N
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain.
Nur-e-Alam
Mohammad
M
Braña
Alfredo F
AF
Rohr
Jürgen
J
Salas
José A
JA
Méndez
Carmen
C
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D014128:Chromomycin A3 / Q000031:analogs & derivatives / Q000096:biosynthesis*; D003001:Cloning, Molecular; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D005798:Genes, Bacterial; D006031:Glycosylation; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D013305:Streptomyces griseus / Q000201:enzymology / Q000235:genetics*
D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D014128:Chromomycin A3; D000429:Alcohol Oxidoreductases; C087192:polyketide synthase ketoreductase