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.
|Number of pages||12|
|Journal||Chemistry and Biology|
|State||Published - Jan 2004|
Bibliographical noteFunding Information:
This work was supported by grants of the Spanish Ministry of Science and Technology (PB98-1572 and BMC2002-03599, to C.M.), a grant of the Plan Regional de Investigación del Principado de Asturias (GE-MEDO1-05, to J.A.S.), and of the NIH (CA 91901, to J.R.). N.M. was the recipient of a pre-doctoral fellowship of the Plan Regional de Investigación del Principado de Asturias. Dr. Jack Goodman (University of Kentucky mass spectrometry facility) is acknowledged for excellent mass spectra. We thank Lorena Castro for helpful technical assistance and Ignacio Aguirrezabalaga for helping in designing oligoprimers. We thank Pharmamar S.A. for helping in the antitumor tests.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry