Biosynthesis of the Antitumor Chromomycin A3 in Streptomyces griseus: Analysis of the Gene Cluster and Rational Design of Novel Chromomycin Analogs

Nuria Menéndez; Mohammad Nur-e-Alam; Alfredo F. Braña; J. Ürgen Rohr; José A. Salas; Carmen Méndez

doi:10.1016/S1074-5521(03)00283-7

Biosynthesis of the Antitumor Chromomycin A₃ in Streptomyces griseus: Analysis of the Gene Cluster and Rational Design of Novel Chromomycin Analogs

Nuria Menéndez, Mohammad Nur-e-Alam, Alfredo F. Braña, J. Ürgen Rohr, José A. Salas, Carmen Méndez

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	21-32
Number of pages	12
Journal	Chemistry and Biology
Volume	11
Issue number	1
DOIs	https://doi.org/10.1016/S1074-5521(03)00283-7
State	Published - Jan 2004

Bibliographical note

Funding 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.

Funding

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.

Funders	Funder number
Plan Regional de Investigación del Principado de Asturias	GE-MEDO1-05
National Institutes of Health (NIH)	CA 91901
Ministerio de Ciencia, Tecnología e Innovación Productiva	BMC2002-03599, PB98-1572

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/S1074-5521(03)00283-7

Cite this

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title = "Biosynthesis of the Antitumor Chromomycin A3 in Streptomyces griseus: Analysis of the Gene Cluster and Rational Design of Novel Chromomycin Analogs",

abstract = "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.",

author = "Nuria Men{\'e}ndez and Mohammad Nur-e-Alam and Bra{\~n}a, {Alfredo F.} and Rohr, {J. {\"U}rgen} and Salas, {Jos{\'e} A.} and Carmen M{\'e}ndez",

note = "Funding 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 Investigaci{\'o}n 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 Investigaci{\'o}n 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. ",

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AU - Braña, Alfredo F.

AU - Rohr, J. Ürgen

AU - Salas, José A.

AU - Méndez, Carmen

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