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Journal of Bacteriology, January 1999, p. 642-647, Vol. 181, No. 2
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Mithramycin Gene Cluster of Streptomyces argillaceus Contains a Positive Regulatory Gene and Two Repeated DNA Sequences That Are Located at Both Ends of the Cluster

Felipe Lombó, Alfredo F. Braña, Carmen Méndez, and José A. Salas*

Departamento de Biología Funcional e Instituto Universitario de Biotecnología de Asturias (I.U.B.A.-C.S.I.C.), Universidad de Oviedo, 33006 Oviedo, Spain

Received 13 July 1998/Accepted 5 November 1998

Sequencing of a 4.3-kb DNA region from the chromosome of Streptomyces argillaceus, a mithramycin producer, revealed the presence of two open reading frames (ORFs). The first one (orfA) codes for a protein that resembles several transport proteins. The second one (mtmR) codes for a protein similar to positive regulators involved in antibiotic biosynthesis (DnrI, SnoA, ActII-orf4, CcaR, and RedD) belonging to the Streptomyces antibiotic regulatory protein (SARP) family. Both ORFs are separated by a 1.9-kb, apparently noncoding region. Replacement of the mtmR region by an antibiotic resistance cassette completely abolished mithramycin biosynthesis. Expression of mtmR in a high-copy-number vector in S. argillaceus caused a 16-fold increase in mithramycin production. The mtmR gene restored actinorhodin production in Streptomyces coelicolor JF1 mutant, in which the actinorhodin-specific activator ActII-orf4 is inactive, and also stimulated actinorhodin production by Streptomyces lividans TK21. A 241-bp region located 1.9 kb upstream of mtmR was found to be repeated approximately 50 kb downstream of mtmR at the other end of the mithramycin gene cluster. A model to explain a possible route for the acquisition of the mithramycin gene cluster by S. argillaceus is proposed.

* Corresponding author. Mailing address: Departamento de Biología Funcional e Instituto Universitario de Biotecnología de Asturias (I.U.B.A.-C.S.I.C.), Universidad de Oviedo, 33006 Oviedo, Spain. Phone: (34-8)5103652. Fax: (34-8)5103652. E-mail: Jasf{at}sauron.quimica.uniovi.es.

Journal of Bacteriology, January 1999, p. 642-647, Vol. 181, No. 2
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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