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Antimicrobial Agents and Chemotherapy, April 2003, p. 1291-1296, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1291-1296.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Engineering Anthracycline Biosynthesis toward Angucyclines

Mikko Metsä-Ketelä,1* Kaisa Palmu,1 Tero Kunnari,2 Kristiina Ylihonko,2 and Pekka Mäntsälä1

Department of Biochemistry, University of Turku, FIN-20014 Turku,1 Galilaeus Oy, FIN-20781 Kaarina, Finland2

Received 2 October 2002/ Returned for modification 1 November 2002/ Accepted 6 January 2003

The biosynthesis pathways of two anthracyclines, nogalamycin and aclacinomycin, were directed toward angucyclines by using an angucycline-specific cyclase, pgaF, isolated from a silent antibiotic biosynthesis gene cluster. Addition of pgaF to a gene cassette that harbored the early biosynthesis genes of nogalamycin resulted in the production of two known angucyclinone metabolites, rabelomycin and its precursor, UWM6. Substrate flexibility of pgaF was demonstrated by replacement of the nogalamycin minimal polyketide synthase genes in the gene cassette with the equivalent aclacinomycin genes together with aknE2 and aknF, which specify the unusual propionate starter unit in aclacinomycin biosynthesis. This modification led to the production of a novel angucyclinone, MM2002, in which the expected ethyl side chain was incorporated into the fourth ring.

* Corresponding author. Mailing address: Department of Biochemistry and Food Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland. Phone: 358-2-333 6847. Fax: 358-2-333 6860. E-mail: mianme{at}utu.fi.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1291-1296, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1291-1296.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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