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Applied and Environmental Microbiology, May 2009, p. 2869-2878, Vol. 75, No. 9
0099-2240/09/$08.00+0     doi:10.1128/AEM.02326-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Biosynthesis of Sibiromycin, a Potent Antitumor Antibiotic{triangledown} ,{dagger}

Wei Li, Ankush Khullar, ShenChieh Chou, Ashley Sacramo,{ddagger} and Barbara Gerratana*

Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742

Received 9 October 2008/ Accepted 25 February 2009

Pyrrolobenzodiazepines, a class of natural products produced by actinomycetes, are sequence selective DNA alkylating compounds with significant antitumor properties. Among the pyrrolo[1,4]benzodiazepines (PBDs) sibiromycin, one of two identified glycosylated PBDs, displays the highest affinity for DNA and the most potent antitumor properties. Despite the promising antitumor properties clinical trials of sibiromycin were precluded by the cardiotoxicity effect in animals attributed to the presence of the C-9 hydroxyl group. As a first step toward the development of sibiromycin analogs, we have cloned and localized the sibiromycin gene cluster to a 32.7-kb contiguous DNA region. Cluster boundaries tentatively assigned by comparative genomics were verified by gene replacement experiments. The sibiromycin gene cluster consisting of 26 open reading frames reveals a "modular" strategy in which the synthesis of the anthranilic and dihydropyrrole moieties is completed before assembly by the nonribosomal peptide synthetase enzymes. In addition, the gene cluster identified includes open reading frames encoding enzymes involved in sibirosamine biosynthesis, as well as regulatory and resistance proteins. Gene replacement and chemical complementation studies are reported to support the proposed biosynthetic pathway.

* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, Bldg. 091, University of Maryland, College Park, MD 20742. Phone: (301) 405-1541. Fax: (301) 314-9121. E-mail: bgerrata{at}umd.edu

{triangledown} Published ahead of print on 6 March 2009.

{dagger} Supplemental material for this article may be found at http://aem.asm.org/.

{ddagger} Present address: Department of Biochemistry, University of Wisconsin, Madison, WI 53706.

Applied and Environmental Microbiology, May 2009, p. 2869-2878, Vol. 75, No. 9
0099-2240/09/$08.00+0     doi:10.1128/AEM.02326-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, W., Chou, S., Khullar, A., Gerratana, B. (2009). Cloning and Characterization of the Biosynthetic Gene Cluster for Tomaymycin, an SJG-136 Monomeric Analog. Appl. Environ. Microbiol. 75: 2958-2963 [Abstract] [Full Text]  


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