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Journal of Bacteriology, December 2002, p. 7013-7024, Vol. 184, No. 24
0021-9193/02/$04.00+0     DOI: 10.1128/JB.184.24.7013-7024.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification and Localization of the Gene Cluster Encoding Biosynthesis of the Antitumor Macrolactam Leinamycin in Streptomyces atroolivaceus S-140

Yi-Qiang Cheng,1 Gong-Li Tang,1 and Ben Shen1,2*

Division of Pharmaceutical Sciences,1 Department of Chemistry, University of Wisconsin, Madison, Wisconsin 537052

Received 26 June 2002/ Accepted 15 September 2002

Leinamycin (LNM), produced by Streptomyces atroolivaceus, is a thiazole-containing hybrid peptide-polyketide natural product structurally characterized with an unprecedented 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a 18-member macrolactam ring. LNM exhibits a broad spectrum of antimicrobial and antitumor activities, most significantly against tumors that are resistant to clinically important anticancer drugs, resulting from its DNA cleavage activity in the presence of a reducing agent. Using a PCR approach to clone a thiazole-forming nonribosomal peptide synthetase (NRPS) as a probe, we localized a 172-kb DNA region from S. atroolivaceus S-140 that harbors the lnm biosynthetic gene cluster. Sequence analysis of 11-kb DNA revealed three genes, lnmG, lnmH, and lnmI, and the deduced product of lnmI is characterized by domains characteristic to both NRPS and polyketide synthase (PKS). The involvement of the cloned gene cluster in LNM biosynthesis was confirmed by disrupting the lnmI gene to generate non-LNM-producing mutants and by characterizing LnmI as a hybrid NRPS-PKS megasynthetase, the NRPS module of which specifies for L-Cys and catalyzes thiazole formation. These results have now set the stage for full investigations of LNM biosynthesis and for generation of novel LNM analogs by combinatorial biosynthesis.

* Corresponding author. Mailing address: Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison, WI 53705. Phone: (608) 263-2673. Fax: (608) 262-2459. E-mail: bshen{at}pharmacy.wisc.edu.

Journal of Bacteriology, December 2002, p. 7013-7024, Vol. 184, No. 24
0021-9193/02/$04.00+0     DOI: 10.1128/JB.184.24.7013-7024.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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