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Journal of Bacteriology, January 2008, p. 251-263, Vol. 190, No. 1
0021-9193/08/$08.00+0     doi:10.1128/JB.00826-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Characterization of the Saframycin A Gene Cluster from Streptomyces lavendulae NRRL 11002 Revealing a Nonribosomal Peptide Synthetase System for Assembling the Unusual Tetrapeptidyl Skeleton in an Iterative Manner^,

Lei Li, Wei Deng, Jie Song, Wei Ding, Qun-Fei Zhao, Chao Peng, Wei-Wen Song, Gong-Li Tang,^* and Wen Liu^*

State Key Laboratory of Bioorganic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Rd., Shanghai 200032, China

Received 26 May 2007/ Accepted 23 October 2007

Saframycin A (SFM-A), produced by Streptomyces lavendulae NRRL 11002, belongs to the tetrahydroisoquinoline family of antibiotics, and its core is structurally similar to the core of ecteinascidin 743, which is a highly potent antitumor drug isolated from a marine tunicate. In this study, the biosynthetic gene cluster for SFM-A was cloned and localized to a 62-kb contiguous DNA region. Sequence analysis revealed 30 genes that constitute the SFM-A gene cluster, encoding an unusual nonribosomal peptide synthetase (NRPS) system and tailoring enzymes and regulatory and resistance proteins. The results of substrate prediction and in vitro characterization of the adenylation specificities of this NRPS system support the hypothesis that the last module acts in an iterative manner to form a tetrapeptidyl intermediate and that the colinearity rule does not apply. Although this mechanism is different from those proposed for the SFM-A analogs SFM-Mx1 and safracin B (SAC-B), based on the high similarity of these systems, it is likely they share a common mechanism of biosynthesis as we describe here. Construction of the biosynthetic pathway of SFM-Y3, an aminated SFM-A, was achieved in the SAC-B producer (Pseudomonas fluorescens). These findings not only shed new insight on tetrahydroisoquinoline biosynthesis but also demonstrate the feasibility of engineering microorganisms to generate structurally more complex and biologically more active analogs by combinatorial biosynthesis.

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* Corresponding author. Mailing address: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Rd., Shanghai, 200032, China. Phone for Wen Liu: 86-21-54925111. Fax: 86-21-64166128. E-mail: wliu{at}mail.sioc.ac.cn. Phone for Gong-Li Tang: 86- 21-54925113. E-mail: gltang{at}mail.sioc.ac.cn

Supplemental material for this article may be found at http://jb.asm.org/.

Published ahead of print on 2 November 2007.

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Journal of Bacteriology, January 2008, p. 251-263, Vol. 190, No. 1
0021-9193/08/$08.00+0     doi:10.1128/JB.00826-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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