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J. Biol. Chem., Vol. 282, Issue 22, 16362-16368, June 1, 2007

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Molecular Basis for Chloronium-mediated Meroterpene Cyclization

CLONING, SEQUENCING, AND HETEROLOGOUS EXPRESSION OF THE NAPYRADIOMYCIN BIOSYNTHETIC GENE CLUSTER^*

Jaclyn M. Winter¹, Michelle C. Moffitt, Emmanuel Zazopoulos, James B. McAlpine, Pieter C. Dorrestein^¶, and Bradley S. Moore^¶2

From the Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093-0204, Ecopia BioSciences Inc., Quebec, H4S 2A1, Canada, and ^¶Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093

Structural inspection of the bacterial meroterpenoid antibiotics belonging to the napyradiomycin family of chlorinated dihydroquinones suggests that the biosynthetic cyclization of their terpenoid subunits is initiated via a chloronium ion. The vanadium-dependent haloperoxidases that catalyze such reactions are distributed in fungi and marine algae and have yet to be characterized from bacteria. The cloning and sequence analysis of the 43-kb napyradiomycin biosynthetic cluster (nap) from Streptomyces aculeolatus NRRL 18422 and from the undescribed marine sediment-derived Streptomyces sp. CNQ-525 revealed 33 open reading frames, three of which putatively encode vanadium-dependent chloroperoxidases. Heterologous expression of the CNQ-525-based nap biosynthetic cluster in Streptomyces albus produced at least seven napyradiomycins, including the new analog 2-deschloro-2-hydroxy-A80915C. These data not only revealed the molecular basis behind the biosynthesis of these novel meroterpenoid natural products but also resulted in the first in vivo verification of vanadium-dependent haloperoxidases.

Received for publication, November 30, 2006 , and in revised form, March 23, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EF397638 and EF397639.

^* This work was partially supported by National Institutes of Health Grant AI52445 (to B. S. M.), the University of California at San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, and the Department of Chemistry and Biochemistry (to P. C. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Ruth L. Kirschstein National Research Service Award from the Marine Biomedicine and Biotechnology Training Program at Scripps Institution of Oceanography (GM067550).

² To whom correspondence should be addressed: Ctr. for Marine Biotechnology and Biomedicine, Scripps Inst. of Oceanography, UCSD, 8655 Discovery Way, La Jolla, CA 92037-0204. Tel.: 858-822-6650; Fax: 858-822-6652; E-mail: bsmoore{at}ucsd.edu.

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