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J. Biol. Chem., Vol. 283, Issue 13, 8183-8189, March 28, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/13/8183    most recent M710421200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Zhao, B. Articles by Cane, D. E. PubMed PubMed Citation Articles by Zhao, B. Articles by Cane, D. E. Social Bookmarking                      What's this?

Biosynthesis of the Sesquiterpene Antibiotic Albaflavenone in Streptomyces coelicolor A3(2)^*

Bin Zhao¹², Xin Lin¹, Li Lei, David C. Lamb^¶, Steven L. Kelly^¶, Michael R. Waterman, and David E. Cane

From the Department of Biochemistry and the Institute of Chemical Biology, and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, Department of Chemistry, Brown University, Providence, Rhode Island 02912-9108, and ^¶Institute of Life Science, Swansea Medical School, University of Wales Swansea, Swansea SA2 8PP, United Kingdom

Cytochrome P450 170A1 (CYP170A1) is encoded by the sco5223 gene of the Gram-positive, soil-dwelling bacterium Streptomyces coelicolor A3(2) as part of a two-gene cluster with the sco5222 gene. The SCO5222 protein is a sesquiterpene synthase that catalyzes the cyclization of farnesyl diphosphate to the novel tricyclic hydrocarbon, epi-isozizaene (Lin, X., Hopson, R., and Cane, D. E. (2006) J. Am. Chem. Soc. 128, 6022–6023). The presence of CYP170A1 (sco5223) suggested that epiisozizaene might be further oxidized by the transcriptionally coupled P450. We have now established that purified CYP170A1 carries out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to the sesquiterpene antibiotic albaflavenone. Gas chromatography/mass spectrometry analysis of S. coelicolor culture extracts established the presence of albaflavenone in the wild-type strain, along with its precursors epi-isozizaene and the albaflavenols. Disruption of the CYP170A1 gene abolished biosynthesis of both albaflavenone and the albaflavenols, but not epi-isozizaene. The combined results establish for the first time the presence of albaflavenone in S. coelicolor and clearly demonstrate that the biosynthesis of this antibiotic involves the coupled action of epi-isozizaene synthase and CYP170A1.

Received for publication, December 21, 2007 , and in revised form, January 29, 2008.

^* This work was supported by National Institutes of Health Grants GM69970 (to M. R. W.), ES00267 (to M. R. W.), and GM30301 (to D. E. C.) and by a Leverhulme Trust research fellowship (to D. C. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University School of Medicine, 864 Robinson Research Bldg., 23rd and Pierce Aves., Nashville, TN 37232-0146. Tel.: 615-343-4644; Fax: 615-343-0704; E-mail: bin.zhao{at}vanderbilt.edu.

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