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Journal of Bacteriology, February 2006, p. 1236-1244, Vol. 188, No. 4
0021-9193/06/$08.00+0     doi:10.1128/JB.188.4.1236-1244.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Biosynthesis of a Natural Polyketide-Isoprenoid Hybrid Compound, Furaquinocin A: Identification and Heterologous Expression of the Gene Cluster

Takashi Kawasaki,1 Yutaka Hayashi,1 Tomohisa Kuzuyama,2 Kazuo Furihata,3 Nobuya Itoh,1 Haruo Seto,4 and Tohru Dairi1*

Biotechnology Research Center, Toyama Prefectural University, Toyama 939-0398, Japan,1 Biotechnology Research Center, The University of Tokyo, Bunkyo-ku 113-8657, Japan,2 Division of Agriculture and Agricultural Life Science, The University of Tokyo, Bunkyo-ku 113-8657, Japan,3 Faculty of Applied Bio-science, Tokyo University of Agriculture, Setagaya-ku 156-8502, Japan4

Received 2 September 2005/ Accepted 13 November 2005

Furaquinocin (FQ) A, produced by Streptomyces sp. strain KO-3988, is a natural polyketide-isoprenoid hybrid compound that exhibits a potent antitumor activity. As a first step toward understanding the biosynthetic machinery of this unique and pharmaceutically useful compound, we have cloned an FQ A biosynthetic gene cluster by taking advantage of the fact that an isoprenoid biosynthetic gene cluster generally exists in flanking regions of the mevalonate (MV) pathway gene cluster in actinomycetes. Interestingly, Streptomyces sp. strain KO-3988 was the first example of a microorganism equipped with two distinct mevalonate pathway gene clusters. We were able to localize a 25-kb DNA region that harbored FQ A biosynthetic genes (fur genes) in both the upstream and downstream regions of one of the MV pathway gene clusters (MV2) by using heterologous expression in Streptomyces lividans TK23. This was the first example of a gene cluster responsible for the biosynthesis of a polyketide-isoprenoid hybrid compound. We have also confirmed that four genes responsible for viguiepinol [3-hydroxypimara-9(11),15-diene] biosynthesis exist in the upstream region of the other MV pathway gene cluster (MV1), which had previously been cloned from strain KO-3988. This was the first example of prokaryotic enzymes with these biosynthetic functions. By phylogenetic analysis, these two MV pathway clusters were identified as probably being independently distributed in strain KO-3988 (orthologs), rather than one cluster being generated by the duplication of the other cluster (paralogs).

* Corresponding author. Mailing address: Biotechnology Research Center, Toyama Prefectural University, Toyama 939-0398, Japan. Phone: 81-766-56-7500. Fax:. 81-766-56-2498. E-mail: dairi{at}pu-toyama.ac.jp.

Journal of Bacteriology, February 2006, p. 1236-1244, Vol. 188, No. 4
0021-9193/06/$08.00+0     doi:10.1128/JB.188.4.1236-1244.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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