Nature Biotechnology
21, 187 - 190 (2003)
Published online: 21 January 2003; | doi:10.1038/nbt784
A genomics-guided approach for discovering and expressing cryptic metabolic pathwaysEmmanuel Zazopoulos1, Kexue Huang1, Alfredo Staffa1, Wen Liu2, Brian O. Bachmann1, Koichi Nonaka2, Joachim Ahlert2, 3, Jon S. Thorson2, 3, Ben Shen2, 4
& Chris M. Farnet11
Ecopia BioSciences, Inc., 7290 Frederick Banting, Montreal, Quebec H4S 2A1, Canada. 2
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53706. 3
Laboratory for Biosynthetic Chemistry, University of Wisconsin, Madison, WI 53706. 4
Department of Chemistry, University of Wisconsin, Madison, WI 53706.
Correspondence should be addressed to Chris M. Farnet farnet@ecopiabio.comGenome analysis of actinomycetes has revealed the presence of numerous cryptic gene clusters encoding putative natural products1,
2. These loci remain dormant until appropriate chemical or physical signals induce their expression. Here we demonstrate the use of a high-throughput genome scanning method to detect and analyze gene clusters involved in natural-product biosynthesis. This method was applied to uncover biosynthetic pathways encoding enediyne antitumor antibiotics in a variety of actinomycetes. Comparative analysis of five biosynthetic loci representative of the major structural classes of enediynes reveals the presence of a conserved cassette of five genes that includes a novel family of polyketide synthase (PKS)3,
4. The enediyne PKS (PKSE) is proposed to be involved in the formation of the highly reactive chromophore ring structure (or "warhead") found in all enediynes3,
4. Genome scanning analysis indicates that the enediyne warhead cassette is widely dispersed among actinomycetes. We show that selective growth conditions can induce the expression of these loci, suggesting that the range of enediyne natural products may be much greater than previously thought. This technology can be used to increase the scope and diversity of natural-product discovery.
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REFERENCE
Actinomyces spores
Nature Encyclopaedia of Life Sciences
NEWS AND VIEWS
New enzymes for "warheads"
Nature Biotechnology Research News (01 Oct 2002)
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