A genomics-guided approach for discovering and expressing cryptic metabolic pathways

Emmanuel Zazopoulos; Kexue Huang; Alfredo Staffa; Wen Liu; Brian O. Bachmann; Koichi Nonaka; Joachim Ahlert; Jon S. Thorson; Ben Shen; Chris M. Farnet

doi:10.1038/nbt784

A genomics-guided approach for discovering and expressing cryptic metabolic pathways

Emmanuel Zazopoulos, Kexue Huang, Alfredo Staffa, Wen Liu, Brian O. Bachmann, Koichi Nonaka, Joachim Ahlert, Jon S. Thorson, Ben Shen, Chris M. Farnet

Research output: Contribution to journal › Article › peer-review

283 Scopus citations

Abstract

Genome analysis of actinomycetes has revealed the presence of numerous cryptic gene clusters encoding putative natural products. 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). The enediyne PKS (PKSE) is proposed to be involved in the formation of the highly reactive chromophore ring structure (or "warhead") found in all enediynes. 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.

Original language	English
Pages (from-to)	187-190
Number of pages	4
Journal	Nature Biotechnology
Volume	21
Issue number	2
DOIs	https://doi.org/10.1038/nbt784
State	Published - Feb 1 2003

Bibliographical note

Funding Information:
Acknowledgments We thank S. Mercure, V. Dodelet, and M. Piraee for helpful discussions and J. McAlpine for critical reading of the manuscript. B.S. is a recipient of a NSF CAREER Award (MCB9733938) and a NIH Independent Scientist Award (AI51689). Enediyne studies in the Shen lab are supported in part by NIH grant CA78747. Research in the Thorson lab is supported in part by NIH grants CA84347, GM58196, and AI52218. J.S.T. is an Alfred P. Sloan Fellow.

Funding

Acknowledgments We thank S. Mercure, V. Dodelet, and M. Piraee for helpful discussions and J. McAlpine for critical reading of the manuscript. B.S. is a recipient of a NSF CAREER Award (MCB9733938) and a NIH Independent Scientist Award (AI51689). Enediyne studies in the Shen lab are supported in part by NIH grant CA78747. Research in the Thorson lab is supported in part by NIH grants CA84347, GM58196, and AI52218. J.S.T. is an Alfred P. Sloan Fellow.

Funders	Funder number
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases	K02AI051689, R01AI052218
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM058196
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	MCB9733938
National Institutes of Health (NIH)	CA84347
National Childhood Cancer Registry – National Cancer Institute	R01CA078747

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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abstract = "Genome analysis of actinomycetes has revealed the presence of numerous cryptic gene clusters encoding putative natural products. 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). The enediyne PKS (PKSE) is proposed to be involved in the formation of the highly reactive chromophore ring structure (or {"}warhead{"}) found in all enediynes. 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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A genomics-guided approach for discovering and expressing cryptic metabolic pathways

Abstract

Bibliographical note

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ASJC Scopus subject areas

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