Laureti, L., Song, Lijiang, Huang, S., Corre, Christophe, Leblond, Pierre, Challis, Gregory L. and Aigle, B.. (2011) Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens. Proceedings of the National Academy of Sciences of the United States of America, Vol.108 (No.15). pp. 6258-6263. ISSN 0027-8424

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Abstract

There is a constant need for new and improved drugs to combat infectious diseases, cancer, and other major life-threatening conditions. The recent development of genomics-guided approaches for novel natural product discovery has stimulated renewed interest in the search for natural product-based drugs. Genome sequence analysis of Streptomyces ambofaciens ATCC23877 has revealed numerous secondary metabolite biosynthetic gene clusters, including a giant type I modular polyketide synthase (PKS) gene cluster, which is composed of 25 genes (nine of which encode PKSs) and spans almost 150 kb, making it one of the largest polyketide biosynthetic gene clusters described to date. The metabolic product(s) of this gene cluster are unknown, and transcriptional analyses showed that it is not expressed under laboratory growth conditions. The constitutive expression of a regulatory gene within the cluster, encoding a protein that is similar to Large ATP binding of the LuxR (LAL) family proteins, triggered the expression of the biosynthetic genes. This led to the identification of four 51-membered glycosylated macrolides, named stambomycins A–D as metabolic products of the gene cluster. The structures of these compounds imply several interesting biosynthetic features, including incorporation of unusual extender units into the polyketide chain and in trans hydroxylation of the growing polyketide chain to provide the hydroxyl group for macrolide formation. Interestingly, the stambomycins possess promising antiproliferative activity against human cancer cell lines. Database searches identify genes encoding LAL regulators within numerous cryptic biosynthetic gene clusters in actinomycete genomes, suggesting that constitutive expression of such pathway-specific activators represents a powerful approach for novel bioactive natural product discovery.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QR Microbiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Streptomyces, Polyketides, Biosynthesis, Antineoplastic agents, Genomics, Macrolide antibiotics
Journal or Publication Title:	Proceedings of the National Academy of Sciences of the United States of America
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date:	28 March 2011
Volume:	Vol.108
Number:	No.15
Page Range:	pp. 6258-6263
Identification Number:	10.1073/pnas.1019077108
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Sixth Framework Programme (European Commission) (FP6)
Grant number:	FP6-5224 (FP6)
Conference Paper Type:	Paper
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URI:	http://wrap.warwick.ac.uk/id/eprint/40407

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