Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products

The structures of complex polyketide natural products, such as erythromycin, are programmed by multifunctional polyketide synthases (PKSs) that contain modular arrangements of functional domains. The colinearity between the activities of modular PKS domains and structure of the polyketide product po...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.1846-1851
Main Authors: McDaniel, Robert, Thamchaipenet, Arinthip, Gustafsson, Claes, Fu, Hong, Betlach, Melanie, Betlach, Mary, Ashley, Gary
Format: Article
Language:English
Subjects:
Acetates
Biological Sciences
Biosynthesis
Catalytic Domain
Chemicals
Cloning, Molecular
Erythromycin - analogs & derivatives
Erythromycin - chemical synthesis
Erythromycin - chemistry
Escherichia coli
Genetic engineering
Genetic Engineering - methods
Libraries
Macrolides
Mass spectra
Multienzyme Complexes - genetics
Multienzyme Complexes - metabolism
Mutagenesis
Mutagenesis, Insertional
Mutagenesis, Site-Directed
Polyketides
Polymerase Chain Reaction
Recombinant Proteins - metabolism
Streptomyces - genetics
Streptomyces - metabolism
Structure-Activity Relationship
Substrate Specificity
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Summary:The structures of complex polyketide natural products, such as erythromycin, are programmed by multifunctional polyketide synthases (PKSs) that contain modular arrangements of functional domains. The colinearity between the activities of modular PKS domains and structure of the polyketide product portends the generation of novel organic compounds--"unnatural" natural products--by genetic manipulation. We have engineered the erythromycin polyketide synthase genes to effect combinatorial alterations of catalytic activities in the biosynthetic pathway, generating a library of >50 macrolides that would be impractical to produce by chemical methods. The library includes examples of analogs with one, two, and three altered carbon centers of the polyketide products. The manipulation of multiple biosynthetic steps in a PKS is an important milestone toward the goal of producing large libraries of unnatural natural products for biological and pharmaceutical applications.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.5.1846