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PMID: 10051557 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel "unnatural" natural products.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 5 ·1999-03-02 ·Pages 1846-51

McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G

Abstract

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.

MeSH Terms
Catalytic Domain Cloning, Molecular Erythromycin/analogs & derivatives,chemical synthesis,chemistry Escherichia coli Genetic Engineering/methods Multienzyme Complexes/genetics,metabolism Mutagenesis, Insertional Mutagenesis, Site-Directed Polymerase Chain Reaction Recombinant Proteins/metabolism Streptomyces/genetics,metabolism Structure-Activity Relationship Substrate Specificity
Chemicals
Multienzyme Complexes Recombinant Proteins Erythromycin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
McDaniel R
KOSAN Biosciences, Inc., 1450 Rollins Road, Burlingame, CA 94010, USA. mcdaniel@kosan.com
Thamchaipenet A
Gustafsson C
Fu H
Betlach M
Ashley G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.5.1846
Email
mcdaniel@kosan.com
Published
1999-03-02
Pages
1846-51
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC26699
Subset
IM
Corrections
ErratumIn
-
ErratumIn
-
CommentIn
PMID: 10097038
External Links
PubMed source DOI: 10.1073/pnas.96.5.1846 PMC Full Text View journal details
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