Loading…
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...
Saved in:
| Published in: | Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.1846-1851 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643 |
| container_end_page | 1851 |
| container_issue | 5 |
| container_start_page | 1846 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 96 |
| creator | McDaniel, Robert Thamchaipenet, Arinthip Gustafsson, Claes Fu, Hong Betlach, Melanie Betlach, Mary Ashley, Gary |
| description | 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. |
| doi_str_mv | 10.1073/pnas.96.5.1846 |
| format | article |
| fullrecord | <record><control><sourceid>jstor_proqu</sourceid><recordid>TN_cdi_proquest_journals_201375734</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>46976</jstor_id><sourcerecordid>46976</sourcerecordid><originalsourceid>FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643</originalsourceid><addsrcrecordid>eNp9kU1v1DAURSMEokNhywIJZM2iuwQ78VckNqhqC9K0VIKuLY_zwnjI2IPtVGTJP2-iDNXAgpUtvXOfztPNstcEFwSL6v3e6VjUvGAFkZQ_yRYE1yTntMZPswXGpcglLelJ9iLGLca4ZhI_z04IxowwJhbZ7-u-S3bfAboCB8kadO0b21qjk_UuIt-itAF0EYa0CX43GOvQre-GHyPbAPo6uLTREVDy6Db4pjeANFrZddBhmMI3_h46tLxzTqc-6G6JbubPAU_xZfas1V2EV4f3NLu7vPh2_ilffbn6fP5xlZvROeW0aQSpKmFKWZJWlFpAXUlGa7MmUK7bhjPMQRqOmSDUUKFpVUrGpASQJafVafZh3rvv1ztoDLg0aqh9sLvRVXlt1d8TZzfqu79XJed1PcbPDvHgf_YQk9rZaKDrtAPfR0UEYVJIPoLLf8Ct74MbT1MlJpVgoppkihkywccYoH30IFhNxaqpWFVzxdRU7Bh4d2x_hM9NjsDbAzAF_4yPF5z9b67avusS_Eoj-GYGtzH58EhSXgtePQCufsFb</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201375734</pqid></control><display><type>article</type><title>Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products</title><source>PubMed (Medline)</source><source>JSTOR Archival Journals</source><creator>McDaniel, Robert ; Thamchaipenet, Arinthip ; Gustafsson, Claes ; Fu, Hong ; Betlach, Melanie ; Betlach, Mary ; Ashley, Gary</creator><creatorcontrib>McDaniel, Robert ; Thamchaipenet, Arinthip ; Gustafsson, Claes ; Fu, Hong ; Betlach, Melanie ; Betlach, Mary ; Ashley, Gary</creatorcontrib><description>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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.96.5.1846</identifier><identifier>PMID: 10051557</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (5), p.1846-1851</ispartof><rights>Copyright 1993-1999 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 2, 1999</rights><rights>Copyright © 1999, The National Academy of Sciences 1999</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643</citedby><cites>FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/96/5.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/46976$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/46976$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10051557$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McDaniel, Robert</creatorcontrib><creatorcontrib>Thamchaipenet, Arinthip</creatorcontrib><creatorcontrib>Gustafsson, Claes</creatorcontrib><creatorcontrib>Fu, Hong</creatorcontrib><creatorcontrib>Betlach, Melanie</creatorcontrib><creatorcontrib>Betlach, Mary</creatorcontrib><creatorcontrib>Ashley, Gary</creatorcontrib><title>Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Acetates</subject><subject>Biological Sciences</subject><subject>Biosynthesis</subject><subject>Catalytic Domain</subject><subject>Chemicals</subject><subject>Cloning, Molecular</subject><subject>Erythromycin - analogs & derivatives</subject><subject>Erythromycin - chemical synthesis</subject><subject>Erythromycin - chemistry</subject><subject>Escherichia coli</subject><subject>Genetic engineering</subject><subject>Genetic Engineering - methods</subject><subject>Libraries</subject><subject>Macrolides</subject><subject>Mass spectra</subject><subject>Multienzyme Complexes - genetics</subject><subject>Multienzyme Complexes - metabolism</subject><subject>Mutagenesis</subject><subject>Mutagenesis, Insertional</subject><subject>Mutagenesis, Site-Directed</subject><subject>Polyketides</subject><subject>Polymerase Chain Reaction</subject><subject>Recombinant Proteins - metabolism</subject><subject>Streptomyces - genetics</subject><subject>Streptomyces - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNp9kU1v1DAURSMEokNhywIJZM2iuwQ78VckNqhqC9K0VIKuLY_zwnjI2IPtVGTJP2-iDNXAgpUtvXOfztPNstcEFwSL6v3e6VjUvGAFkZQ_yRYE1yTntMZPswXGpcglLelJ9iLGLca4ZhI_z04IxowwJhbZ7-u-S3bfAboCB8kadO0b21qjk_UuIt-itAF0EYa0CX43GOvQre-GHyPbAPo6uLTREVDy6Db4pjeANFrZddBhmMI3_h46tLxzTqc-6G6JbubPAU_xZfas1V2EV4f3NLu7vPh2_ilffbn6fP5xlZvROeW0aQSpKmFKWZJWlFpAXUlGa7MmUK7bhjPMQRqOmSDUUKFpVUrGpASQJafVafZh3rvv1ztoDLg0aqh9sLvRVXlt1d8TZzfqu79XJed1PcbPDvHgf_YQk9rZaKDrtAPfR0UEYVJIPoLLf8Ct74MbT1MlJpVgoppkihkywccYoH30IFhNxaqpWFVzxdRU7Bh4d2x_hM9NjsDbAzAF_4yPF5z9b67avusS_Eoj-GYGtzH58EhSXgtePQCufsFb</recordid><startdate>19990302</startdate><enddate>19990302</enddate><creator>McDaniel, Robert</creator><creator>Thamchaipenet, Arinthip</creator><creator>Gustafsson, Claes</creator><creator>Fu, Hong</creator><creator>Betlach, Melanie</creator><creator>Betlach, Mary</creator><creator>Ashley, Gary</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>5PM</scope></search><sort><creationdate>19990302</creationdate><title>Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products</title><author>McDaniel, Robert ; Thamchaipenet, Arinthip ; Gustafsson, Claes ; Fu, Hong ; Betlach, Melanie ; Betlach, Mary ; Ashley, Gary</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Acetates</topic><topic>Biological Sciences</topic><topic>Biosynthesis</topic><topic>Catalytic Domain</topic><topic>Chemicals</topic><topic>Cloning, Molecular</topic><topic>Erythromycin - analogs & derivatives</topic><topic>Erythromycin - chemical synthesis</topic><topic>Erythromycin - chemistry</topic><topic>Escherichia coli</topic><topic>Genetic engineering</topic><topic>Genetic Engineering - methods</topic><topic>Libraries</topic><topic>Macrolides</topic><topic>Mass spectra</topic><topic>Multienzyme Complexes - genetics</topic><topic>Multienzyme Complexes - metabolism</topic><topic>Mutagenesis</topic><topic>Mutagenesis, Insertional</topic><topic>Mutagenesis, Site-Directed</topic><topic>Polyketides</topic><topic>Polymerase Chain Reaction</topic><topic>Recombinant Proteins - metabolism</topic><topic>Streptomyces - genetics</topic><topic>Streptomyces - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McDaniel, Robert</creatorcontrib><creatorcontrib>Thamchaipenet, Arinthip</creatorcontrib><creatorcontrib>Gustafsson, Claes</creatorcontrib><creatorcontrib>Fu, Hong</creatorcontrib><creatorcontrib>Betlach, Melanie</creatorcontrib><creatorcontrib>Betlach, Mary</creatorcontrib><creatorcontrib>Ashley, Gary</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McDaniel, Robert</au><au>Thamchaipenet, Arinthip</au><au>Gustafsson, Claes</au><au>Fu, Hong</au><au>Betlach, Melanie</au><au>Betlach, Mary</au><au>Ashley, Gary</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1999-03-02</date><risdate>1999</risdate><volume>96</volume><issue>5</issue><spage>1846</spage><epage>1851</epage><pages>1846-1851</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10051557</pmid><doi>10.1073/pnas.96.5.1846</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (5), p.1846-1851 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_proquest_journals_201375734 |
| source | PubMed (Medline); JSTOR Archival Journals |
| 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 |
| title | Multiple Genetic Modifications of the Erythromycin Polyketide Synthase to Produce a Library of Novel "Unnatural" Natural Products |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T13%3A57%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multiple%20Genetic%20Modifications%20of%20the%20Erythromycin%20Polyketide%20Synthase%20to%20Produce%20a%20Library%20of%20Novel%20%22Unnatural%22%20Natural%20Products&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=McDaniel,%20Robert&rft.date=1999-03-02&rft.volume=96&rft.issue=5&rft.spage=1846&rft.epage=1851&rft.pages=1846-1851&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.96.5.1846&rft_dat=%3Cjstor_proqu%3E46976%3C/jstor_proqu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c580t-4dd71337c2821f72a7e938549cb1e2bfd6506e8c605714c47a43285588ee82643%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=201375734&rft_id=info:pmid/10051557&rft_jstor_id=46976&rfr_iscdi=true |