The Presence of Two Cyclase Thioesterases Expands the Conformational Freedom of the Cyclic Peptide Occidiofungin
Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar activity produced by the Gram-negative bacterium Burkholderia contaminans. The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thio...
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| Veröffentlicht in: | Journal of natural products (Washington, D.C.) D.C.), 2013-02, Vol.76 (2), p.150-156 |
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| container_title | Journal of natural products (Washington, D.C.) |
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| creator | Ravichandran, Akshaya Gu, Ganyu Escano, Jerome Lu, Shi-En Smith, Leif |
| description | Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar activity produced by the Gram-negative bacterium Burkholderia contaminans. The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thioesterases is used to increase the conformational repertoire of the cyclic peptide. The loss of the OcfN cyclic thioesterase by mutagenesis results in a reduction of conformational variants and an appreciable decrease in bioactivity against Candida species. Presumably, the presence of both asparagine and β-hydroxyasparagine variants coordinates the enzymatic function of both of the cyclase thioesterases. OcfN has presumably evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi. The enhancement of the antifungal activity from the incorporation of an additional cyclase thioesterase into the biosynthetic gene cluster of occidiofungin supports the need to explore new conformational variants of other therapeutic or potentially therapeutic cyclic peptides. |
| doi_str_mv | 10.1021/np3005503 |
| format | Article |
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The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thioesterases is used to increase the conformational repertoire of the cyclic peptide. The loss of the OcfN cyclic thioesterase by mutagenesis results in a reduction of conformational variants and an appreciable decrease in bioactivity against Candida species. Presumably, the presence of both asparagine and β-hydroxyasparagine variants coordinates the enzymatic function of both of the cyclase thioesterases. OcfN has presumably evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi. The enhancement of the antifungal activity from the incorporation of an additional cyclase thioesterase into the biosynthetic gene cluster of occidiofungin supports the need to explore new conformational variants of other therapeutic or potentially therapeutic cyclic peptides.</description><identifier>ISSN: 0163-3864</identifier><identifier>EISSN: 1520-6025</identifier><identifier>DOI: 10.1021/np3005503</identifier><identifier>PMID: 23394257</identifier><language>eng</language><publisher>United States: American Chemical Society and American Society of Pharmacognosy</publisher><subject>Antifungal Agents - chemistry ; Antifungal Agents - isolation & purification ; Antifungal Agents - pharmacology ; Burkholderia - chemistry ; Burkholderia - genetics ; Candida - drug effects ; Glycopeptides ; Microbial Sensitivity Tests ; Molecular Structure ; Multigene Family ; Nuclear Magnetic Resonance, Biomolecular ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - isolation & purification ; Peptides, Cyclic - pharmacology ; Thiolester Hydrolases - genetics ; Thiolester Hydrolases - metabolism</subject><ispartof>Journal of natural products (Washington, D.C.), 2013-02, Vol.76 (2), p.150-156</ispartof><rights>Copyright © 2013 American Chemical Society and American Society of Pharmacognosy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a405t-81c39d526740f0de17a534a050fb93402a4cc05293126c55d6704cf367d5fdcd3</citedby><cites>FETCH-LOGICAL-a405t-81c39d526740f0de17a534a050fb93402a4cc05293126c55d6704cf367d5fdcd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/np3005503$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/np3005503$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23394257$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ravichandran, Akshaya</creatorcontrib><creatorcontrib>Gu, Ganyu</creatorcontrib><creatorcontrib>Escano, Jerome</creatorcontrib><creatorcontrib>Lu, Shi-En</creatorcontrib><creatorcontrib>Smith, Leif</creatorcontrib><title>The Presence of Two Cyclase Thioesterases Expands the Conformational Freedom of the Cyclic Peptide Occidiofungin</title><title>Journal of natural products (Washington, D.C.)</title><addtitle>J. Nat. Prod</addtitle><description>Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar activity produced by the Gram-negative bacterium Burkholderia contaminans. The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thioesterases is used to increase the conformational repertoire of the cyclic peptide. The loss of the OcfN cyclic thioesterase by mutagenesis results in a reduction of conformational variants and an appreciable decrease in bioactivity against Candida species. Presumably, the presence of both asparagine and β-hydroxyasparagine variants coordinates the enzymatic function of both of the cyclase thioesterases. OcfN has presumably evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi. The enhancement of the antifungal activity from the incorporation of an additional cyclase thioesterase into the biosynthetic gene cluster of occidiofungin supports the need to explore new conformational variants of other therapeutic or potentially therapeutic cyclic peptides.</description><subject>Antifungal Agents - chemistry</subject><subject>Antifungal Agents - isolation & purification</subject><subject>Antifungal Agents - pharmacology</subject><subject>Burkholderia - chemistry</subject><subject>Burkholderia - genetics</subject><subject>Candida - drug effects</subject><subject>Glycopeptides</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Structure</subject><subject>Multigene Family</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - isolation & purification</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Thiolester Hydrolases - genetics</subject><subject>Thiolester Hydrolases - metabolism</subject><issn>0163-3864</issn><issn>1520-6025</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtKAzEUhoMotl4WvoBk48LF6MltprMRpLQqFNpFXQ9pLm1KmwzJVO3bO7VaFFwdDuf__gMfQlcE7ghQcu9rBiAEsCPUJYJClgMVx6gLJGcZ6-W8g85SWgIAg1Kcog5lrORUFF1UTxcGT6JJxiuDg8XT94D7W7WSyeDpwgWTGhPbJeHBRy29TrhpiX7wNsS1bFzwcoWH0Rgd1jv-69ryTuGJqRunDR4r5bQLduPnzl-gEytXyVx-z3P0OhxM-8_ZaPz00n8cZZKDaLIeUazUguYFBwvakEIKxiUIsLOScaCSKwWClozQXAmh8wK4siwvtLBaaXaOHva99Wa2NloZ30S5quro1jJuqyBd9ffi3aKah7eKE04LQtqC232BiiGlaOyBJVDttFcH7W32-vezQ_LHcxu42QekStUybGJrLf1T9AmZlIqn</recordid><startdate>20130222</startdate><enddate>20130222</enddate><creator>Ravichandran, Akshaya</creator><creator>Gu, Ganyu</creator><creator>Escano, Jerome</creator><creator>Lu, Shi-En</creator><creator>Smith, Leif</creator><general>American Chemical Society and American Society of Pharmacognosy</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>5PM</scope></search><sort><creationdate>20130222</creationdate><title>The Presence of Two Cyclase Thioesterases Expands the Conformational Freedom of the Cyclic Peptide Occidiofungin</title><author>Ravichandran, Akshaya ; Gu, Ganyu ; Escano, Jerome ; Lu, Shi-En ; Smith, Leif</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-81c39d526740f0de17a534a050fb93402a4cc05293126c55d6704cf367d5fdcd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antifungal Agents - chemistry</topic><topic>Antifungal Agents - isolation & purification</topic><topic>Antifungal Agents - pharmacology</topic><topic>Burkholderia - chemistry</topic><topic>Burkholderia - genetics</topic><topic>Candida - drug effects</topic><topic>Glycopeptides</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular Structure</topic><topic>Multigene Family</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - isolation & purification</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Thiolester Hydrolases - genetics</topic><topic>Thiolester Hydrolases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ravichandran, Akshaya</creatorcontrib><creatorcontrib>Gu, Ganyu</creatorcontrib><creatorcontrib>Escano, Jerome</creatorcontrib><creatorcontrib>Lu, Shi-En</creatorcontrib><creatorcontrib>Smith, Leif</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of natural products (Washington, D.C.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ravichandran, Akshaya</au><au>Gu, Ganyu</au><au>Escano, Jerome</au><au>Lu, Shi-En</au><au>Smith, Leif</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Presence of Two Cyclase Thioesterases Expands the Conformational Freedom of the Cyclic Peptide Occidiofungin</atitle><jtitle>Journal of natural products (Washington, D.C.)</jtitle><addtitle>J. Nat. Prod</addtitle><date>2013-02-22</date><risdate>2013</risdate><volume>76</volume><issue>2</issue><spage>150</spage><epage>156</epage><pages>150-156</pages><issn>0163-3864</issn><eissn>1520-6025</eissn><abstract>Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar activity produced by the Gram-negative bacterium Burkholderia contaminans. The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thioesterases is used to increase the conformational repertoire of the cyclic peptide. The loss of the OcfN cyclic thioesterase by mutagenesis results in a reduction of conformational variants and an appreciable decrease in bioactivity against Candida species. Presumably, the presence of both asparagine and β-hydroxyasparagine variants coordinates the enzymatic function of both of the cyclase thioesterases. OcfN has presumably evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi. The enhancement of the antifungal activity from the incorporation of an additional cyclase thioesterase into the biosynthetic gene cluster of occidiofungin supports the need to explore new conformational variants of other therapeutic or potentially therapeutic cyclic peptides.</abstract><cop>United States</cop><pub>American Chemical Society and American Society of Pharmacognosy</pub><pmid>23394257</pmid><doi>10.1021/np3005503</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0163-3864 |
| ispartof | Journal of natural products (Washington, D.C.), 2013-02, Vol.76 (2), p.150-156 |
| issn | 0163-3864 1520-6025 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4142711 |
| source | American Chemical Society; MEDLINE |
| subjects | Antifungal Agents - chemistry Antifungal Agents - isolation & purification Antifungal Agents - pharmacology Burkholderia - chemistry Burkholderia - genetics Candida - drug effects Glycopeptides Microbial Sensitivity Tests Molecular Structure Multigene Family Nuclear Magnetic Resonance, Biomolecular Peptides, Cyclic - chemistry Peptides, Cyclic - isolation & purification Peptides, Cyclic - pharmacology Thiolester Hydrolases - genetics Thiolester Hydrolases - metabolism |
| title | The Presence of Two Cyclase Thioesterases Expands the Conformational Freedom of the Cyclic Peptide Occidiofungin |
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