Computational Redesign of Human Butyrylcholinesterase for Anticocaine Medication
Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocain...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (46), p.16656-16661 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Yongmei Pan Daquan Gao Wenchao Yang Hoon Cho Guangfu Yang Tai, Hsin-Hsiung Chang-Guo Zhan |
| description | Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an ≈(456 ± 41)-fold improved catalytic efficiency of A199S/S287G/A328W/Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transition-state simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery. |
| doi_str_mv | 10.1073/pnas.0507332102 |
| format | Article |
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The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an ≈(456 ± 41)-fold improved catalytic efficiency of A199S/S287G/A328W/Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transition-state simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0507332102</identifier><identifier>PMID: 16275916</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Atoms ; Biological Sciences ; Butyrylcholinesterase - chemistry ; Butyrylcholinesterase - genetics ; Butyrylcholinesterase - metabolism ; Catalysis ; Chemical reactions ; Cocaine ; Cocaine - antagonists & inhibitors ; Cocaine - metabolism ; Cocaine-Related Disorders - drug therapy ; Covalent bonds ; DNA ; Drug Design ; Enzymes ; Esters ; Humans ; Hydrogen ; Hydrogen Bonding ; Hydrogen bonds ; Hydrolysis ; Mutagenesis, Site-Directed ; Mutation ; Oxygen</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-11, Vol.102 (46), p.16656-16661</ispartof><rights>Copyright 2005 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Nov 15, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-a648e578feab20d617695951f6306db7623604c7a62873d37936558972a122483</citedby><cites>FETCH-LOGICAL-c529t-a648e578feab20d617695951f6306db7623604c7a62873d37936558972a122483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/46.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/4152276$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/4152276$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16275916$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yongmei Pan</creatorcontrib><creatorcontrib>Daquan Gao</creatorcontrib><creatorcontrib>Wenchao Yang</creatorcontrib><creatorcontrib>Hoon Cho</creatorcontrib><creatorcontrib>Guangfu Yang</creatorcontrib><creatorcontrib>Tai, Hsin-Hsiung</creatorcontrib><creatorcontrib>Chang-Guo Zhan</creatorcontrib><title>Computational Redesign of Human Butyrylcholinesterase for Anticocaine Medication</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an ≈(456 ± 41)-fold improved catalytic efficiency of A199S/S287G/A328W/Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transition-state simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.</description><subject>Atoms</subject><subject>Biological Sciences</subject><subject>Butyrylcholinesterase - chemistry</subject><subject>Butyrylcholinesterase - genetics</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Catalysis</subject><subject>Chemical reactions</subject><subject>Cocaine</subject><subject>Cocaine - antagonists & inhibitors</subject><subject>Cocaine - metabolism</subject><subject>Cocaine-Related Disorders - drug therapy</subject><subject>Covalent bonds</subject><subject>DNA</subject><subject>Drug Design</subject><subject>Enzymes</subject><subject>Esters</subject><subject>Humans</subject><subject>Hydrogen</subject><subject>Hydrogen Bonding</subject><subject>Hydrogen bonds</subject><subject>Hydrolysis</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation</subject><subject>Oxygen</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9rFDEUB_Agit1Wz15EBg8FD9MmL78vQl3UChVF9ByyM5l2lkyyJhlx_3uz7tJVL54Sks_7kpeH0DOCLwiW9HITbL7AvG4pEAwP0IJgTVrBNH6IFhiDbBUDdoJOc15jjDVX-DE6IQIk10Qs0OdlnDZzsWWMwfrmi-tdHm9DE4fmep5saN7MZZu2vruLfgwuF5dsds0QU3MVytjFztbj5qPrx-53yBP0aLA-u6eH9Qx9e_f26_K6vfn0_sPy6qbtOOjSWsGU41INzq4A94JIobnmZBAUi34lBVCBWSetACVpT6WmgnOlJVgCwBQ9Q6_3uZt5Nbm-c6Ek680mjZNNWxPtaP6-CeOduY0_DAFFFcgacH4ISPH7XDsz05g7570NLs7ZEM0EYZpX-PIfuI5zqr-VDWBChVCgK7rcoy7FnJMb7l9CsNmNyuxGZY6jqhUv_mzg6A-zqaA5gF3lMQ4ME1UJviOv_kPMMHtf3M9S7fO9XecS0z1mhANIQX8B-K2xPw</recordid><startdate>20051115</startdate><enddate>20051115</enddate><creator>Yongmei Pan</creator><creator>Daquan Gao</creator><creator>Wenchao Yang</creator><creator>Hoon Cho</creator><creator>Guangfu Yang</creator><creator>Tai, Hsin-Hsiung</creator><creator>Chang-Guo Zhan</creator><general>National Academy of Sciences</general><general>National Acad 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>20051115</creationdate><title>Computational Redesign of Human Butyrylcholinesterase for Anticocaine Medication</title><author>Yongmei Pan ; Daquan Gao ; Wenchao Yang ; Hoon Cho ; Guangfu Yang ; Tai, Hsin-Hsiung ; Chang-Guo Zhan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-a648e578feab20d617695951f6306db7623604c7a62873d37936558972a122483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Atoms</topic><topic>Biological Sciences</topic><topic>Butyrylcholinesterase - chemistry</topic><topic>Butyrylcholinesterase - genetics</topic><topic>Butyrylcholinesterase - metabolism</topic><topic>Catalysis</topic><topic>Chemical reactions</topic><topic>Cocaine</topic><topic>Cocaine - antagonists & inhibitors</topic><topic>Cocaine - metabolism</topic><topic>Cocaine-Related Disorders - drug therapy</topic><topic>Covalent bonds</topic><topic>DNA</topic><topic>Drug Design</topic><topic>Enzymes</topic><topic>Esters</topic><topic>Humans</topic><topic>Hydrogen</topic><topic>Hydrogen Bonding</topic><topic>Hydrogen bonds</topic><topic>Hydrolysis</topic><topic>Mutagenesis, Site-Directed</topic><topic>Mutation</topic><topic>Oxygen</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yongmei Pan</creatorcontrib><creatorcontrib>Daquan Gao</creatorcontrib><creatorcontrib>Wenchao Yang</creatorcontrib><creatorcontrib>Hoon Cho</creatorcontrib><creatorcontrib>Guangfu Yang</creatorcontrib><creatorcontrib>Tai, Hsin-Hsiung</creatorcontrib><creatorcontrib>Chang-Guo Zhan</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>Yongmei Pan</au><au>Daquan Gao</au><au>Wenchao Yang</au><au>Hoon Cho</au><au>Guangfu Yang</au><au>Tai, Hsin-Hsiung</au><au>Chang-Guo Zhan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Computational Redesign of Human Butyrylcholinesterase for Anticocaine Medication</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2005-11-15</date><risdate>2005</risdate><volume>102</volume><issue>46</issue><spage>16656</spage><epage>16661</epage><pages>16656-16661</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. 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The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>16275916</pmid><doi>10.1073/pnas.0507332102</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Atoms Biological Sciences Butyrylcholinesterase - chemistry Butyrylcholinesterase - genetics Butyrylcholinesterase - metabolism Catalysis Chemical reactions Cocaine Cocaine - antagonists & inhibitors Cocaine - metabolism Cocaine-Related Disorders - drug therapy Covalent bonds DNA Drug Design Enzymes Esters Humans Hydrogen Hydrogen Bonding Hydrogen bonds Hydrolysis Mutagenesis, Site-Directed Mutation Oxygen |
| title | Computational Redesign of Human Butyrylcholinesterase for Anticocaine Medication |
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