Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain
The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Wa...
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| Veröffentlicht in: | Journal of biochemical and molecular toxicology 2002, Vol.16 (2), p.64-69 |
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| container_title | Journal of biochemical and molecular toxicology |
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| creator | Gavuzzo, Enrico Pomponi, Massimo |
| description | The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67–Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the “back door” hypothesis involving facilitated opening for faster product clearance. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:64–69, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10026 |
| doi_str_mv | 10.1002/jbt.10026 |
| format | Article |
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The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67–Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the “back door” hypothesis involving facilitated opening for faster product clearance. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:64–69, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10026</description><identifier>ISSN: 1095-6670</identifier><identifier>EISSN: 1099-0461</identifier><identifier>DOI: 10.1002/jbt.10026</identifier><identifier>PMID: 11979423</identifier><language>eng</language><publisher>New York: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Acetylcholinesterase - metabolism ; Animals ; Cholinesterase Inhibitors - chemical synthesis ; Cholinesterase Inhibitors - chemistry ; Cholinesterase Inhibitors - pharmacology ; Cysteine Loop (Cys67-Cys94) ; Electrophorus ; Inhibition of AChE ; Models, Molecular ; Physostigmine - analogs & derivatives ; Physostigmine - chemical synthesis ; Physostigmine - chemistry ; Physostigmine - pharmacology ; Steric Effects ; Structure-Activity Relationship</subject><ispartof>Journal of biochemical and molecular toxicology, 2002, Vol.16 (2), p.64-69</ispartof><rights>Copyright © 2002 Wiley Periodicals, Inc.</rights><rights>Copyright 2002 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3596-c3749e07829153e64f78523beeefda3e6c502ea1d79fd5149e6c17a7433c40653</citedby><cites>FETCH-LOGICAL-c3596-c3749e07829153e64f78523beeefda3e6c502ea1d79fd5149e6c17a7433c40653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjbt.10026$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjbt.10026$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,4010,27900,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11979423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gavuzzo, Enrico</creatorcontrib><creatorcontrib>Pomponi, Massimo</creatorcontrib><title>Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain</title><title>Journal of biochemical and molecular toxicology</title><addtitle>J. Biochem. Mol. Toxicol</addtitle><description>The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67–Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the “back door” hypothesis involving facilitated opening for faster product clearance. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:64–69, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10026</description><subject>Acetylcholinesterase - metabolism</subject><subject>Animals</subject><subject>Cholinesterase Inhibitors - chemical synthesis</subject><subject>Cholinesterase Inhibitors - chemistry</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cysteine Loop (Cys67-Cys94)</subject><subject>Electrophorus</subject><subject>Inhibition of AChE</subject><subject>Models, Molecular</subject><subject>Physostigmine - analogs & derivatives</subject><subject>Physostigmine - chemical synthesis</subject><subject>Physostigmine - chemistry</subject><subject>Physostigmine - pharmacology</subject><subject>Steric Effects</subject><subject>Structure-Activity Relationship</subject><issn>1095-6670</issn><issn>1099-0461</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM9u1DAYxC1ERUvhwAsgn5A4hNpxbNfcYAX9owKXIo6W43xu3DrxNvYK8hi8Mc7ulp56sUej34z0DUJvKPlACalPbtu8FeIZOqJEqYo0gj7fal4JIckhepnSLSGEK8lfoENKlVRNzY7Q34ux963PPo44Omws5DnYPgY_QsowmQS4nfG6n1NM2d8MxcdmNCHepI94FUcXp8EscRPwEFsffJ6XJjuX-AKHGNe42wDOEece8NLqLQbnwOaFXEwT7uaAbW_8-AodOBMSvN7_x-jn1y_Xq_Pq6sfZxerTVWUZV6K8slFA5GmtKGcgGidPec1aAHCdKYblpAZDO6lcx2lhhaXSyIYx2xDB2TF6t-tdT_F-U47Vg08WQjAjxE3SksqSUqqA73egnWJKEzi9nvxgpllTopfZddl_K0Rh3-5LN-0A3SO5H7wAJzvgtw8wP92kLz9fP1RWu4Qvy_35nzDTnRaSSa5_fT_TSpx_qy9ZrSX7B006oPU</recordid><startdate>2002</startdate><enddate>2002</enddate><creator>Gavuzzo, Enrico</creator><creator>Pomponi, Massimo</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><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>7X8</scope></search><sort><creationdate>2002</creationdate><title>Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain</title><author>Gavuzzo, Enrico ; Pomponi, Massimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3596-c3749e07829153e64f78523beeefda3e6c502ea1d79fd5149e6c17a7433c40653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Animals</topic><topic>Cholinesterase Inhibitors - chemical synthesis</topic><topic>Cholinesterase Inhibitors - chemistry</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cysteine Loop (Cys67-Cys94)</topic><topic>Electrophorus</topic><topic>Inhibition of AChE</topic><topic>Models, Molecular</topic><topic>Physostigmine - analogs & derivatives</topic><topic>Physostigmine - chemical synthesis</topic><topic>Physostigmine - chemistry</topic><topic>Physostigmine - pharmacology</topic><topic>Steric Effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gavuzzo, Enrico</creatorcontrib><creatorcontrib>Pomponi, Massimo</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biochemical and molecular toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gavuzzo, Enrico</au><au>Pomponi, Massimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain</atitle><jtitle>Journal of biochemical and molecular toxicology</jtitle><addtitle>J. Biochem. Mol. Toxicol</addtitle><date>2002</date><risdate>2002</risdate><volume>16</volume><issue>2</issue><spage>64</spage><epage>69</epage><pages>64-69</pages><issn>1095-6670</issn><eissn>1099-0461</eissn><abstract>The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67–Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the “back door” hypothesis involving facilitated opening for faster product clearance. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:64–69, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10026</abstract><cop>New York</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>11979423</pmid><doi>10.1002/jbt.10026</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of biochemical and molecular toxicology, 2002, Vol.16 (2), p.64-69 |
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| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Acetylcholinesterase - metabolism Animals Cholinesterase Inhibitors - chemical synthesis Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacology Cysteine Loop (Cys67-Cys94) Electrophorus Inhibition of AChE Models, Molecular Physostigmine - analogs & derivatives Physostigmine - chemical synthesis Physostigmine - chemistry Physostigmine - pharmacology Steric Effects Structure-Activity Relationship |
| title | Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain |
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