Monoclonal Anti-Idiotypic Antibodies as Functional Internal Images of Enzyme Active Sites: Production of a Catalytic Antibody with a Cholinesterase Activity
Monoclonal antibody 9A8 was selected by immunizing mice with AE-2, a monoclonal antibody directed against the active site of acetylcholinesterase. In accordance with the idiotypic network theory, monoclonal anti-idiotypic antibody 9A8 displayed internal-image properties of the original immunogen, th...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1993-10, Vol.90 (19), p.8876-8880 |
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description | Monoclonal antibody 9A8 was selected by immunizing mice with AE-2, a monoclonal antibody directed against the active site of acetylcholinesterase. In accordance with the idiotypic network theory, monoclonal anti-idiotypic antibody 9A8 displayed internal-image properties of the original immunogen, the acetylcholinesterase active site. Hydrolysis of acetylthiocholine and related esters of thiocholine by 9A8 follows saturation kinetics and kinetic parameters were determined. The hydrolytic activity is characterized by a lowered kcatvalue (81 s-1) and an increased Kmvalue (0.6 mM) when compared with the original enzyme. However, the rate acceleration (kcat/kuncat= 4.15 x 108) remains higher than for the esterase activities usually described for catalytic antibodies directed against transition-state analogs. The 9A8 activity exhibits a relaxation of specificity toward both substrates and inhibitors. This specificity does not correspond to a known enzymatic activity. The anti-idiotypic approach should be valuable for producing different structural and functional copies of the same enzyme active site. This should allow further insights into structure-activity relationships. Furthermore, use of chemically modified enzymes as immunogens may result in anti-idiotypic antibodies with catalytic activities not found in the native enzymes. |
doi_str_mv | 10.1073/pnas.90.19.8876 |
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H ; ROSETO, A ; THOMAS, D</creator><creatorcontrib>IZADYAR, L ; FRIBOULET, A ; REMY, M. H ; ROSETO, A ; THOMAS, D</creatorcontrib><description>Monoclonal antibody 9A8 was selected by immunizing mice with AE-2, a monoclonal antibody directed against the active site of acetylcholinesterase. In accordance with the idiotypic network theory, monoclonal anti-idiotypic antibody 9A8 displayed internal-image properties of the original immunogen, the acetylcholinesterase active site. Hydrolysis of acetylthiocholine and related esters of thiocholine by 9A8 follows saturation kinetics and kinetic parameters were determined. The hydrolytic activity is characterized by a lowered kcatvalue (81 s-1) and an increased Kmvalue (0.6 mM) when compared with the original enzyme. However, the rate acceleration (kcat/kuncat= 4.15 x 108) remains higher than for the esterase activities usually described for catalytic antibodies directed against transition-state analogs. The 9A8 activity exhibits a relaxation of specificity toward both substrates and inhibitors. This specificity does not correspond to a known enzymatic activity. The anti-idiotypic approach should be valuable for producing different structural and functional copies of the same enzyme active site. This should allow further insights into structure-activity relationships. Furthermore, use of chemically modified enzymes as immunogens may result in anti-idiotypic antibodies with catalytic activities not found in the native enzymes.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.90.19.8876</identifier><identifier>PMID: 8415624</identifier><identifier>CODEN: PNASA6</identifier><language>eng</language><publisher>Washington, DC: National Academy of Sciences of the United States of America</publisher><subject>Acetylcholinesterase - metabolism ; Active sites ; Animals ; Anti idiotypic antibodies ; Antibodies ; Antibodies, Anti-Idiotypic - isolation & purification ; Antibodies, Anti-Idiotypic - metabolism ; Antibodies, Monoclonal - isolation & purification ; Antibodies, Monoclonal - metabolism ; Antigens ; Binding Sites ; Biochemistry ; Biological and medical sciences ; Biotechnology ; Butyrylcholinesterase - metabolism ; Catalysis ; Catalytic activity ; Cholinesterase Inhibitors - pharmacology ; Cholinesterases - metabolism ; Clone Cells ; Enzyme engineering ; Enzymes ; Esters ; Fundamental and applied biological sciences. Psychology ; Hybridomas ; Hydrolysis ; Immune Sera - metabolism ; Immunity (Disease) ; Immunoglobulin Fab Fragments - isolation & purification ; Immunoglobulin Fab Fragments - metabolism ; Kinetics ; Medical research ; Methods. Procedures. Technologies ; Mice ; Miscellaneous ; Substrate Specificity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1993-10, Vol.90 (19), p.8876-8880</ispartof><rights>Copyright 1993 The National Academy of Sciences of the United States of America</rights><rights>1994 INIST-CNRS</rights><rights>Copyright National Academy of Sciences Oct 1, 1993</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4646-41240c180ffaa06ba34d8771bfd6440f41e285a1d651a601a70ef8937f217f843</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/90/19.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2363047$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2363047$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3785653$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8415624$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>IZADYAR, L</creatorcontrib><creatorcontrib>FRIBOULET, A</creatorcontrib><creatorcontrib>REMY, M. H</creatorcontrib><creatorcontrib>ROSETO, A</creatorcontrib><creatorcontrib>THOMAS, D</creatorcontrib><title>Monoclonal Anti-Idiotypic Antibodies as Functional Internal Images of Enzyme Active Sites: Production of a Catalytic Antibody with a Cholinesterase Activity</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Monoclonal antibody 9A8 was selected by immunizing mice with AE-2, a monoclonal antibody directed against the active site of acetylcholinesterase. In accordance with the idiotypic network theory, monoclonal anti-idiotypic antibody 9A8 displayed internal-image properties of the original immunogen, the acetylcholinesterase active site. Hydrolysis of acetylthiocholine and related esters of thiocholine by 9A8 follows saturation kinetics and kinetic parameters were determined. The hydrolytic activity is characterized by a lowered kcatvalue (81 s-1) and an increased Kmvalue (0.6 mM) when compared with the original enzyme. However, the rate acceleration (kcat/kuncat= 4.15 x 108) remains higher than for the esterase activities usually described for catalytic antibodies directed against transition-state analogs. The 9A8 activity exhibits a relaxation of specificity toward both substrates and inhibitors. This specificity does not correspond to a known enzymatic activity. The anti-idiotypic approach should be valuable for producing different structural and functional copies of the same enzyme active site. This should allow further insights into structure-activity relationships. Furthermore, use of chemically modified enzymes as immunogens may result in anti-idiotypic antibodies with catalytic activities not found in the native enzymes.</description><subject>Acetylcholinesterase - metabolism</subject><subject>Active sites</subject><subject>Animals</subject><subject>Anti idiotypic antibodies</subject><subject>Antibodies</subject><subject>Antibodies, Anti-Idiotypic - isolation & purification</subject><subject>Antibodies, Anti-Idiotypic - metabolism</subject><subject>Antibodies, Monoclonal - isolation & purification</subject><subject>Antibodies, Monoclonal - metabolism</subject><subject>Antigens</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Catalysis</subject><subject>Catalytic activity</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cholinesterases - metabolism</subject><subject>Clone Cells</subject><subject>Enzyme engineering</subject><subject>Enzymes</subject><subject>Esters</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hybridomas</subject><subject>Hydrolysis</subject><subject>Immune Sera - metabolism</subject><subject>Immunity (Disease)</subject><subject>Immunoglobulin Fab Fragments - isolation & purification</subject><subject>Immunoglobulin Fab Fragments - metabolism</subject><subject>Kinetics</subject><subject>Medical research</subject><subject>Methods. Procedures. 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H ; ROSETO, A ; THOMAS, D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4646-41240c180ffaa06ba34d8771bfd6440f41e285a1d651a601a70ef8937f217f843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Active sites</topic><topic>Animals</topic><topic>Anti idiotypic antibodies</topic><topic>Antibodies</topic><topic>Antibodies, Anti-Idiotypic - isolation & purification</topic><topic>Antibodies, Anti-Idiotypic - metabolism</topic><topic>Antibodies, Monoclonal - isolation & purification</topic><topic>Antibodies, Monoclonal - metabolism</topic><topic>Antigens</topic><topic>Binding Sites</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Butyrylcholinesterase - metabolism</topic><topic>Catalysis</topic><topic>Catalytic activity</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cholinesterases - metabolism</topic><topic>Clone Cells</topic><topic>Enzyme engineering</topic><topic>Enzymes</topic><topic>Esters</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hybridomas</topic><topic>Hydrolysis</topic><topic>Immune Sera - metabolism</topic><topic>Immunity (Disease)</topic><topic>Immunoglobulin Fab Fragments - isolation & purification</topic><topic>Immunoglobulin Fab Fragments - metabolism</topic><topic>Kinetics</topic><topic>Medical research</topic><topic>Methods. Procedures. Technologies</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>IZADYAR, L</creatorcontrib><creatorcontrib>FRIBOULET, A</creatorcontrib><creatorcontrib>REMY, M. 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H</au><au>ROSETO, A</au><au>THOMAS, D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Monoclonal Anti-Idiotypic Antibodies as Functional Internal Images of Enzyme Active Sites: Production of a Catalytic Antibody with a Cholinesterase Activity</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1993-10-01</date><risdate>1993</risdate><volume>90</volume><issue>19</issue><spage>8876</spage><epage>8880</epage><pages>8876-8880</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><coden>PNASA6</coden><abstract>Monoclonal antibody 9A8 was selected by immunizing mice with AE-2, a monoclonal antibody directed against the active site of acetylcholinesterase. In accordance with the idiotypic network theory, monoclonal anti-idiotypic antibody 9A8 displayed internal-image properties of the original immunogen, the acetylcholinesterase active site. Hydrolysis of acetylthiocholine and related esters of thiocholine by 9A8 follows saturation kinetics and kinetic parameters were determined. The hydrolytic activity is characterized by a lowered kcatvalue (81 s-1) and an increased Kmvalue (0.6 mM) when compared with the original enzyme. However, the rate acceleration (kcat/kuncat= 4.15 x 108) remains higher than for the esterase activities usually described for catalytic antibodies directed against transition-state analogs. The 9A8 activity exhibits a relaxation of specificity toward both substrates and inhibitors. This specificity does not correspond to a known enzymatic activity. The anti-idiotypic approach should be valuable for producing different structural and functional copies of the same enzyme active site. This should allow further insights into structure-activity relationships. Furthermore, use of chemically modified enzymes as immunogens may result in anti-idiotypic antibodies with catalytic activities not found in the native enzymes.</abstract><cop>Washington, DC</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>8415624</pmid><doi>10.1073/pnas.90.19.8876</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acetylcholinesterase - metabolism Active sites Animals Anti idiotypic antibodies Antibodies Antibodies, Anti-Idiotypic - isolation & purification Antibodies, Anti-Idiotypic - metabolism Antibodies, Monoclonal - isolation & purification Antibodies, Monoclonal - metabolism Antigens Binding Sites Biochemistry Biological and medical sciences Biotechnology Butyrylcholinesterase - metabolism Catalysis Catalytic activity Cholinesterase Inhibitors - pharmacology Cholinesterases - metabolism Clone Cells Enzyme engineering Enzymes Esters Fundamental and applied biological sciences. Psychology Hybridomas Hydrolysis Immune Sera - metabolism Immunity (Disease) Immunoglobulin Fab Fragments - isolation & purification Immunoglobulin Fab Fragments - metabolism Kinetics Medical research Methods. Procedures. Technologies Mice Miscellaneous Substrate Specificity |
title | Monoclonal Anti-Idiotypic Antibodies as Functional Internal Images of Enzyme Active Sites: Production of a Catalytic Antibody with a Cholinesterase Activity |
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