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
Hauptverfasser: IZADYAR, L, FRIBOULET, A, REMY, M. H, ROSETO, A, THOMAS, D
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container_end_page 8880
container_issue 19
container_start_page 8876
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 90
creator IZADYAR, L
FRIBOULET, A
REMY, M. H
ROSETO, A
THOMAS, D
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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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. 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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. 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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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