title: [Catalytic antibodies: generation of a new class of protein catalysts exploiting the immune system].
abstract: Since the diversity of the immune response permits antibodies to be generated against virtually any substance, catalytic antibodies have the potential to provide catalysts for many chemical transformations. Such catalysts could be tailored by immunization with rationally designed transition state analogs, which is the main attraction of the catalytic antibody research field. However, when mice are immunized with a hapten conjugated to a carrier protein, a few, and occasionally several, of the dozens of antibodies that bind the hapten are characterized as catalytic. The diversity of the immune response can provide a panel of catalytic antibodies that possess varying degrees of catalytic activity and substrate specificity. These results have raised the following fundamental questions: how different are catalytic antibodies which were generated by immunization with a single hapten on a structural or mechanistic basis? We want to study the correlation between the antigen combining site structures and the chemical properties within a panel of catalytic antibodies elicited against a single hapten, which can potentially provide a more global understanding of the molecular mechanisms by which catalytic antibodies are generated in immune responses. We have demonstrated prodrug activation via catalytic antibodies that catalyze the hydrolysis of the nonbioactive chloramphenicol monoester derivative (1) to generate chloramphenicol (2). Immunization with a KLH conjugate of the transition state analog (3), designed on the basis of the transition state stabilization concept, yielded twelve immunoglobulin G (Ig G) proteins binding to 3, six of which were found to catalyze the hydrolysis with varying degrees of activity. This antibody system seems to be a suitable model for studies of the diversity of catalytic antibodies. Therefore, we have examined the biochemical and structural properties of these catalytic and non-catalytic antibodies, to enhance our understanding of the active site structure and function relationship assignments.
authors.affiliation: Biomolecular Engineering Research Institute (Protein Engineering Research Institute, Osaka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D000916:Antibody Diversity; D002241:Carbohydrates; D002352:Carrier Proteins; D002384:Catalysis; D004952:Esters; D006241:Haptens / Q000276:immunology; D006868:Hydrolysis; D007107:Immune System; D051379:Mice; D008969:Molecular Sequence Data; D011355:Prodrugs; D013379:Substrate Specificity
chemical_list: D000906:Antibodies; D002241:Carbohydrates; D002352:Carrier Proteins; D004952:Esters; D006241:Haptens; D011355:Prodrugs