title: A catalytic antibody against a tocopherol cyclase inhibitor.
abstract: The cyclic ammonium cation 5 and its guanidinium analogue 4 are inhibitors of tocopherol cyclase. Monoclonal antibodies were raised against protein conjugates of the haptens 1-3 and screened for catalytic reactions with alkene 8, a short chain analogue of the natural substrate phytyl-hydroquinone 6, and its enol ether analogues 10a,b. Antibody 16E7 raised against hapten 3 was found to catalyze the hydrolysis of Z enol ether 10a to form hemiacetal 12 with an apparent rate acceleration of k(cat)/k(uncat)=1400. Antibody 16E7 also catalyzed the elimination of Kemp's benzisoxazole 59. The absence of cyclization in the reaction of enol ether 10a was attributed to the competition of water molecules for the oxocarbonium cation intermediate within the antibody binding pocket. Hapten and reaction design features contributing to this outcome are discussed. Antibody 16E7 provides the first example of a carboxyl group acting both as an acid in an intrinsically acid-catalyzed process and as a base in an intrinsically base-catalyzed process, as expected from first principles. In contrast to the many examples of general-acid-catalyzed processes known to be catalyzed by catalytic antibodies, the specific-acid-catalyzed cyclization of phytyl-hydroquinone 6 or its analogue 8 still eludes antibody catalysis.
authors.affiliation: Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Martine T
authors.initials: MT
authors.lastname: Reymond
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Woggon
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D017151:Antibodies, Catalytic / Q000096:biosynthesis / Q000737:chemistry* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology; D002384:Catalysis; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D006241:Haptens / Q000737:chemistry / Q000276:immunology; D006433:Hemocyanins / Q000737:chemistry / Q000276:immunology; D006825:Hybridomas / Q000276:immunology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D013379:Substrate Specificity; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D017151:Antibodies, Catalytic; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D006241:Haptens; D006433:Hemocyanins; D019751:Intramolecular Transferases; C103397:tocopherol cyclase; C032808:keyhole-limpet hemocyanin