Catalysis of 3-carboxy-1,2-benzisoxazole decarboxylation by hydrophobic antibody binding pockets

Abstract

Monoclonal antibodies were generated against a 3-phenyl-1,2-benzisoxazole derivative and shown to catalyze the solvent-sensitive decarboxylation of 3-carboxy-1,2-benzisoxazoles. In addition to rate accelerations up to 2300-fold over background, the antibodies exhibit distinctive selectivities for substrates bearing 5- or 6-NO2 substituents, with preferential decarboxylation of the less reactive substrate in one case. These effects are the likely consequence of substrate destabilization, achieved by forcing the carboxylate group into a relatively apolar binding pocket and stabilization of the charge-delocalized transition state through dispersive interactions. Comparison with a more active antibody decarboxylase previously raised against 2-acetamidonaphthalene-1,5-disulfonate suggests, however, that a judicious mix of polar and apolar interactions may ultimately be more effective for achieving high decarboxylase activity.