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

Monoclonal antibodies were generated against a 3-phenyl-1,2-benzisoxazole d erivative and shown to catalyze the solvent-sensitive decarboxylation of 3- carboxy-1,2-benzisoxazoles. In addition to rare accelerations up to 2300-fo ld over background, the antibodies exhibit distinctive selectivities for su bstrates bearing 5- or 6-NO2 substituents, with preferential decarboxylatio n of the less reactive substrate in one case. These effects are the likely consequence of substrate destabilization, achieved by forcing the carboxyla te group into a relatively apolar binding pocket and stabilization of the c harge-delocalized transition state through dispersive interactions. Compari son with a more active antibody decarboxylase previously raised against 2-a cetamido-naphthalene-1,5-disulfonate suggests, however, that a judicious mi x of polar and apolar interactions may ultimately be more effective for ach ieving high decarboxylase activity.