Catalysis of 3‐Carboxy‐1,2‐benzisoxazole Decarboxylation by Hydrophobic Antibody Binding Pockets

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‐acetamido‐naphthalene‐1,5‐disulfonate suggests, however, that a judicious mix of polar and apolar interactions may ultimately be more effective for achieving high decarboxylase activity.