Antibody Catalysis by Transition State Stabilization

Abstract

A key element in the evolution of enzymatic catalysts is the development of selective ligand-binding sites. The immune system is capable of producing antibodies, which, like enzymes, bind both macromolecules and small synthetic molecules with high specificities and high affinities (Landsteiner 1944; Pressman and Grossberg 1968; Nisonoff et al. 1975). Immunoglobulin combining sites, although lacking the ability to catalyze selective chemical transformations can, unlike enzymes, be rapidly and selectively generated against virtually any molecule of interest (Goding 1986). Consequently, the development of strategies for introducing catalytic activity into the combining sites of antibodies may enable us to generate rationally enzyme-like catalysts with tailored specificities and catalytic properties. We are currently exploring three such strategies: (1) generation of antibodies that selectively stabilize the rate-limiting transition state on a reaction pathway, (2) generation of antibodies that bind and orient substrates in a reactive conformation for intra- or intermolecular reactions, and (3) selective...