Antibody catalysis of carbon-carbon bond formation.

Abstract

We have used rationally designed transition state analogues to generate antibodies that catalyse two important carbon-carbon bond forming reactions: a bimolecular Diels-Alder cycloaddition and a unimolecular Claisen rearrangement. Our tailored immunoglobulin catalysts (abzymes) exhibit all the properties of naturally occurring enzymes, including substantial rate accelerations, substrate specificity, and high regio- and stereoselectivity. As first generation abzymes are generally inferior to naturally occurring enzymes, we are also employing classical genetic selection strategies to augment their chemical efficiency. We have expressed the antibody that catalyses the Claisen rearrangement of chorismate in yeast cells that lack natural chorismate mutase activity. Improved versions of the abzyme will be identified, following random mutagenesis, by their ability to repair this metabolic defect. The development and study of highly efficient catalytic antibodies promises to advance our understanding of how enzymes work and evolve, how protein function correlates with structure, and how entirely new enzymic activities can be created for use in research, industry and medicine.