The rational design of enzyme-like catalysts is an important long range goal. This proposal explores the possibility of using antibodies, which are exquisite receptor molecules, to catalyze chemical reactions. Our strategy involved synthesis of compounds which mimic the transition state structure of a particular reaction, eliciting immune responses against such substances, and characterization of the specific antibodies generated. Two reactions will be examined: the unimolecular Claisen rearrangement of chorismate to prephenate and the bimolecular Diels-Alder process. These reactions are good to model, since they do not require nucleophilic or general acid-base catalysis but should be susceptible to induced strain and proximity effects. The latter mechanisms of catalysis are what distinguish enzymes from most chemical catalysts. It is important to understand how enzymes work, and antibodies that mediate the Claisen and Diels-Alder reactions would be useful tools for investigating how enzymes utilize binding energy to achieve enormous rate enhancements and remarkable regio- and stereoselectivity. Furthermore, the Claisen and Diels-Alder reactions are among the most valuable synthetic reactions available to organic chemists for preparation of important health-related natural products. The ability to catalyze these processes with the high rates and selectivities typical of enzymes would therefore represent a significant scientific advance. We expect, finally, that the knowledge gained in this project will lead to the elaboration of general strategies for design of artificial enzymes for any chemical reaction, capitalizing on the virtually limitless supply of highly specific antibody binding sites.
| Debler, Erik W; Müller, Roger; Hilvert, Donald et al. (2009) An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket. Proc Natl Acad Sci U S A 106:18539-44 |
