Our specific aim is to develop strategies for introducing catalytic activity into the combining sites of immunoglobins. Because antibodies can be elicited against most biologically active macromolecules (proteins, nucleic acids and sugars) as well as small synthetic molecules, this approach may enable us to tailor- make semisynthetic molecules, this approach may enable us to tailor-make semisynthetic catalysts with enzyme-like specificities. We are purusing three strategies for introducing catalytic activity into antibody combining sites: (1) transition state stabilization by antibodies, (2) orientational catalysis by antibodies, and (3) site specific chemical modification of antibody binding sites with nucleophiles and cofactors. Antibodies will be elicited against tetrahedral phosphonates and planar bipyridyls as transition state analogues for hydrolysis of the corresponding esters and racemization of bridged-2,2'-bipyridyls, respectively. Antibodies will also be elicited against a cyclic seven-membered ring phosphonate as a transition state analogue for transesterification of an acyclic 6-hydroxy-ester. In addition, antibodies elicited to peptides and L-amino acids will be affinity labeled with thiols and pyridoxamine to afford catalysts for hydrolytic and transamination reactions, respectively. If successful, this work will be a first step in defining those elements necessary for the design and synthesis of catalytic antibodies with defined binding specificities.
| Romesberg, F E; Schultz, P G (1999) A mutational study of a Diels-Alderase catalytic antibody. Bioorg Med Chem Lett 9:1741-4 |
| Romesberg, F E; Santarsiero, B D; Spiller, B et al. (1998) Structural and kinetic evidence for strain in biological catalysis. Biochemistry 37:14404-9 |
| Pedersen, H; Holder, S; Sutherlin, D P et al. (1998) A method for directed evolution and functional cloning of enzymes. Proc Natl Acad Sci U S A 95:10523-8 |
| Hsieh-Wilson, L C; Schultz, P G; Stevens, R C (1996) Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution. Proc Natl Acad Sci U S A 93:5363-7 |
| Jacobsen, J R; Schultz, P G (1995) The scope of antibody catalysis. Curr Opin Struct Biol 5:818-24 |
| Jacobsen, J R; Schultz, P G (1994) Antibody catalysis of peptide bond formation. Proc Natl Acad Sci U S A 91:5888-92 |
| Lesley, S A; Patten, P A; Schultz, P G (1993) A genetic approach to the generation of antibodies with enhanced catalytic activities. Proc Natl Acad Sci U S A 90:1160-5 |
| Jacobsen, J R; Prudent, J R; Kochersperger, L et al. (1992) An efficient antibody-catalyzed aminoacylation reaction. Science 256:365-7 |
| Pollack, S J; Nakayama, G R; Schultz, P G (1988) Introduction of nucleophiles and spectroscopic probes into antibody combining sites. Science 242:1038-40 |
| Schultz, P G (1988) The interplay between chemistry and biology in the design of enzymatic catalysts. Science 240:426-33 |
