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Science 8 October 1993:
Vol. 262. no. 5131, pp. 204 - 208
DOI: 10.1126/science.8211138
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Articles

Science, Vol 262, Issue 5131, 204-208
Copyright © 1993 by American Association for the Advancement of Science

articles

Control of the exo and endo pathways of the Diels-Alder reaction by antibody catalysis

VE Gouverneur, KN Houk, B de Pascual-Teresa, B Beno, KD Janda, and RA Lerner

Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037.

Catalytic antibodies that control the reaction pathways of the Diels-Alder cycloaddition have been generated. One antibody catalyzes the favored endo and the other the disfavored exo pathway to yield the respective cis and trans adducts in enantiomerically pure form. A comparison of the x-ray structure of the hapten with the calculated geometry of the transition structure showed that [2.2.2] bicyclic compounds are excellent mimics of the transition state of the Diels-Alder reaction. To achieve catalysis and the high degree of stereoselectivity shown here, the antibody must simultaneously control the conformation of the individual reactants and their relation to each other. In the case of the disfavored process, binding energy must be used to reroute the reaction along a higher energy pathway. The rerouting of reaction pathways has become a major focus of antibody catalysis and other disfavored reactions can be expected to be catalyzed so long as the energy barrier is not extreme. The energy requirements needed for absolute control of all of the stereoisomers of many Diels-Alder reactions fall in the energy range (approximately 20 kilocalories per mole) deliverable by antibody binding.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A structural basis for the activity of retro-Diels-Alder catalytic antibodies: Evidence for a catalytic aromatic residue.
M. Hugot, N. Bensel, M. Vogel, M. T. Reymond, B. Stadler, J.-L. Reymond, and U. Baumann (2002)
PNAS 99, 9674-9678
   Abstract »    Full Text »    PDF »
Immunological Origins of Binding and Catalysis in a Diels-Alderase Antibody.
F. E. Romesberg, B. Spiller, P. G. Schultz, and R. C. Stevens (1998)
Science 279, 1929-1933
   Abstract »    Full Text »
An Antibody exo Diels-Alderase Inhibitor Complex at 1.95 Angstrom Resolution.
A. Heine, E. A. Stura, J. T. Yli-Kauhaluoma, C. Gao, Q. Deng, B. R. Beno, K. N. Houk, K. D. Janda, and I. A. Wilson (1998)
Science 279, 1934-1940
   Abstract »    Full Text »
Efficient Aldolase Catalytic Antibodies That Use the Enamine Mechanism of Natural Enzymes.
Jür. Wagner, R. A. Lerner, and C. F. Barbas III (1995)
Science 270, 1797-1800
   Abstract »    PDF »
From molecular diversity to catalysis: lessons from the immune system.
P. Schultz and R. Lerner (1995)
Science 269, 1835-1842
   Abstract »    PDF »


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