Skip to main content
SpringerLink
Log in

Transition-state stabilization as a measure of the efficiency of antibody catalysis

  • Letter
  • Published:

From Nature

View current issue Submit your manuscript

Abstract

THERE are now about 60 examples of reactions that have been successfully catalysed by monoclonal antibodies1–3. Not surprisingly, many of the early examples involved reactions that were already favoured kinetically (such as carbonate and ester hydrolysis). But it has since been shown that antibodies can also accelerate reaction pathways that are normally disfavoured kinetically (by at least a few kcal mol–1)4–7. Here we use transition-state theory to provide a quantitative analysis of the scope and limitations of antibody catalysis. We show that the observed rate accelerations can be predicted from the ratio of equilibrium binding constants of the reaction substrate and the transition-state analogue used to raise the antibody. This scheme allows us to rationalize the product selectivity displayed in antibody catalysis of disfavoured reactions, to predict the degree of rate acceleration that catalytic antibodies may ultimately afford, and to highlight some differences between the way that they and enzymes catalyse reactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Stewart, J. D., Liotta, L. J. & Benkovic, S. J. Acc. Chem. Res. 26, 396–404 (1993).

    Article  CAS  Google Scholar 

  2. Stewart, J. D. & Benkovic, S. J. Chem. Soc. Rev. 22, 213–219 (1993).

    Article  CAS  Google Scholar 

  3. Lerner, R. A., Benkovic, S. J. & Schultz, P. G. Science 252, 659–667 (1991).

    Article  ADS  CAS  Google Scholar 

  4. Li, T., Janda, K. D., Ashley, J. A. & Lerner, R. A. Science 264, 1289–1293 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Cravatt, B. F., Ashley, J. A., Janda, K. D., Boger, D. L. & Lerner, R. A. J. Am. chem. Soc. 116, 6013–6014 (1994).

    Article  CAS  Google Scholar 

  6. Na, J., Houk, K. N., Shevlin, C. G., Janda, K. D. & Lerner, R. A. J. Am. chem. Soc. 115, 8453–8454 (1993).

    Article  CAS  Google Scholar 

  7. Gouverneur, V. E. et al. Science 262, 204–208 (1993).

    Article  ADS  CAS  Google Scholar 

  8. Wolfenden, R. A. Rev. Biophys. Bioengng 5, 271–306 (1976).

    Article  CAS  Google Scholar 

  9. Benkovic, S. J., Napper, A. D. & Lerner, R. A. Proc. natn. Acad. Sci. U.S.A. 85, 5355–5358 (1988).

    Article  ADS  CAS  Google Scholar 

  10. Jacobs, J. W. Bio/Technology 9, 258–262 (1991).

    CAS  PubMed  Google Scholar 

  11. Jackson, D. Y., Prudent, J. R., Baldwin, E. P. & Schultz, P. G. Proc. natn. Acad. Sci. U.S.A. 88, 58–62 (1991).

    Article  ADS  CAS  Google Scholar 

  12. Stewart, J. D., Roberts, V. A., Thomas, N., Getzoff, E. D. & Benkovic, S. J. Biochemistry 33, 1991–2003 (1994).

    Article  Google Scholar 

  13. Posner, B., Smiley, J., Lee, I. & Benkovic, S. Trends biochem. Sci. 19, 145–150 (1994).

    Article  CAS  Google Scholar 

  14. Stewart, J. D. et al. Proc. natn. Acad. Sci. U.S.A. 91, 7404–7409 (1994).

    Article  ADS  CAS  Google Scholar 

  15. Hirschmann, R. et al. Science 265, 234–237 (1994).

    Article  ADS  CAS  Google Scholar 

  16. Radzicka, A. & Wolfenden, R. Science 267, 90–93 (1995).

    Article  ADS  CAS  Google Scholar 

  17. Rini, J. M., Schulze-Gahmen, U. & Wilson, I. A. Science 255, 959–965 (1992).

    Article  ADS  CAS  Google Scholar 

  18. Benkovic, S. J., Adams, J. A., Borders, C. L. Jr, Janda, K. D. & Lerner, R. A. Science 250, 1135–1139 (1990).

    Article  ADS  CAS  Google Scholar 

  19. Tramontano, A., Janda, K. D. & Lerner, R. A. Science 234, 1566–1570 (1986).

    Article  ADS  CAS  Google Scholar 

  20. Hilvert, D., Carpenter, S. H., Nared, K. D. & Auditor, M.-T. M. Proc. natn. Acad. Sci. U.S.A. 85, 4953–4955 (1988).

    Article  ADS  CAS  Google Scholar 

  21. Jacobs, J., Schultz, P. G., Sugasawara, R. & Powell, M. J. Am. chem. Soc. 109, 2174–2176 (1987).

    Article  CAS  Google Scholar 

  22. Cochran, A. G. & Schultz, P. G. Science 240, 781–783 (1990).

    Article  ADS  Google Scholar 

  23. Janda, K. D., Benkovic, S. J. & McLeod, D. A. Tetrahedron 47, 2503–2506 (1991).

    Article  CAS  Google Scholar 

  24. Iwabuchi, Y. et al. J. Am. chem. Soc. 116, 771–772 (1994).

    Article  CAS  Google Scholar 

  25. Reymond, J.-L., Janda, K. D. & Lerner, R. A. Angew. Chem. int. Edn. engl. 30, 1711–1713 (1991).

    Article  Google Scholar 

  26. Pollack, S. J., Jacobs, J. W. & Schultz, P. G. Science 234, 1570–1573 (1986).

    Article  ADS  CAS  Google Scholar 

  27. Napper, A. D., Benkovic, S. J., Tramontano, A. & Lerner, R. A. Science 237, 1041–1043 (1987).

    Article  ADS  CAS  Google Scholar 

  28. Campbell, D. A. et al. J. Am. chem. Soc. 116, 2165–2166 (1994).

    Article  CAS  Google Scholar 

  29. Iverson, B. L., Cameron, K. E., Jahangiri, G. K. & Pasternak, D. S. J. Am. chem. Soc. 112, 5320–5323 (1990).

    Article  CAS  Google Scholar 

  30. Shokat, K. M., Leumann, C. J., Sugasawara, R. & Schultz, P. G. Nature 338, 269–271 (1989).

    Article  ADS  CAS  Google Scholar 

  31. Janda, K. D., Benkovic, S. J. & Lerner, R. A. Science 244, 437–440 (1989).

    Article  ADS  CAS  Google Scholar 

  32. Tramontano, A., Ammann, A. A. & Lerner, R. A. J. Am. chem. Soc. 110, 2282–2286 (1988).

    Article  CAS  Google Scholar 

  33. Gibbs, R. A., Benkovic, P. A., Janda, K. D., Lerner, R. A. & Benkovic, S. J. J. Am. chem. Soc. 114, 3528–3534 (1992).

    Article  CAS  Google Scholar 

  34. Martin, M. T., Napper, A. D., Schultz, P. G. & Rees, A. G. Biochemistry 30, 9757–9761 (1991).

    Article  CAS  Google Scholar 

  35. Lewis, C., Krämer, T., Robinson, S. & Hilvert, D. Science 253, 1019–1022 (1991).

    Article  ADS  CAS  Google Scholar 

  36. Ashley, J. A., Lo, C.-H. L., McElhaney, G. P., Wirsching, P. & Janda, K. D. J. Am. chem. Soc. 115, 2515–2516 (1993).

    Article  CAS  Google Scholar 

  37. Jacobsen, J. R., Prudent, J. R., Kochersperger, L., Yonkovich, S. & Schultz, P. G. Science 256, 365–367 (1992).

    Article  ADS  CAS  Google Scholar 

  38. Jacobsen, J. R. & Schultz, P. G. Proc. natn. Acad. Sci. U.S.A. 91, 5888–5892 (1994).

    Article  ADS  CAS  Google Scholar 

  39. Cochran, A. G., Pham, T., Sugasawara, R. & Schultz, P. G. J. Am. chem. Soc. 113, 6670–6672 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Florida, Gainesville, Florida, 32611, USA

    Jon D. Stewart

  2. Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, 16801, USA

    Stephen J. Benkovic

Authors
  1. Jon D. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen J. Benkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, J., Benkovic, S. Transition-state stabilization as a measure of the efficiency of antibody catalysis. Nature 375, 388–391 (1995). https://doi.org/10.1038/375388a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/375388a0

  • Springer Nature Limited

This article is cited by

Search

Navigation