Analysis of Structure-Activity Relationships of the Bowman-Birk Inhibitor of Serine Proteinases

Toward a Rational Design of New Cancer Chemopreventive Agents
  • Peter Flecker


Proteinase inhibitors are a class of the various dietary inhibitors of mutagenesis and carcinogenesis (Hayatsu et al., 1988). Schelp and Pongpaew (1988) have recently hypothesized that protection against cancer may result from an increase of endogenous proteinase inhibitors such as α2-macroglobulin induced by diets that are low in calories and fat. The Bowman-Birk inhibitor (BBI) of serine proteinases, a double-headed polypeptide-inhibitor of trypsin and chymotrypsin, is one of the most potent cancer chemopreventive agents (Yavelow et al., 1983, 1985). Recently, this property has been substantiated in an in vivo investigation using mice (St. Clair et al., 1990) that were exposed to dimethylhydrazine, a potent chemical carcinogen. Therefore, BBI is currently being considered as an attractive candidate for studies directed toward the prevention of several forms of cancer that are widespread in Western societies. BBI is a small single-chain polypeptide of 71 amino acids with two subdomains directed toward trypsin and chymotrypsin/elastase, respectively (Fig. 1). This protein is the prototype of a family of proteinase inhibitors occurring in legumes. The three-dimensional structure of several BBI-type proteinase inhibitors in the free form (Suzuki et al., 1987; Chen et al., 1992) and complexed with trypsin (Tsunogae et al., 1986) were published recently. The structure of BBI in solution has been determined by NMR spectroscopy (Werner and Wemmer, 1991, 1992). The inhibitory subdomains of BBI are rigidified into a polycyclic, clearly arranged and highly conserved structural framework. BBI-type proteinase inhibitors fulfill many of the criteria of an attractive model for protein engineering studies (Fersht, 1985). Presently, major efforts are devoted to the pathophysiological elucidation and pathobiochemical characterization of the role of limited proteolysis in the course of malignant transformation. However, these efforts will eventually culminate in the rational design of specific chemical agents directed toward those proteolytic enzymes that are involved in malignant transformation.


Proteinase Inhibitor Cancer Chemopreventive Agent Complementary Structure Proteolytic Reaction Cancer Chemopreventive Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahmed, A. K., Schaffer, S. W., and Wettlaufer, C. B., 1975, J. Biol. Chem. 250:8477–8482.PubMedGoogle Scholar
  2. Barrett, A. J., Rawlings, N. D., Davies, M. E., Machleidt, G., Salvesen, G., and Turk, V., 1986, in: Proteinase Inhibitors (A. J. Barrett and G. Salvesen, eds.), Elsevier, Amsterdam, pp. 515–587.Google Scholar
  3. Billings, P. C., Carew, J. A., Keller-McGandy, C., Goldberg, A. L., and Kennedy, A. R., 1987, Proc. Natl. Acad. Sci. USA 84:4801–4805.PubMedCrossRefGoogle Scholar
  4. Billings, P. C., St. Clair, W., Owen, A. J., and Kennedy, A. R., 1988, Cancer Res. 48:1798–1802.PubMedGoogle Scholar
  5. Birk, Y., Jibson, M. D., and Bewley, T. A., 1980, Int. J. Peptide Protein Res. 15:193–199.CrossRefGoogle Scholar
  6. Blundell, T., Carney, D., Gardner, S., Hayes, F., Howlin, B., Hubbard, T., Overington, J., Singh, D. A., Sibanda, B. L., and Sutcliffe, M., 1988, Eur. J. Biochem. 172:513–520.PubMedCrossRefGoogle Scholar
  7. Chen, P., Rose, J., Love, R., Wei, C. H., and Wang, B. C., 1992, J. Biol. Chem. 267:1990–1994.PubMedGoogle Scholar
  8. Craik, C. S., Largman, C., Fletcher, T., Roczniak, S., Barr, P. J., Fletterick, P., and Rutter, W. J., 1985, Science 228:291–297.PubMedCrossRefGoogle Scholar
  9. Creighton, T. E., 1980, J. Mol. Biol. 144:521–550.PubMedCrossRefGoogle Scholar
  10. Elion, G. B., 1989, Science 244:41–47.PubMedCrossRefGoogle Scholar
  11. Engel, J., 1989, FEBS Lett. 251:1–7.PubMedCrossRefGoogle Scholar
  12. Engels, J. W., and Uhlmann, E., 1989, Agnew. Chem. 101:733–752.CrossRefGoogle Scholar
  13. Fersht, A., 1985, Enzyme Structure and Mechanism, Freeman, San Francisco.Google Scholar
  14. Flecker, P., 1987, Eur. J. Biochem. 166:151–156.PubMedCrossRefGoogle Scholar
  15. Flecker, P., 1989, FEBS Lett. 252:153–157.CrossRefGoogle Scholar
  16. Fritz, H., 1980, Ciba Found. Symp. 75:351–379.Google Scholar
  17. Goldenberg, D. P., Frieden, R. W., Haack, J. A., and Morrison, T. B., 1989, Nature 338:127–132.PubMedCrossRefGoogle Scholar
  18. Green, N. M. and Work, E., 1953, Biochem. J. 54:347–352.PubMedGoogle Scholar
  19. Hammond, R. W., Foard, D. E., and Larkins, B. A., 1984, J. Biol. Chem. 259:9883–9890.PubMedGoogle Scholar
  20. Hayatsu, H., Arimoto, S., and Negishi, T., 1988, Mutat. Res. 202:429–446.PubMedCrossRefGoogle Scholar
  21. Hiwasa, T., 1988, Biol. Chem. Hoppe-Seyler 369(Suppl.):239–241.PubMedGoogle Scholar
  22. Hiwasa, T., Sakiyama, S., Noguchi, S., Ha, J. M., Miyazawa, T., and Yokoyama, S., 1987a, Biochem. Biophys. Res. Commun. 146:731–738.PubMedCrossRefGoogle Scholar
  23. Hiwasa, T., Yokoyama, S., Ha, J. M., Noguchi, S., and Sakiyama, S., 1987b, FEBS Lett. 211:23–26.PubMedCrossRefGoogle Scholar
  24. Hogle, J. M., and Liener, I. E., 1973, Can. J. Biochem. 51:1014–1020.PubMedCrossRefGoogle Scholar
  25. Ikenaka, T. and Norioka, S., 1986, in: Prokeinase Inhibitors (A. J. Barrett and G. Salvesen, eds.) Elsevier, Amsterdam, pp. 301–474.Google Scholar
  26. Ikenaka, T., and Norioka, S., 1983, in: Proteinase Inhibitors: Medical and Biological Aspects (N. Katunuma, H. Umezawa, and H. Holzer}, eds.), Jpn. Sci. Soc. Press, Tokyo/Springer-Verlag, Berlin, pp. 45–53.Google Scholar
  27. Iwamoto, Y, Robey, F. A., Graf, J., Sasaki, M., Kleinman, H. K., Yamada, Y, and Martin, G. R., 1987, Science 238:1132–1134.PubMedCrossRefGoogle Scholar
  28. Jaenicke, R., 1987, Prog. Biophys. Mol. Biol. 49:117–237.PubMedCrossRefGoogle Scholar
  29. Knowles, J. R., 1987, Science 236:1252–1258.PubMedCrossRefGoogle Scholar
  30. Laskowski, M., Jr., and Kato, I., 1980, Annu. Rev. Biochem. 49:593–626.PubMedCrossRefGoogle Scholar
  31. Laumas, S., Abdel-Ghany, M., Leister, K., Resnick, R., Kandrach, A., and Racker, E., 1989, Proc. Natl. Acad. Sci. USA 86:3021–3025.PubMedCrossRefGoogle Scholar
  32. Nilsson, B., Bermann-Marks, C., Hober, S., and Anderson, S., 1989, Anniversary Congress of the University of Groningen, “Prospects in Protein Engineering,” Poster Abstract No. 040.Google Scholar
  33. Odani, S., and Ikenaka, T., 1978, J. Biochem. 83:747–753.PubMedGoogle Scholar
  34. Pigiet, V. P., and Schuster, B. J., 1986, Proc. Natl. Acad. Sci. USA 83:7643–7647.PubMedCrossRefGoogle Scholar
  35. St. Clair, W. H., Billings, P. C., Carew, J. A., Keller-McGandy, C., Newberne, P., and Kennedy, A. R., 1990, Cancer Res. 50:580–586.Google Scholar
  36. Schelp, F. P., and Pongpaew, P., 1988, Int. J. Epidemiol. 17:287–292.PubMedCrossRefGoogle Scholar
  37. Schönthal, A., Herrlich, P., Rahmsdorf, H. J., and Ponta, H., 1988, Cell 54:325–334.PubMedCrossRefGoogle Scholar
  38. Seidl, D. S. and Liener, I. E., 1972, J. Biol. Chem. 247:3533–3538.PubMedGoogle Scholar
  39. Suzuki, A., Tsunogae, Y, Tanaka, L, Yamane, T., Ashida, T., Norioka, S., Hara, S., and Ikenaka, T., 1987, J. Biochem. 101:267–274.PubMedGoogle Scholar
  40. Terranova, V. P., Williams, J. E., Liotta, L. A., and Martin, G. R., 1984, Science 226:982–985.PubMedCrossRefGoogle Scholar
  41. Thim, L., 1989, FEBS Lett. 250:85–90.PubMedCrossRefGoogle Scholar
  42. Troll, W., and Kennedy, A. R., (eds.), 1989, Cancer Res. 49:499–502.Google Scholar
  43. Tsunogae, Y., Tanaka, I., Yamane, T., Kikkawa, J., Ashida, T., Ishikawa, C., Wanatabe, K., Nakamura, S., and Takahashi, K., 1986, J. Biochem. 100:1637–1646.PubMedGoogle Scholar
  44. Werner, M. H., and Wemmer, D. E., 1991, Biochemistry 30:3356–3364.PubMedCrossRefGoogle Scholar
  45. Werner, M. H., and Wemmer, D. E., 1992, Biochemistry 31:999–1010.PubMedCrossRefGoogle Scholar
  46. Witkop, B., 1981, Naturwiss. Rundsch. 34(9):361–379.Google Scholar
  47. Yavelow, J., Finlay, T. H., Kennedy, A. R., and Troll, W., 1983, Cancer Res. (Suppl.) 43:2454s–2459s.PubMedGoogle Scholar
  48. Yavelow, J., Collins, M., Birk, Y., Troll, W., and Kennedy, A. R., 1985, Proc. Natl. Acad. Sci. USA 82:5395–5399.PubMedCrossRefGoogle Scholar
  49. Yavelow, J., Caggana, M., and Beck, K. A., 1987a, Cancer Res. 47:1598–1601.PubMedGoogle Scholar
  50. Yavelow, J., Scott, C. B., and Mayer, T. A., 1987, Cancer Res. 47:1602–1607.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Peter Flecker
    • 1
  1. 1.Institute for Physiological ChemistryUniversity of MainzMainzGermany

Personalised recommendations