Specific Inhibitors of Aminopeptidase P

Peptides and Pseudopeptides of 2-Hydroxy-3-Amino Acids
  • Angela Stöckel
  • Beate Stiebitz
  • Klaus Neubert
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 421)

Abstract

Aminopeptidase P (APP, EC 3.4.11.9) is a metal-dependent proline-specific peptidase. The enzyme splits N-terminal Xaa-Pro peptide bonds and plays an important role in the regulation of the physiological activity of peptides, e. g. bradykinin.1, 2 Only recently, the first specific inhibitor of APP, apstatin, was discovered.’ It is known, however, that peptides containing N-terminal 2-hydroxy-3-amino acids like bestatin and amastatin are inhibitors of the metal-dependent peptidases leucine aminopeptidase (LAP), aminopeptidase B and aminopeptidase M.4 X-ray crystallografic results demonstrated the bestatin chelation of one of the active Zinc ions of bovine lens LAP.’ Bestatin seems to be a natural mimetic of the tetrahedral intermediat of LAP-catalyzed substrate hydrolysis.

Keywords

Double Reciprocal Plot Tetrahedral Intermediat Peptide Hydrolysis Cellular Peptidase Continuous Assay 
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.

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References

  1. 1.
    Yaron, A. and Naider, F.: Proline-Dependent Structural and Biological Properties of Peptides and Proteins. Crit. Rev. Biochem. Mol. Biol. 28: 31–81, 1993.PubMedCrossRefGoogle Scholar
  2. 2.
    Simmons, W. H. and Orawski, A. T.: Membrane-bound Aminopeptidase P from Bovine Lung. J. Biol. Chem. 267: 4897–4903, 1992.PubMedGoogle Scholar
  3. 3.
    Prechel, M. M., Orawski, A. T., Maggiora, L. L. and Simmons, W. H.: Effect of a New Aminopeptidase P Inhibitor, Apstatin, on Bradykinin Degradation in the Rat Lung. J. Pharmacol. Exp. Ther. 275: 1136–1142, 1995.PubMedGoogle Scholar
  4. 4.
    Rich, D. H.. Moon, B. J. and Harbeson, S.: Inhibition of Aminopeptidases by Amastatin and Bestatin Derivates. Effect of Inhibitor Structure on Slow-Binding Processes. J. Med. Chem. 27: 417–422, 1984.Google Scholar
  5. 5.
    Burley, S. K., David, P. R. and Lipscomb, W. N.: Leucine Aminopeptidase: Bestatin Inhibition and a Model for Enzyme-Catalyzed Peptide Hydrolysis. Proc. Natl. Acad. Sci. USA. 88: 6916–66920, 1991.PubMedCrossRefGoogle Scholar
  6. 6.
    Herranz, R., Castro-Pichel, J., Vinuesa, S. and Garcia-Lopez, M. T.: An Improved One-Pot Method for the Stereoselective Synthesis of the (2S,3R)-3-Amino-2-hydroxy Acids: Key Intermediates for Bestatin and Amastatin. J. Org. Chem. 55: 2232–2234, 1990.CrossRefGoogle Scholar
  7. 7.
    Stiebitz. B., Stöckel, A., Lasch, J. and Neubert, K.: Development of a Continuous Assay for Aminopeptidase P: Substrate Design and Substrate Specificity, Symposium: Cellular Peptidases in Immune Functions and Diseases; poster - abstract, Magdeburg, 1996.Google Scholar
  8. 8.
    Segel, I. H.: Enzyme Kinetics. p. 170–178, John Wiley & Sons, Inc., New York, 1993.Google Scholar
  9. 9.
    Yoshimoto, T., Orawski, A. T. and Simmons, W. H.: Substrate Specifity of Aminopeptidase P from Escherichia coli: Comparison with Membrane-Bound Forms from Rat and Bovine Lung. Arch. Biochem. Biophys. 311: 28–34, 1994.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Angela Stöckel
    • 1
  • Beate Stiebitz
    • 1
  • Klaus Neubert
    • 1
  1. 1.Department of Biochemistry and Biotechnology Institute of BiochemistryMartin-Luther-UniversityHalleGermany

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