Physiological Roles of Ectoenzymes Indicated by the Use of Aminopeptidase Inhibitors

  • Takaaki Aoyagi
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Most biological processes, from ontogenesis through death, in normal or diseased conditions, are catalyzed by specific en-zymes. Intrinsic inhibitors of these enzymes also play an important role in controlling some of these processes. In order to elucidate the role of aminopeptidases in diseases and to design aminopeptidase-based therapeutics, it is essential to understand the mechanisms of action of these enzymes and the physiological roles of the inhibitors.


Leucine Aminopeptidase Aminopeptidase Activity P388 Leukemia Dipeptidyl Aminopeptidase Aminopeptidase Inhibitor 
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. 1.
    Umezawa H. Enzyme Inhibitors of Microbial Origin. University of Tokyo Prees, Tokyo 1972: 1–114.Google Scholar
  2. 2.
    Aoyagi T, Umezawa H. Structures and activities of protease inhibitors of microbial origin. In: Reich E, Rifkin D, Shaw E, eds. Proteaseases and Biological Control. Cold Spring Harbor Laboratory, 1975: 429–454.Google Scholar
  3. 3.
    Aoyagi T, Ishizuka M, Takeuchi T et al. Enzyme inhibitors in relation to cancer therapy. Jap J Antibiotics (Suppl) 1977; 30-S:121–132.Google Scholar
  4. 4.
    Aoyagi T. Bioactive peptides produced by microorganisms. In: Umezawa H, Shiba T, Takita T, eds. Kodansha Scientific Press, 1978: 129–151.Google Scholar
  5. 5.
    Aoyagi T, Umezawa H. Industrial and clinical enzymology. In: Vitale L, Simeon V, eds. FEBS Federation of European Biochemical Societies. 61. Oxford and New York: Pergamon Press, 1980: 89–91.Google Scholar
  6. 6.
    Umezawa H. Annual review of microbiology. In: Starr MP, Balows A, Schmidt JM, eds. Vol. 36. Palo Alto: Annual Reviews Inc., 1982: 75–99.Google Scholar
  7. 7.
    Aoyagi T. Horizons on antibiotic research. In: Davis BD, Ichikawa T, Maeda K, Mitcher LA, eds. Tokyo: Japan Antibiotics Research Association, 1987: 75–90.Google Scholar
  8. 8.
    Aoyagi T. Progress in Industrial Microbiology. Bushell ME, Grafe U, eds. Vol. 27. New York, Oxford: Elsevier, 1989: 403–418.Google Scholar
  9. 9.
    Aoyagi T. Small molecular protease inhibitors and their biological effects. In: Kleinkauf H, Dohren H, eds. Biochemistry of Peptide Antibiotics. Berlin, New York: Walter de Gruyter, 1990: 311–363.Google Scholar
  10. 10.
    Aoyagi T, Nerome K, Suzuki J et al. Change of enzyme activities during the early stage of influenza virus infection. Biochem Biophys Res Commun 1974; 60: 1178–1184.PubMedCrossRefGoogle Scholar
  11. 11.
    Aoyagi T, Suda H, Nagai M et al. Aminopeptidase activities on the surface of mammalian cells. Biochim Biophys Acta 1976; 452: 131–143.PubMedCrossRefGoogle Scholar
  12. 12.
    Aoyagi T, Nagai M, Iwabuchi M et al. Aminopeptidase activities on the surface of mammalian cells. Cancer Res 1978; 38: 3505–3508.PubMedGoogle Scholar
  13. 13.
    Kalckar HM. Science 1965; 150: 305–308.PubMedCrossRefGoogle Scholar
  14. 14.
    Aoyagi T, Suzuki J, Nerome K et al. Sialic acid residues exposed on mammalian cell surface: the effect of adsorption of denatured virus particles. Biochem Biophys Res Commun 1974; 57: 271–278.PubMedCrossRefGoogle Scholar
  15. 15.
    Aoyagi T, Komiyama T, Nerome K et al. Characterization of myxovirus sialidase. Experientia 1975; 31: 896–897.PubMedCrossRefGoogle Scholar
  16. 16.
    Aoyagi T, Umezawa H. Hydrolytic enzymes on the cellular surface and their inhibitors found in microorganisms. In: Vitale L, Simon V, eds. Industrial and Clinical Enzymology. Oxford and New York: Pergamon Press, 1980: 89–99.Google Scholar
  17. 17.
    Aoyagi T, Umezawa H. The relationships between enzyme inhibitors and function of mammalian cells. Acta Biol Med Germ 1981; 40: 1523–1529.PubMedGoogle Scholar
  18. 18.
    Fujii H, Nakajima I, Tsuruo T. Role of aminopeptidases on metastasis. Hematology & Oncology (in Japanese) 1994; 29: 288–296.Google Scholar
  19. 19.
    Sanderink GJ, Artur Y, Siest G. Human aminopeptidases: a review of the literature. J Clin Chem Clin Biochem 1988; 26: 795–805.PubMedGoogle Scholar
  20. 20.
    Kenny AJ, Stephanson SL, Turner AJ. Research monographs in cell and tissue physiology. In: Mammalin Ectoenzyme. Amsterdam: Elsevier; 1987: 169–210.Google Scholar
  21. 21.
    Lalu K, Lampelo S, Vanha-Perttula T. Characterization of three aminopeptidases purified from maternal serum. Biochim Biophys Acta 1986; 873: 190–198.PubMedCrossRefGoogle Scholar
  22. 22.
    Look AT, Ashmun RA, Shapiro LH et al. Human mycloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase. J Clin Invest 1989; 83: 1299–1307.PubMedCrossRefGoogle Scholar
  23. 23.
    Sanderink GJ, Artur Y, Schiele F et al. Alanine aminopeptidase in serum: biological variations and reference limits. Clin Chem 1988; 34: 1422–1430.PubMedGoogle Scholar
  24. 24.
    Hersh LB. Characterization of membrane-bound aminopeptidases from rat brain: identification of the enkephalin-degrading aminopeptidase. J Neurochem 1985; 44: 1427–1435.PubMedCrossRefGoogle Scholar
  25. 25.
    Bausback HH, Ward PE. Degradation of low-molecular-weight opioid peptides by vascular plasma membrane aminopeptidase M. Biochim Biophys Acta 1986; 882: 437–442.PubMedCrossRefGoogle Scholar
  26. 26.
    Amoscato AA, Balasubramaniam A, Alexander JW et al. Degradation of thymopentin by human lymphocytes: evidence for aminopeptidase activity. Biochim Biophys Acta 1988; 955: 164–174.PubMedCrossRefGoogle Scholar
  27. 27.
    Aoyagi T, Tobe H, Kojima F et al. Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes. J Antibiotics 1978; 31: 636–638.CrossRefGoogle Scholar
  28. 28.
    Umezawa H, Aoyagi T, Suda H et al. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. J Antibiotics 1976; 29: 97–99.CrossRefGoogle Scholar
  29. 29.
    Nishizawa R, Saino T, Takita T et al. Synthesis and structure-activity relationships of bestatin analogues, inhibitors of aminopeptidase B. J Med Chem 1977; 20: 510–515.PubMedCrossRefGoogle Scholar
  30. 30.
    Umezawa H, Ishizuka M, Aoyagi T et al. Enhancement of delayed-type hypersensitivity by bestatin, an inhibitor of aminopeptidase B and leucine aminopeptidase. J Antibiotics 1976; 29: 857–859.CrossRefGoogle Scholar
  31. 31.
    Umezawa H, Aoyagi T, Ohuchi S et al. Arphamenine A and B, new inhibitors of aminopeptidase B, produced by bacteria. J. Antibiotics 1983; 36: 1572–1575.CrossRefGoogle Scholar
  32. 32.
    Ohuchi S, Suda H, Naganawa H et al. The structure of arphamenine A and B. J Antibiotics 1983; 36: 1576–1580.CrossRefGoogle Scholar
  33. 33.
    Okuyama A, Ohuchi S, Tanaka T et al. Cell-free biosynthesis of arphamenine A. Biochem Int 1986; 12: 485–491.PubMedGoogle Scholar
  34. 34.
    Yamamoto K, Suda H, Ishizuak M et al. Isolation of a-aminoacyl arginines in screening of aminopeptidase B inhibitors. J Antibiotics 1980; 33: 1597–1599.CrossRefGoogle Scholar
  35. 35.
    Look TA, Ashmun RA, Shapiro LH et al. Human myeloid plasma membrane glycoprotein CD13 (gp150) in identical to aminopeptidase N. J Clin Invest 1989; 83: 1299–1307.CrossRefGoogle Scholar
  36. 36.
    Aoyagi T, Yoshida S, Nakamura Y et al. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyces azureus MH663–2F6. I. Taxonomy, production, isolation, physico-chemical properties and biological activities. J Antibiotics 1990; 43: 143–148.CrossRefGoogle Scholar
  37. 37.
    Yoshida S, Nakamura Y, Naganawa H et al. Probestin, a new inhibitor of aminopeptidase M, produced by Streptomyes azureus MH663–2F6. II. Structure determination of probestin. J Antibiotics 1990; 43: 149–153.CrossRefGoogle Scholar
  38. 38.
    Aoyagi T, Yoshida S, Matsuda N et al. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI15614F1. I. Taxonomy, production, isolation, physico-chemcial properties and biological activities. J Antibiotics 1991; 44: 573–578.CrossRefGoogle Scholar
  39. 39.
    Yoshida S, Naganawa H, Aoyagi T et al. Leuhistin, a new inhibitor of aminopeptidase M, produced by Bacillus laterosporus BMI156–14F1. II. Structure determination of leuhistin. J Antibiotics 1991; 38: 579–581.CrossRefGoogle Scholar
  40. 40.
    Umezawa H, Aoyagi T, Tanaka T et al. Production of actinonin, an inhibitor of aminopeptidase M, by actinomycetes. J Antibiotics 1985; 38: 1629–1630.CrossRefGoogle Scholar
  41. 41.
    Umezawa H, Aoyagi T, Uotani K et al. Ebelactone, an inhibitor of esterase, produced by actinomycetes. J Antibiotics 1980; 33: 1594–1596.CrossRefGoogle Scholar
  42. 42.
    Uotani K, Naganawa H, Kondo S et al. Structure studies on ebelactones A and B, esterase inhibitors produced by actinomycetes. J Antibiotics 1982; 35: 1495–1499.CrossRefGoogle Scholar
  43. 43.
    Umezawa H, Aoyagi T, Hazato T et al. Esterastin, an inhibitor of esterase, produced by actinomycetes. J Antibiotics 1978; 31: 639–641.CrossRefGoogle Scholar
  44. 44.
    Hegen M, Niedobitek G, Klein CE et al. The T cell triggering molecule Tp103 is associated with dipeptidyl aminopeptidase IV activity. J Immunol 1990; 144: 2908–2914.PubMedGoogle Scholar
  45. 45.
    Ulmer AJ, Mattem T, Feller AC et al. CD26 antigen is a surface dipeptidyl peptidase IC (DPP IV) as characterized by monoclonal antibodies done TII–19–4–7 and 4ELIC7. Scand J Immunol 1990; 31: 429 – 435.PubMedCrossRefGoogle Scholar
  46. 46.
    Torimoto Y, Dang NH, Tanaka T et al. Biochemical characterization of CD26 (dipeptidyl peptidase IV): functional comparison of direct epitopes recognized by various anti-CD26 monoclonal antibodies. Mol Immunol 1992; 29: 183–192.PubMedCrossRefGoogle Scholar
  47. 47.
    Umezawa H, Aoyagi T, Ogawa K et al. Diprotins A and B, inhibitors of dipeptidyl aminopeptidase IV, produced by bacteria. J Antibiotics 1984; 37: 422–425.CrossRefGoogle Scholar
  48. 48.
    Ishizuka M, Sato J, Sugiyama Y et al. Mitogenic effect of bestatin on lymphocytes. J Antibiotics 1980; 33: 653–662.CrossRefGoogle Scholar
  49. 49.
    Naito M, Aoyagi T, Umezawa H et al. Bestatin, a new specific inhibitor of aminopeptidases, enhances activation of small lymphocytes by concanavalin. Biochem Biophys Res Commun 1977; 76: 525–533.Google Scholar
  50. 50.
    Abe F, Kuramochi H, Takahashi K et al. Biological activity of the main metabolites of ubenimex in humans. J Antibiotics 1988; 41: 1862–1867.CrossRefGoogle Scholar
  51. 51.
    Talmadge JE, Lenz BF, Pennington R et al. Immunomodulatory and therapeutic properties of bestatin in mice. Cancer Res 1986; 46: 4505–4510.PubMedGoogle Scholar
  52. 52.
    Muller WEG, Zahn RK, Arendes J et al. Activation of DNA metabolism in T-cells by bestatin. Biochem Pharmacol 1979; 28: 3131–3137.PubMedCrossRefGoogle Scholar
  53. 53.
    Talmadge JE, Koyama M, Matsuda A et al. Immunotherapeutic properties of bestatin: mechanism of activity. In: Umezawa H, ed. Recent Results of Bestatin 1986-A biological response modifier. Tokyo: Jpn Antibiot Res Associ, 1986: 8–25.Google Scholar
  54. 54.
    Ishizuka M, Masuda T, Kanbayashi N et al. Effect of bestatin on mouse immune system and experimental murine tumors. J Antibiotics 1980; 33: 642–652.CrossRefGoogle Scholar
  55. 55.
    Abe F, Shibuya K, Uchida M et al. Effect of bestatin on syngeneic tumors in mice. Gann 1984; 75: 89–94.PubMedGoogle Scholar
  56. 56.
    Tsuruo T, Naganuma H, Iida H et al. Inhibition of lymph node metastasis of P388 leukemia by bestatin. J Antibiotics 1981; 34: 1206–1209.CrossRefGoogle Scholar
  57. 57.
    Ebihara K, Abe F, Yamashita T et al. The effect of ubenimex on N-methyl-N’-nitro-N-nitrosoguanidine-induced stomach tumor in rats. J Antibiotics 1986; 39: 966–970.CrossRefGoogle Scholar
  58. 58.
    Horiuchi K, Miyamoto T et al. Radioprotective effect of ubenimex (bestatin) on C3H and BALB/c mice. 16th ICC proceedings, Jerusalem, 1989.Google Scholar
  59. 59.
    Fidler IJ, Fabra A, Nakajima M et al. Genetic and Epigenetic regulation of human colon carcinoma metastasis. Contrib Oncol 1992; 44: 13–21.Google Scholar
  60. 60.
    Nicolson GL. Paracrine and autocrine growth mechanisms in tumor metastasis specific sites with particular emphasis on brain and lung metastasis. Cancer Metastasis Rev 1993; 12: 325–338.PubMedCrossRefGoogle Scholar
  61. 61.
    Nakajima M, Chop AM. Tumor invasion and extracellular matrix degrading enzyme: Regulation of activity by organ factors. Semin Cancer Bio1. 1991; 2: 115–123.Google Scholar
  62. 62.
    Tsuruo T, Naganuma K, Iida H et al. Inhibition of lymph node metastasis of P388 leukemia by bestatin in mice. J Antibiotics 1981; 34: 1206–1209.CrossRefGoogle Scholar
  63. 63.
    Talmadge JE, Lenz BF, Pennington R et al. Immunomodulatory and therapeutic properties of bestatin in mice. Cancer Res 1986; 46: 4505–4510.PubMedGoogle Scholar
  64. 64.
    Saiki I, Murata J, Watanabe K et al. Inhibition of tumor cell invasion by ubenimex (bestatin) in vitro. Jap J Cancer Res 1989; 80: 873–878.CrossRefGoogle Scholar
  65. 65.
    Saiki I, Fujii H, Yoneda J et al. Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation. Int J Cancer 1993; 54: 137–143.Google Scholar
  66. 66.
    Taylor A, Sawan S, James T. On the binding of leucyl-o-sulfonic acid in leucine aminopeptidase. Interaction between this substrate analog and the activation site metal-viewed by NMR. J Biol Chem 1982; 257: 11571–6.PubMedGoogle Scholar
  67. 67.
    Taylor A, Peltier CZ, Torre FJ et al. Inhibition of bovine lens leucine aminopeptidases by bestatin: number of binding sites and slow binding of this inhibitor. Biochemistry 1993; 32: 784–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Taylor A, Peltier CZ, Jahngen EGE et al. Use of azidobestatin as a photoaffinity label to identify the active site peptide of leucine aminopeptidase. Biochemistry 1992; 31: 4141–4150.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • Takaaki Aoyagi

There are no affiliations available

Personalised recommendations