Arginyl Aminopeptidase

  • Sandrine Cadel
  • Christophe Piesse
  • Cécile Gouzy-Darmon
  • Paul Cohen
  • Thierry Foulon
Part of the Proteases in Biology and Disease book series (PBAD, volume 2)


Aminopeptidase B (Ap-B; EC. was originally defined as an exopeptidase able to trim out basic amino acid residues from the Nt2-terminus of peptides. Purification of Ap-B from rat testes showed that this enzyme is a monomeric 72 kDa Zn2+-dependent exopeptidase, which selectively removes Arg and/or Lys residues from the NH2-terminus of various peptides. In vitro, Ap-B exhibits a weak ability to hydrolyze leukotriene A4 into leukotriene B4, a lipid mediator of inflammation. The in vivo bi-functionality of Ap-B remains to be demonstrated. Elucidation of the rat, human and mouse Ap-B primary structures allows its classification in the Ml family of Zn2+-aminopeptidases and reveals a structural relationship with leukotriene A4 hydrolase, an important enzyme of the arachidonic pathway. The human Ap-B gene (rnpep) is localized on chromosome 1 band q32 in a high transcript density chromosomal region. The gene is bracketed by tim17a and elf3, which encode a pre-protein translocase of the inner mitochondrial membrane and an ETS family transcription factor, respectively. The recent description of the mouse genome allows to localize the mouse Ap-B encoding gene on chromosome 1, in a putative inversed synthenic region. Ap-B is widely distributed in a number of rat and human tissues. Ap-B expression level varies depending on the cells or tissues considered and likely in a species-dependent manner. Both the constitutive and the regulated pathways secrete the enzyme. Moreover, in PC12 cells, the protein is associated, as an active form, to the external face of the plasma membrane. Although the physiological function of Ap-B remains an open question, several data strongly support the hypothesis that Ap-B could participate in the final stages of precursor processing mechanisms and thereby in some inflammatory processes and tumour developments.

Key words

Zn2+-metallopeptidase aminopeptidase B leukotriene A4 hydrolase prohormone processing 


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  1. Aurich-Costa, J., Cadel, S., Gouzy, C., Foulon, T., Chérif, D., Cohen, P., 1997, Assignment of the aminopeptidase B gene (RNPEP) to human chromosome 1 band q32 by in situ hybridization. Cytogenet Cell Genet. 79: 143–144.PubMedCrossRefGoogle Scholar
  2. Azaryan, A.V. and Hook, V.Y.H., 1994, Unique cleavage specificity of “prohormone thiol protease” related to proenkephalin processing. FEBS Lett. 341: 197–202.PubMedCrossRefGoogle Scholar
  3. Balogh, A., Cadel, S., Foulon, T., Picart, R., Der Garabedian, A., Rousselet, A., Tougard, C., Cohen, P., 1998, Aminopeptidase B: a processing enzyme secreted and associated with the plasma membrane of rat pheochromocytoma (PC12) cells. J Cell Sci. 111: 161–169.PubMedGoogle Scholar
  4. Barrett, A.J., Rawlings, N.D., Woessner, J.F., 1998, In: Handbook of Proteolytic Enzymes. Barrett AJ, Rawlings ND and Woessner JF. Eds. Academic Press, London.Google Scholar
  5. Bauer, M.F., Gempel, K., Reichert, A.S., Rappold, G.A., Lichtner, P., Gerbiitz, K.D., Neupert, W., Brunner, M., Hofmann, S., 1999, Genetic and structural characterization of the human mitochondrial inner membrane translocase. J Mol Biol. 289: 69–82.PubMedCrossRefGoogle Scholar
  6. Beinfeld, M.C., 1998, Prohormone and proneuropeptide processing. Recent progress and future challenges. Endocrine 8: 1–5.PubMedCrossRefGoogle Scholar
  7. Belhacène, N., Mari, B., Rossi, B., Auberger, P., 1993, Characterization and purification of T lymphocyte aminopeptidase B: a putative marker of T cell activation. Eur. J. Immunol. 23: 1948–1955.PubMedCrossRefGoogle Scholar
  8. Cadel S, Pierotti, A.R., Foulon, T., Créminon, C., Barré, N., Segrétain, D. and Cohen, P., 1995, Aminopeptidase B in the rat testes: isolation, functional properties and cellular localization in the seminiferous tubules. Mol. Cell. Endocrinol. 110: 149–160.PubMedCrossRefGoogle Scholar
  9. Cadel, S., Foulon, T., Viron, A., Balogh, A., Midol-Monnet, S., Noel, N., Cohen, P., 1997, Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A4 hydrolase.Proc Natl Acad Sci U S A 94: 2963–2968.PubMedCrossRefGoogle Scholar
  10. Castro, M.G., Birch, N.P., Peng Loh, Y., 1989, Regulated secretion of pro-opiomelanocortin converting enzyme and an aminopeptidase B-like enzyme from dispersed bovine intermediate lobe pituitary cells. J. Neurochem. 52: 1620–1628.CrossRefGoogle Scholar
  11. Chesneau, V., Pierotti, A.R., Barré, N., Créminon, C., Tougard, C., Cohen, P., 1994, Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the aminoterminus of arginine residues. J. Biol. Chem. 269: 2056–2061.PubMedGoogle Scholar
  12. Cohen, P., 1987, Proteolytic events in the post-translational processing of polypeptide hormone precursors. Biochimie 69: 87–89.PubMedCrossRefGoogle Scholar
  13. Darby, N. J. and Smyth, D. G., 1990, Endopeptidases and prohormones processing. Biosc. Reports 10: 1–13.CrossRefGoogle Scholar
  14. Devi, L. and Goldstein, A., 1985, Neuropeptide processing by single step cleavage: conversion of leumorphin (dynorphin B-29) to dynorphin B. Biochem. Biophys. Res. Comm. 130: 1168–1176.PubMedCrossRefGoogle Scholar
  15. Devi, L., 1991, Consensus sequence for processing of peptide precursors at monobasic sites. FEBS Lett. 2: 189–194CrossRefGoogle Scholar
  16. Draoui, M., Bellincampi, L., Hospital, V., Cadel S., Foulon, T., Prat, A., Barré, N., Reichert, U., Melino, G., Cohen, P., 1995, Expression and retinoic modulation of N-arginine dibasic convertase and of an aminopeptidase-B in human neuroblastoma cell lines. J. Neurooncol. 31: 99–106.CrossRefGoogle Scholar
  17. Eberlein, G.A., Eysselein, V.E., Davis, M.T., Lee, T.D., Shively, J.E., Grandt, D., Niebel, W., Williams, R., Moessner, J., Zeeh, Meyer, H.E., Goebell, H., Zeeh, J., Meyer, H.E., Goebell, H., Reeve J.R., 1992, Patterns of prohormone processing order revealed by a new procholecystokinin-derived peptide. J. Biol. Chem. 267: 1517–1521.PubMedGoogle Scholar
  18. Flores, M., Aristoy, M.C., Toldra, F., 1993, HPLC purification and characterization of porcine muscle aminopeptidase B. Biochimie 75: 861–867.PubMedCrossRefGoogle Scholar
  19. Foulon T., Cadel, S., Chesneau, V., Draoui, M., Prat, A., Cohen, P., 1996, Two novel metallopeptidases with a specificity for basic residues. Functional properties, structure and cellular distribution. Ann. N.Y. Acad. Sci. 780: 106–120.PubMedCrossRefGoogle Scholar
  20. Foulon, T., Cadel, S., Prat, A., Chesneau, V., Hospital, V., Segretain, D., Cohen, P., 1997, NRD convertase and aminopeptidase B: two processing metallopeptidases with a selectivity for basic residues. Ann Endocrinol. (Paris) 58: 357–364.Google Scholar
  21. Foulon, T., Cadel, S. Cohen, P., 1998, Aminopeptidase B. In: Handbook of Proteolytic Enzymes. Barrett AJ, Rawlings ND and Woessner JF. Eds. Academic Press, London, pp. 1026–1029.Google Scholar
  22. Freitas J.R., Guimaràes, J.A., Borges, D.R., Prado, J.L., 1979, Two arylamidases from human liver and their kinin-converting activity. Int. J. Biochem. 10: 81–89.PubMedCrossRefGoogle Scholar
  23. Flicker, L.D., 1992, Peptide processing exopeptidases: amino and carboxypeptidases involved with peptide biosynthesis. In: Peptide biosynthesis and processing E. Flicker LD. Ed. Telford Press/ Caldwell, NJ, pp. 1–16.Google Scholar
  24. Fukasawa, K.M., Fukasawa, K., Kanai, M., Fujii, S., Harada, M., 1996, Molecular cloning and expression of rat liver aminopeptidase B. J Biol Chem. 271: 30731–30735.PubMedCrossRefGoogle Scholar
  25. Fukasawa, K.M., Fukasawa, K., Harada, M., Hirose, J., Izumi, T., Shimizu, T., 1999, Aminopeptidase B is structurally related to leukotriene-A4 hydrolase but is not a bifunctional enzyme with epoxide hydrolase activity. Biochem. J. 339: 497–502.PubMedCrossRefGoogle Scholar
  26. Gainer, H., Rüssel, J.T., Peng Loh, Y., 1984, An aminopeptidase activity in bovine pituitary secretory vesicles that cleaves the N-terminal arginine from □-lipotropin. FEBS Lett. 175: 135–139.PubMedCrossRefGoogle Scholar
  27. Gluschankof, P., Gomez, S., Morel, A., Cohen, P., 1987, Enzymes that process somatostatin precursors. A novel endoprotease that cleaves before the arginine-lysine doublet is involved in somatostatin-28 convertase activity of the rat brain cortex. J. Biol. Chem. 262: 9515–9520.Google Scholar
  28. Gomez, S., Glushankof, P., Lepage, A., Cohen, P., 1988, Relationship between endo and exopeptidase in a processing enzyme system: activation of an endoprotease by the aminopeptidase B-like activity in somatostatin-28 convertase. Proc. Natl Acad. Sci. USA 85: 5468–5472.PubMedCrossRefGoogle Scholar
  29. Haeggström, J.Z., 1998. Leukotriene A4 hydrolase. In: Handbook of Proteolytic Enzymes. Barrett AJ, Rawlings ND and Woessner JF. Eds. Academic Press, London, pp. 1022–1025.Google Scholar
  30. Hattori, A., Matsumoto, K., Mizutani, S., Tsujimoto, M., 2001, Genomic organization of the human adipocyte-derived leucine aminopeptidase gene and its relationship to the placental leucine aminopeptidase/oxytocinase gene. J Biochem (Tokyo) 130: 235–241.CrossRefGoogle Scholar
  31. Hooper, N.M., 1994, Families of zinc metalloproteases. FEBS Lett. 354: 1–6.PubMedCrossRefGoogle Scholar
  32. Hopsu, V.K., Kantonen, U.M., Glenner, G.G., 1964, A peptidase from rat tissues selectively hydrolysing N-terminal arginine and lysine residues. Life Sci. 3: 1449–1453.PubMedCrossRefGoogle Scholar
  33. Hopsu, V. K., Mäkinen, K.K., Glenner G.G., 1966, Purification of a mammalian peptidase selective for N-terminal arginine and lysine residues: aminopeptidase B. Arch. Biochem. Biophys. 114: 557–566.PubMedCrossRefGoogle Scholar
  34. Hopsu, V.K. and Mäkinen, K.K., 1966, Formation of bradikynin from kallydin-10 by aminopeptidase B. Nature. 212: 1271–1272.CrossRefGoogle Scholar
  35. Hui, K-S., Lo, E.-S., Hui, M.P.-P, 1994, An endogenous aminoenkephalinase inhibitor: purification and characterization of Arg°-Met5-enkephalin from bovine striatum. J. Neurochem. 63: 1748–1756.PubMedCrossRefGoogle Scholar
  36. Ishiura, S., Yamamoto, T., Yamamoto, M., Nojima, M., Aoyagi, T., Sugita, H., 1987, Human skeletal muscle contains two major aminopeptidases: an anion-activated aminopeptidase B and an aminopeptidase M-like enzyme. J. Biochem. 102: 1023–1031.PubMedGoogle Scholar
  37. Kawata, S., Takayama, S., Ninomiya, K., Makisumi, S., 1980, Porcine liver aminopeptidase B. J. Biochem. 88: 1601–1605.Google Scholar
  38. Lerche, C., Vogel, L.K., Shapiro, L.H., Noren, O., Sjostrom, H., 1996, Human aminopeptidase N is encoded by 20 exons. Mamm Genome 7: 712–713.PubMedCrossRefGoogle Scholar
  39. Mancini, J.A. and Evans, J.F., 1995, Cloning and characterization of the human leukotriene A4 hydrolase gene. Eur J Biochem. 231: 65–71.PubMedCrossRefGoogle Scholar
  40. Mantle, D., Lauffart, B., McDermott, J.R., Kidd, A.M., Pennington, R.J.T., 1985, Purification and characterization of two Cl-activated aminopeptidases hydrolysing basic termini from human skelettal muscle. Eur. J. Biochem. 147: 307–312.PubMedCrossRefGoogle Scholar
  41. McDermott, J.R., Mantle, D., Lauffart, B., Gibson, A.M., Biggins, J.A., 1988, Purification and characterization of two soluble Cl activated arginyl aminopeptidases from human brain and their endopeptidase action on neuropeptides. J. Neurochem. 50: 177–182.CrossRefGoogle Scholar
  42. Misono, K.S., Fukumi, H., R.T. Grammer, Inagami, T., 1984, Rat atrial natriuretic factor: complete amino acid sequence and disulflde linkage essential for biological activity. Biochem. Biophys. Res. Comm. 119: 524–529.PubMedCrossRefGoogle Scholar
  43. Ocain, T.D. and Rich, D.H., 1987, L-lysine thiol: a subnanomolar inhibitor of aminopeptidase B. Biochem. Biophys. Res. Comm. 145: 1038–1042.PubMedCrossRefGoogle Scholar
  44. Oettgen, P., Alani, R.M., Barcinski, M. Brown, L., Akbarali, Y., Boltax, J., Kunsch, C., Munger, K., Libermann, T.A., 1997, Isolation and characterization of a novel epithelium-specific transcription factor, ESE-1, a member of the ets family. Mol Cell Biol. 17: 4419–4433.PubMedGoogle Scholar
  45. Orning L., Gierse, J.K., Fitzpatrick, F.A., 1994, The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J. Biol. Chem. 269: 11269–11273.PubMedGoogle Scholar
  46. Parish, D.C., Tujeta, R., Alstein, M., Gainer, H., Peng Loh, Y., 1986, Purification and characterization of a paired basic residue-specific prohormone converting enzyme from bovine pituitary neural lobe secretory vesicles. J. Biol. Chem. 261: 14392–14397.PubMedGoogle Scholar
  47. Piesse, C., Tymms, M., Garrafa, E., Gouzy, C., Lacasa, M., Cadel, S., Cohen, P., Foulon, T., 2002, Human aminopeptidase B (rnpep) on chromosome Iq32.2: complementary DNA, genomic structure and expression. Gene 292: 129–140.PubMedCrossRefGoogle Scholar
  48. Rasmussen, T.E., Pedraza-Diaz, S., Hardre, R., Laustsen, P.G., Carrion, G., Kristensen, T., 2000, Structure of the human oxytocinase/insulin-regulated aminopeptidase gene and localization to chromosome 5q21. Eur J Biochem. 2611: 2297–2306.CrossRefGoogle Scholar
  49. Rawlings, N.D. and Barrett., A.J., 1993, Evolutionary families of peptidases. Biochem. J. 290: 205–218.PubMedGoogle Scholar
  50. Regoli, D. and Barabé, J., 1980, Pharmacology of bradikynin and related kinins. Pharmacol. Rev. 32: 1–46.PubMedGoogle Scholar
  51. Saiki, I., Murata, J., Watanabe, K., Fujii, H., Abe, F., Azuma, I., 1989, Inhibition of tumor cell invasion by ubenimex (bestatin) in vitro. Jpn. J. Cancer Res. 80: 873–878.PubMedCrossRefGoogle Scholar
  52. Sebti S.M. and Lazo J.S., 1987, Separation of the protective enzyme bleomycin hydrolase from rabbit pulmonary aminopeptidases. Biochemistry 26: 432–437.PubMedCrossRefGoogle Scholar
  53. Söderling E., 1983, Substrates specificities of Cl--activated arginine aminopeptidase from human and rat origin. Arch. Biochem. Biophys. 220: 1–10.PubMedCrossRefGoogle Scholar
  54. Söderling, E and Mäkinen, K.K., 1983, Modification of the Cl--activated arginine aminopeptidase from rat liver and human erythrocytes: a comparative study. Arch. Biochem. Biophys. 220: 11–21.PubMedCrossRefGoogle Scholar
  55. Suda, H., Aoyagi, T., Takeuchi, T., Umezawa, H., 1976, Inhibition of aminopeptidase B and leucine aminopeptidase by bestatin and its stereoisomer. Arch. Biochem. Biophys. 177: 196–200.PubMedCrossRefGoogle Scholar
  56. Thoïdis, G., Kupriyanova, T., Cunningham, J.M., Chen, P., Cadel, S., Foulon, T., Cohen, P., Fine, R.E., Kandror, K.V., 1999, Glucose transporter Glut3 is targeted to secretory vesicles in neurons and PC12 cells. J Biol Chem. 274: 14062–14066.PubMedCrossRefGoogle Scholar
  57. Thompson, M.W., Tobler, A., Fontana, A., Hersh, L.B., 1999, Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase. Biochem Biophys Res Commun. 258: 234–240.PubMedCrossRefGoogle Scholar
  58. Tymms, M. J., Ng, A. Y., Thomas, R. S., Schutte, B. C., Zhou, J., Eyre, H. J., Sutherland, G. R., Seth, A., Rosenberg, M., Papas, T., Debouck, C., Kola, I., 1997. A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to Iq32.2 and expression in tissues and cancer. Oncogene 15: 2449–2462.PubMedCrossRefGoogle Scholar
  59. Umezawa, H., Hori, S;, Tsutomu, S., Toshioka, T., Takeuchi, T., 1974, A bleomycininactivating enzyme in mouse liver. J. Antibiot. 27: 419–424.PubMedCrossRefGoogle Scholar
  60. Umezawa, H., Aoyagi, T., Ohuchi, S., Okuyama, A., Suda, H., Takita, T., Hamada, M., Takeuchi, T., 1983, Arphamenine A and B, new inhibitors of aminopeptidase B, produced by bacteria. J. Antibiot. 36: 1572–1575.PubMedCrossRefGoogle Scholar
  61. Yamada, M., Sukenaga, Y., Fujii, H., Abe, F., Takeuchi, T., 1994, Purification and characterization of a ubenimex (Bestatin)-sensitive aminopeptidase B-like enzyme from K562 human chronic myeloid leukemia cells. FEBS Lett. 342: 53–56.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Sandrine Cadel
    • 1
  • Christophe Piesse
    • 1
  • Cécile Gouzy-Darmon
    • 1
  • Paul Cohen
    • 1
  • Thierry Foulon
    • 1
  1. 1.Laboratoire de Biochimie des Signaux Régulateurs Cellulaires et MoléculairesUnité Mixte de Recherche 7631 — Université Pierre et Marie Curie — Centre National de la Recherche ScientifiqueParisFrance

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