Advertisement

Structural Studies of Aminopeptidase P

A Novel Cellular Peptidase
  • Anthony J. Turner
  • Ralph J. Hyde
  • Jaeseung Lim
  • Nigel M. Hooper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 421)

Abstract

The plasma membrane of many cell types contains a cohort of peptidases that serve to modulate the activity of circulating regulatory peptides. Many of these are zinc metallopeptidases and these enzymes are particularly abundant in the brush border membranes of renal and intestinal microvilli. Some of them such as neprilysin (NEP; EC 3.4.24.11) and aminopeptidase N (AP-N; EC 3.4.11.2) also exist as cluster differentiation antigens (CD10 and CD 13 respectively) on the surface of leukocytes and may play a role in regulation of the immune system1. Both NEP and AP-N also have roles in the metabolism of certain cardiovascular and neuropeptides, e.g. natriuretic peptides2 and enkephalins3. NEP and AP-N are type ll integral membrane proteins and possess the typical HExxH zincin motif4 characteristic of many zinc peptidases. Recently, we have focused on another brush border zinc peptidase, aminopeptidase P (AP-P; X-Pro aminopeptidase; EC 3.4.11.9) which we showed to be unusual among the membrane peptidases in being anchored to the membrane by a glycosylphosphatidylinositol (GPI) moiety5. AP-P also shows a number of other atypical features which led us to attempt the molecular cloning of the pig kidney enzyme.

Keywords

Angiotensin Converting Enzyme Brush Border Membrane Dipeptidyl Peptidase Methionine Aminopeptidase eDNA Clone 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. I. Turner, A.J. (1993) Membrane peptidases of the nervous and immune systems. Adv. Neuroimmunol. 3, 163–170.CrossRefGoogle Scholar
  2. 2.
    Kenny, A.J. and Stephenson, S.L. (1988) Role of endopeptidase-24.11 in the inactivation of atrial natriuretic peptide. FEBS Lett. 232, 1–8.Google Scholar
  3. 3.
    Turner. A.J. (1987) Metabolism ofenkephalins. ISI Atlas of Sci. Pharmacol. 1, 74–77.Google Scholar
  4. 4.
    Hooper, N.M. (1994) Families of zinc metalloproteases. FEBS Lett. 354, 1–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Hooper, N.M. and Turner, A.J. (1988) Ectoenzymes of the kidney microvillur membrane. Aminopeptidase P is anchored by a glycosyl-phosphatidylinositol moiety. FEBS Lett. 229, 340–344.Google Scholar
  6. 6.
    Yaron. A. (1987) The role of proline in the proteolytic regulation of biologically active peptides. Biopolymers 26, S215 - S222.PubMedCrossRefGoogle Scholar
  7. 7.
    Mentlein, R. (1988) Proline residues in the maturation and degradation of peptide hormones and neuropeptides. FEBS Leu. 234, 251–256.CrossRefGoogle Scholar
  8. 8.
    Vanhoof, G., Goossens, F., De Meester, I., Hendriks, D. and Scharpé, S. (1995) Proline motifs in peptides and their biological processing. FASEB J. 9, 736–744.PubMedGoogle Scholar
  9. 9.
    Kenny, A.J., Booth, A.G. and Macnair, R.D. (1977) Peptidases of the kidney microvillus membrane. Acne Biol. Med. Germ. 36, 1575–1585.Google Scholar
  10. 10.
    Lasch, J.. Koelsch, R., Ladhoff, A.-M., and Hartrodt, B. (1986) Is the proline-specific aminopeptidase P of the intestinal brush border an integral membrane enzyme? Biomed. Biochem. Actc, 45, 833–843.Google Scholar
  11. 11.
    Orawski. A•T.. Susz, J.P. and Simmons. W.H. (1989) Aminopeptidase P from bovine lung: soluhilisation, properties and potential role in bradykinin degradation. Mol. Cell. Biochem. 75, 123–132.Google Scholar
  12. 12.
    Orawski, A.T. and Simmons. W.H. (1992) Purification and properties of membrane-bound aminopeptidase P from rat lung. Biochemist 34, 11227–11236.CrossRefGoogle Scholar
  13. 13.
    Holtzmann, E..I.. Pillay, G.. Rosenthal, G. and Yaron. A. (198 7) Aminopeptidase P activity in rat organs and human serum. Ancth2. Biochem. 162, 476–484.Google Scholar
  14. 14.
    Harbeck, H.-T. and Mentlein, R. (1991) Aminopeptidase P from rat brain. Purification and action on bioactive peptides. Eur..1. Biochem. 198, 451–458.CrossRefGoogle Scholar
  15. 15.
    Vanhoof, G., De Meester, I., Goossens, F., Hendriks, D., Scharpé, S. and Yaron, A. (1992) Kininase activity in human platelets: cleavage of the Arg1-Pro’ bond of bradykinin by aminopeptidase P. Biochem. Pharmacol. 44, 479–487.PubMedCrossRefGoogle Scholar
  16. 16.
    Kohno, H. and Kanno, T. (1985) Properties and activities of arvinopeptidases in normal and mitogen-stimulated human lymphocytes. Biochem… 226, 59–65.Google Scholar
  17. 17.
    Hendriks, D., De Meester, I., Umiel, T., Vanhoof, G., van Sande, M., Scharpé, S. and Yaron, A. (1991) Aminopeptidase P and dipeptidyl peptidase IV activity in human leukocytes and in stimulated lymphocytes. CIO,.,,. Chin,. Acne 196, 87–96.Google Scholar
  18. 18.
    Dehm, P. and Nordwig, A. (1970) The cleavage of prolyl peptides by kidney peptidases. Partial purification of a “X-prolyl-aminopeptidase” from swine kidney microsomes. Eu,: J. Biochem. 17, 364–371.Google Scholar
  19. 19.
    Blau, N., Niederwieser, A. and Shmerling, D.H. (1988) Peptiduria presumably caused by aminopeptidase P deficiency. A new inborn error of metabolism. J. Inhe,: Metah. Dis. 11, 240–242.Google Scholar
  20. 20.
    Prechel, M.M., Orawski, A.T., Maggiora, L.L. and Simmons, W.H. (1995) Effect of a new aminopeptidase P inhibitor, apstatin, on bradykinin degradation in the rat lung. J. Pharmacol. Exp. Therap. 275, 1136–1142.Google Scholar
  21. 21.
    Medeiros, M.S. and Turner, A.J. (1994) Processing and metabolism of peptide YY: pivotal roles for dipeptidyl peptidase IV, aminopeptidase P and endopeptidase-24.11. Endocrinology 134, 2088–2094.PubMedCrossRefGoogle Scholar
  22. 22.
    Mcntlein, R., Dahms, P., Grandt, D. and Krüger, R. (1993) Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Peptides 49, 133–134.CrossRefGoogle Scholar
  23. 23.
    Lloyd, G.S., Hryszko, J., Hooper, N.M. and Turner. A.J. (1996) Inhibition and mteal ion activation of pig kidney aminopeptidase P. dependence on nature of substrate. Biochem. Pharmacol. 52, 229–236.PubMedCrossRefGoogle Scholar
  24. 24.
    Matsas, R., Fulcher, I.S.. Kenny, A.J. and Turner, A.J. (1983) Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is-identical with the endopeptidase of kidney microvilli. Proc. Natl. Acad. Sci. U.S.A. 80, 3111–3115.Google Scholar
  25. 25.
    Rusu, I. and Yaron, A. (1992) Aminopeptidase P from human leukocytes. Eu,: J. Biochem. 210, 93–100.Google Scholar
  26. 26.
    Lasch, J., Koelsch, R., Steinmetzer, J., Neumann, V. and Demuth, H.-V. (1988) Enzymic properties of intestinal aminopeptidase P: a new continuous assay. FEBS Lett. 227, 171–174.PubMedCrossRefGoogle Scholar
  27. 27.
    Hooper, N.M. and Turner, A.J. (1990) Purification and characterization of pig kidney aminopeptidase P. A glycosyl-phosphatidylinositol-anchored ectoenzyme. Biochem. J. 267, 509–515.PubMedGoogle Scholar
  28. 28.
    Hooper, N.M., Hryszko, J., Oppong, S.Y. and Turner, A.J. (1992) Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P. Hypertension 19, 281–285.PubMedCrossRefGoogle Scholar
  29. 29.
    Simmons, W.H. and Orawski, A.T. (1992) Membrane bound aminopeptidase P from bovine lung. Its purification, properties and degradation of bradykinin. J. Biol. Chem. 267, 4897–4903.PubMedGoogle Scholar
  30. 30.
    Orawski. A.T. and Simmons, W.H. (1995) Purification and properties of membrane-bound aminopeptidase P from rat lung. Biochemish_v 34, 11227–11236.CrossRefGoogle Scholar
  31. 31.
    Hooper, N.M.. and Turner, A.J. (1988) Ectoenzymes of the kidney microvillar membrane. Differential solubilization by detergents can predict a glycosyl-phosphatidylinositol membrane anchor. Biochem. J. 250, 865–869.PubMedGoogle Scholar
  32. 32.
    Hooper, N.M.. and Turner, A.J. (1989) Hydrolysis of the glycosyl-phosphatidylinositol anchors of renal microvillar peptidases by a plasma phospholipase D. Biochem. Soc Trans. 17, 885–886.Google Scholar
  33. 33.
    Koelsch, R., Gottwald, S. and Lasch, J. (1994) Release of GPI-anchored membrane aminopeptidase P by enzymes and detergents has some peculiarities. Biochim. Biophys Acta 1190, 170–172.PubMedCrossRefGoogle Scholar
  34. 34.
    Ryan, J.W., Denslow, N.D., Greenwald, J.A. and Rogoff, M.A. (1994) Immunoaffinity purifications of aminopeptidase P from guinea pig lungs. kidney and serum. Biochem. Biophys. Res Commun. 205. 1796–1802.PubMedCrossRefGoogle Scholar
  35. 35.
    Hooper, N.M., Broomfield, S.J. and Turner, A.J. (1991) Characterization of antibodies to the glycosyl-phosphatidylinositol membrane anchors of mammalian proteins. Biochem. J. 273, 301–306.PubMedGoogle Scholar
  36. 36.
    Turner, A.J. and Hooper, N.M. (1997) The glycolipid-anchored peptidases. In: Cell-surface peptidases (ed. Kenny, A.J. and Boustead, C.M.), Bios, Oxford, in press.Google Scholar
  37. 37.
    Hyde, R.J., Hooper, N.M. and Turner, A.J. (1996) Molecular cloning and expression in COS-I cells of pig kidney aminopeptidase P. Biochem. J. 319, 197–201.PubMedGoogle Scholar
  38. 38.
    Kyte, J. and Doolittle, R.F. (1982) A simple method for displaying the hydropathic character of a protein. J Mol. Biol. 157, 105–132.PubMedCrossRefGoogle Scholar
  39. 39.
    von Heijne, G. (1986) A new method for predicting signal sequence cleavage sites. Nucleic Acids Res 14, 4683–4690.PubMedCrossRefGoogle Scholar
  40. 40.
    Udenfriend, S. and Kodukula, K. (1995) Prediction of co site in nascent precursor of a glycosylphosphatidylinositol protein. Meth. Enwmol. 250, 571–582.CrossRefGoogle Scholar
  41. 41.
    Denslow, N.D., Ryan, J.W. and Nguyen, H.P. (1994) Guinea pig membrane-bound aminopeptidase P is a member of the proline peptidase family. Biochem. Biophys. Res. Commun. 205, 1790–1795.PubMedCrossRefGoogle Scholar
  42. 42.
    Bazan, J.F., Weaver. L.H., Roderick, S.L., Huber, R. and Matthews. B.W. (1994) Sequence and structure comparison suggest that methionine aminopeptidase, prolidase, aminopeptidase P and creatmase share a common fold. Proc. Natl. Acad. Sci. U.S.A. 91, 2473–2477.Google Scholar
  43. 43.
    Vergas Romero, C., Neudorfer, I., Mann, K. and Schäfer, W. (1995) Purification and amino acid sequence of aminopeptidase P from pig kidney. Eue J. Biochem. 229, 262–269.Google Scholar
  44. 44.
    Mock, W.L. and Liu, Y. (1995) Hydrolysis of picolinylprolines by prolidase. A general mechanism for dual-metal ion containing aminopeptidases. J Biol. Chem. 270, 18437–18446.PubMedCrossRefGoogle Scholar
  45. 45.
    Roderick, S.L. and Matthews, B.W. (1993) Structure of the cobalt-dependent methionine aminopeptidase from E. coli: a new type of proteolytic enzyme. Biochemistry 32, 3907–3912.PubMedCrossRefGoogle Scholar
  46. 46.
    Arfin, S.M., Kendall, R.L., Hall, H., Weaver, L.H., Stewart. A.E., Matthews, B.W. and Bradshaw, R.A. (1995) Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent enzymes. Proc. Nall. Acad. Sci. U.S.A. 92, 7714–7718.CrossRefGoogle Scholar
  47. 47.
    Lim, J. and Turner, A.J. (1996) Chemical modification of porcine kidney aminopeptidase P indicates the involvement of two critical histidine residues. FEBS Lett. 381, 188–190.PubMedCrossRefGoogle Scholar
  48. 48.
    Turner, A.J., Medeiros, M.S. and Hooper, N.M. (1991) The molecular biology of GPI-anchored brush border hydrolases. Cell Biol. Int. Reports 15, 1083–1099.CrossRefGoogle Scholar
  49. 49.
    Brewis, I.A., Ferguson, M.A.J., Mehlert, A., Turner, A.J. and Hooper, N.M. (1995) Structures of the glycosylphosphatidylinositol anchors of porcine and human renal membrane dipeptidase. Comprehensive structural studies on the porcine anchor and interspecies comparison of the glycan core structures. J. Biol. Chem. 270, 22946–22956.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Anthony J. Turner
    • 1
  • Ralph J. Hyde
    • 1
  • Jaeseung Lim
    • 1
  • Nigel M. Hooper
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of LeedsLeedsUK

Personalised recommendations