Advertisement

Structure and Function in Dipeptidyl Peptidase IV and Related Proteins

  • Mark D. Gorrell
  • Xin M. Wang
  • Joohong Park
  • Katerina Ajami
  • Denise Ming Tse Yu
  • Heather Knott
  • Devanshi Seth
  • Geoffrey W. McCaughan
Part of the Advances in Experimental Medicine and Biology book series (volume 575)

9. Conclusions

Potential therapeutic applications of DPIV inhibitors have fuelled interest in understanding the biological roles of DPIV and its relatives. Such efforts are confounded by the ubiquitous expression of DPIV, inhibitor selectivity questions and the variety of identified substrates. DPIV is not essential, but is such a useful enzyme that all animal species express it. The enzyme activity’s ancient and primary function is probably nutritional, providing more complete proteolysis of food and recycled proteins. This function is unnecessary in well-fed humans. The development of selective inhibitors of proteolytic activity and identification of ligand binding activities in this gene family would lead to rapid advances in understanding the biology of the POP gene family.

Keywords

Hepatic Stellate Cell Adenosine Deaminase Dipeptidyl Peptidase Fibroblast Activation Protein Gelatinase 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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abbott CA, McCaughan GW, Gorrell MD, 1999a, Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity. FEBS Lett. 458: 278–284.CrossRefPubMedGoogle Scholar
  2. Abbott CA, McCaughan GW, Levy MT, Church WB, Gorrell MD, 1999b, Binding to human dipeptidyl peptidase IV by adenosine deaminase and antibodies that inhibit ligand binding involves overlapping, discontinuous sites on a predicted beta propeller domain. Eur J Biochem. 266: 798–810.CrossRefPubMedGoogle Scholar
  3. Abbott CA, Yu DMT, Woollatt E, Sutherland GR, McCaughan GW, Gorrell MD, 2000, Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur J Biochem. 267: 6140–6150.CrossRefPubMedGoogle Scholar
  4. Abbott CA, Gorrell MD, The family of CD26/DPIV and related ectopeptidases. Ectopeptidases: CD13/Aminopeptidase N and CD26/Dipeptidylpeptidase IV in Medicine and Biology. Edited by Langner J, Ansorge S. NY, Kluwer/Plenum, 2002, pp 171–195.Google Scholar
  5. Abdel-Ghany M, Cheng H, Levine RA, Pauli BU, 1998, Truncated dipeptidyl peptidase IV is a potent anti-adhesion and anti-metastasis peptide for rat breast cancer cells. Invasion Metast. 18: 35–43.CrossRefGoogle Scholar
  6. Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Wallner BP, 2004, PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 64: 5471–5480.CrossRefPubMedGoogle Scholar
  7. Aertgeerts K, Ye S, Tennant MG, Collins B, Rogers J, Sang B, Skene RJ, Webb DR, Prasad GS, 2004, Crystal structure of human Dipeptidyl Peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Sci. 13: 412–421.CrossRefPubMedGoogle Scholar
  8. Aertgeerts K, Levin I, Shi L, Snell GP, et al., 2005, Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein Alpha. J Biol Chem. 280: 19441–19444.CrossRefPubMedGoogle Scholar
  9. Ajami K, Abbott CA, Obradovic M, Gysbers V, Kähne T, McCaughan GW, Gorrell MD, 2003, Structural requirements for catalysis, expression and dimerisation in the CD26/DPIV gene family. Biochemistry 42: 694–701.CrossRefPubMedGoogle Scholar
  10. Ajami K, Abbott CA, McCaughan GW, Gorrell MD, 2004, Dipeptidyl peptidase 9 is cytoplasmic and has two forms, a broad tissue distribution, cytoplasmic localization and DPIV — like peptidase activity. BBA-Gene Struct Expression. 1679: 18–28.CrossRefGoogle Scholar
  11. Allen M, Heinzmann A, Noguchi E, Abecasis G, et al., 2003, Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet. 35: 258–263.CrossRefPubMedGoogle Scholar
  12. Artym VV, Kindzelskii AL, Chen WT, Petty HR, 2002, Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton. Carcinogenesis. 23: 1593–1601.CrossRefPubMedGoogle Scholar
  13. Bartlam M, Wang G, Yang H, Gao R, Zhao X, Xie G, Cao S, Feng Y, Rao Z, 2004, Crystal structure of an acylpeptide hydrolase/esterase from Aeropyrum pernix. Structure. 12: 1481–1488.CrossRefPubMedGoogle Scholar
  14. Bjelke JR, Christensen J, Branner S, Wagtmann N, Olsen C, Kanstrup AB, Rasmussen HB, 2004, Tyrosine 547 constitutes an essential part of the catalytic mechanism of dipeptidyl peptidase IV. J Biol Chem. 279: 34691–34697.CrossRefPubMedGoogle Scholar
  15. Chen T, Ajami K, McCaughan GW, Gai W-P, Gorrell MD, Abbott CA, 2003, Dipeptidyl Peptidase IV gene family. Molecular characterization of a novel dipeptidyl peptidase like 2 short form (DPLZ-S) that is highly expressed in the brain and lacks dipeptidyl peptidase activity. Biochem Biophys Acta, in pressGoogle Scholar
  16. Cheng HC, Abdel-Ghany M, Pauli BU, 2003, A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J Biol Chem. 278: 24600–24607.CrossRefPubMedGoogle Scholar
  17. Chien C-H, Huang L-H, Chou C-Y, Chen Y-S, Han Y-S, Chang G-G, Liang P-H, Chen X, 2004, One site mutation disrupts dimer formation in human DPP-IV proteins. J Biol Chem. 279: 52338–52345.CrossRefPubMedGoogle Scholar
  18. Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth HU, Brandstetter H, 2003, The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci USA. 100: 5063–5068.CrossRefPubMedGoogle Scholar
  19. Fülop V, Bocskei Z, Polgar L, 1998, Prolyl oligopeptidase-an unusual beta-propeller domain regulates proteolysis. Cell. 94: 161–170.CrossRefPubMedGoogle Scholar
  20. Fülop V, Jones DT, 1999, Beta propellers: structural rigidity and functional diversity. Curr Opinion Struc Biol. 9: 715–721.CrossRefGoogle Scholar
  21. Girardi ACC, Degray BC, Nagy T, Biemesderfer D, Aronson PS, 2001, Association of Na+−H+exchanger isoform NHE3 and dipeptidyl peptidase IV in the renal proximal tubule. J Biol Chem. 276: 46671–46677.CrossRefPubMedGoogle Scholar
  22. Gonzalez-Gronow M, Hershfield MS, Arredondo-Vega FX, Pizzo SV, 2004, Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. J Biol Chem. 279: 20993–20998.CrossRefPubMedGoogle Scholar
  23. Gorrell MD, Yu DMT, 2005, Diverse functions in a conserved structure: The dipeptidyl peptidase IV gene family. Trends in Protein Research. Edited by Robinson JW. New York, Nova Biomedical Books pp 1–78.Google Scholar
  24. Hiramatsu H, Yamamoto A, Kyono K, Higashiyama Y, Fukushima C, Shima H, Sugiyama S, Inaka K, R. S, 2004, The crystal structure of human dipeptidyl peptidase (DPPIV) complex with diprotin A. Biol Chem. 385: 561–564.CrossRefPubMedGoogle Scholar
  25. Hough RB, Lengeling A, Bedian V, Lo C, Bucan M, 1998, Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression. Proc Natl Acad Sci USA. 95: 13800–13805.CrossRefPubMedGoogle Scholar
  26. Jerng HH, Qian Y, Pfaffinger PJ, 2004, Modulation of Kv4.2 Channel Expression and Gating by Dipeptidyl Peptidase 10 (DPP10). Biophys J. 87: 2380–2396.CrossRefPubMedGoogle Scholar
  27. Jones B, Adams S, Miller GT, Jesson MI, Watanabe T, Wallner BP, 2003, Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies. Blood. 102: 1641–1648.CrossRefPubMedGoogle Scholar
  28. Kajiyama H, Kikkawa F, Suzuki T, Shibata K, Ino K, Mizutani S, 2002, Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in ovarian carcinoma. Cancer Res. 62: 2753–2757.PubMedGoogle Scholar
  29. Kikkawa F, Kajiyama H, Ino K, Shibata K, Mizutani S, 2003, Increased adhesion potency of ovarian carcinoma cells to mesothelial cells by overexpression of dipeptidyl peptidase IV. Int J Cancer. 105: 779–783.CrossRefPubMedGoogle Scholar
  30. Kobayashi S, Ohnuma K, Uchiyama M, Iino K, Iwata S, Dang NH, Morimoto C, 2004, Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation. Blood. 103: 1002–1010.CrossRefPubMedGoogle Scholar
  31. Leiting B, Pryor KD, Wu JK, Marsilio F, Patel RA, Craik CS, Ellman JA, Cummings RT, Thornberry NA, 2003, Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII. Biochem J. 371: 525–532.CrossRefPubMedGoogle Scholar
  32. Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Mueller A, Rettig WJ, Gorrell MD, 1999, Fibroblast activation protein: A cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology. 29: 1768–1778.CrossRefPubMedGoogle Scholar
  33. Levy MT, McCaughan GW, Marinos G, Gorrell MD, 2002, Intrahepatic expression of the hepatic stellate cell marker fibroblast activation protein correlates with the degree of fibrosis in hepatitis C virus infection. Liver. 22: 93–101.CrossRefPubMedGoogle Scholar
  34. Niedermeyer J, Kriz M, Hilberg F, Garin-Chesa P Bamberger U, Lenter MC, Park J, Viertel B, Puschner H, Mauz M, Rettig WJ, Schnapp A. 2000, Targeted disruption of mouse fibroblast activation protein. Mol Cell Biol. 20: 1089–1094.CrossRefPubMedGoogle Scholar
  35. Oefner C, D’Arcy A, Mac Sweeney A, Pierau S, Gardiner R, Dale GE, 2003, High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl]amino)-acetyl]-2-cyano-(S)-pyrrolidine. Acta Crystallogr D Biol Crystallogr. 59: 1206–1212.CrossRefPubMedGoogle Scholar
  36. Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ, 1999, Fibroblast activation protein: A dual-specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 274: 36505–36512.CrossRefPubMedGoogle Scholar
  37. Pethiyagoda CL, Welch DR, Fleming TP, 2001, Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. Clin Exp Metastasis. 18: 391–400.CrossRefGoogle Scholar
  38. Pineiro-Sanchez ML, Goldstein LA, Dodt J, Howard L, Yeh Y, Chen WT, 1997, Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem. 272: 7595–7601.CrossRefPubMedGoogle Scholar
  39. Qi SY, Riviere PJ, Trojnar J, Junien JL, Akinsanya KO, 2003, Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem J. 373: 179–189.CrossRefPubMedGoogle Scholar
  40. Ramirez-Montagut T, Blachere NE, Sviderskaya EV, Bennett DC, Rettig WJ, Garin-Chesa P, Houghton AN, 2004, FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor. Oncogene. 23: 5435–5446.CrossRefPubMedGoogle Scholar
  41. Rasmussen HB, Branner S, Wiberg FC, Wagtmann N, 2003, Crystal structure of human DPP-IV/CD26 in complex with a substrate analogue. Nat Struct Biol. 10: 19–25.CrossRefPubMedGoogle Scholar
  42. Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP, Old LJ, 1993, Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 53: 3327–3335.PubMedGoogle Scholar
  43. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, Old LJ, Rettig WJ, 1994, Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA. 91: 5657–5661.CrossRefPubMedGoogle Scholar
  44. Strop P, Bankovich AJ, Hansen KC, Garcia KC, Brunger AT, 2004, Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family. J Mol Biol. 343: 1055–1065.CrossRefPubMedGoogle Scholar
  45. Tanaka S, Murakami T, Horikawa H, Sugiura M, Kawashima K, Sugita T, 1997, Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV. Int J Immunopharmacol. 19: 15–24.CrossRefPubMedGoogle Scholar
  46. Thoma R, Loffler B, Stihle M, Huber W, Ruf A, Hennig M, 2003, Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure. 11: 947–959.CrossRefPubMedGoogle Scholar
  47. Wada K, Yokotani N, Hunter C, Doi K, Wenthold RJ, Shimasaki S, 1992, Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family. Proc Natl Acad Sci USA. 89: 197–201.CrossRefPubMedGoogle Scholar
  48. Weihofen WA, Liu J, Reutter W, Saenger W, Fan H, 2004, Crystal structure of CD26/Dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface. J Biol Chem. 41: 43330–43335.CrossRefGoogle Scholar
  49. Wesley UV, Albino AP, Tiwari S, Houghton AN, 1999, A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. J Exp Med. 190: 311–322.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Mark D. Gorrell
    • 1
  • Xin M. Wang
    • 1
  • Joohong Park
    • 1
  • Katerina Ajami
    • 1
  • Denise Ming Tse Yu
    • 1
  • Heather Knott
    • 1
  • Devanshi Seth
    • 1
  • Geoffrey W. McCaughan
    • 1
  1. 1.A. W. Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The Discipline of MedicineUniversity of SydneySydneyAustralia

Personalised recommendations