Dipeptidil Peptidaz- 4 Enzimine Biyokimyasal Yaklaşım

Dipeptidil peptidaz- 4 (DPP-4, EC 3.4. 14.5 ), proteaz ailesinin bir üyesidir. DPP-4 aynı zamanda adenozin deaminazbağlayan protein (ADBP) ya da T-hücre aktivasyon antijeni CD26 olarak da bilinmektedir. Bir serin ekzopeptidaz olanDPP-4; bir proteinin N-terminal dipeptitin en sonunda yer alan prolin, hidroksiprolin, dehidroprolin ya da alaninayrılmasını katalizlemektedir. Enzim kanda, serbest ve bağlı olmak üzere iki formda bulunmaktadır.DPP-4’ün pek çok dokudaki yaygın dağılımı ve fizyolojik olaylarda rol almasına bağlı olarak çeşitli patolojik durumlardada DPP-4 ekspresyonunda ya da aktivitesinde değişiklikler saptanmıştır. Bu patolojik durumlar: diyabet, psikonöroendokrin bozukluklar, otoimmün ve inflamatuar hastalıklar, enfeksiyon hastalıkları, hematolojik malignansiler,solid tümörlerdir. Plazmada değişen CD26/DPP-4 aktivitesi ya da derişimleri fizyolojik ve otoimmün çeşitli patolojikdurumlarla ilgili bulunmuştur. Ayrıca tükürük, serebrospinal, sinoviyal sıvılar, folikül sıvısı, semen ve idrarda da DPP4 aktivitesi bildirilmiştir.

Biochemical Approach to Dipeptidyl Peptidase-4 Enzyme

Dipeptidyl peptidase-4 (DPP-4, EC 3.4. 14.5 ) is a member of protease family. DPP-4, also known as adenosine deaminase binding protein (ADBP) or T-cell activation antigen CD26. DPP-4 is a serine exopeptidase, it cleaves dipeptides from the N-termini of oligopeptides and smaller peptides with proline, hydroxyproline, dehydroproline or alanine. The enzyme is found in two forms in blood, free and bound. Due to its ubiquitous distribution and involvement in various physiological processes, a great number of pathological conditions are associated with altered DPP-4 expression or activity. These pathological conditions are: diabetes, psychoneuroendocrine disorders, autoimmune and inflammatory diseases, infectious diseases, haematological malignancies, solid tumors. The altered CD26 / DPP-4 activity or concentrations in plasma are related to various physiological and autoimmune pathological conditions. DPP-4 activity is detected in saliva, cerebrospinal fluid, synovial fluid, follicular fluid, seminal fluid and urine.

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  • 1. Klemann C, Wagner L, Stephan M, Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4 (DPP4) entanglement in the immune system. Clin Exp Immunol. 2016;185:1-21.
  • 2. Leicht S, Shipkova M, Klett C, Gert H, Altrock E, Wilhelm J. CD26/dipeptidyl peptidase IV: A comparative study of healthy persons and kidney transplant recipients before and early after transplantation. Clin Biochem. 2013;46:1383-8.
  • 3. Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: A key player in chronic liver disease. World J Gastroenterol. 2013;19:2298-2306.
  • 4. Hetmanczyk K, Makaruk B, Kierus K, Izdebska S, Abramczuk DP, Pilch B. Monitoring of dipeptidyl peptidase IV (DPP-IV) activity in patients with mucopolysaccharidoses types I and II on enzyme replacement therapy-Results of a pilot study. Clin Biochem. 2016;49:458-462.
  • 5. Aemaimanan P, Sattayasai N, Wara-aswapati N, Pitiphat W, Suwannarong W, Prajaneh S. Alanine aminopeptidase and Dipeptidyl Peptidase IV in saliva of chronic periodontitis. J Periodontol. 2009;11:1809-14.
  • 6. Ohnuma K, Marimoto C. Dipeptidyl-peptidase 4. Atlas Genet Cytogenet Oncol Haematol. 2012;301-12.
  • 7. Engel M, Hoffman T, Wagner L, Wermann M, Heiser U, Kiefersaver R. The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Biochemistry. 2013;100:5063-8.
  • 8. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci. 2005;108:277-92.
  • 9. Pro B, Dang NH. CD26/dipeptidyl peptidase IV and its role in cancer. Histol Histopathol. 2004;19:1345-51.
  • 10. Cheng HC, Abdel-Ghany M, Pauli BU. A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J Biol Chem. 2003;278:24600–7.
  • 11. Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005;65:1325–34.
  • 12. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci. 2005;108:277–92.
  • 13. Sato T, Yamochi T, Yamochi T, Aytac U, Ohnuma K, McKee KS, Morimoto C, Dang NH. CD26 regulates p38 mitogenactivated protein kinase-dependent phosphorylation of integrin beta1, adhesion to extracellular matrix, and tumorigenicity of T-anaplastic large cell lymphoma Karpas 299. Cancer Res. 2005;65:6950–6.
  • 14. Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, Liu F, Woods J, Zycband E, Moller DE et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci. 2003;100:6825–30.
  • 15. Hildebrandt M, Reutter W, Arck P, Rose M, Klapp BF. A guardian angel:the involvement of dipeptidyl peptidase IV in psychoneuroendocrine function, nutrition and immune defence. Clin Sci. 2000;99:93-104.
  • 16. Umetsu DT, McIntire JJ, Akbari O, Maconubas C, DeKruyff RH. Asthma: an epidemic of dysregulated immunity. Nat Immunol. 2002;3:715-20.
  • 17. Lun SWM, Wong CK, Ko FWS, Hui DSC, Lam CWK. Increased expression of plasma and CD+T lymphocyte costimulatory molecule CD26 in adult patients with allergic asthma. J Clin Immunol. 2007;27:430-7.
  • 18. Reinhold D, Biton A, Pieper S. Dipeptidyl peptidase IV (DPIV, CD26) and aminopeptidase N (APN, CD13) as regulators of T cell function and targets of immunotherapy in CNS inflammation. Int Immunopharmacol. 2006;6:1935-42.
  • 19. Ulusoy H, Kamanli A, İlhan N. Serum levels of soluble CD26 and CD30 and their clinical significance in patients with rheumatoid arthritis. Rheumatol Int. 2011;32:3857-62.
  • 20. Sromova L, Marackova H, Sedova L, BalaziovaA, Sedo A. Dipeptidyl peptidase-IV in synovial fluid mononuclear cells of patients with rheumatoid arthritis. Clin Chim Acta. 2010;410:1046-50.
  • 21. Hildebrandt M, Rose M, Rüter J, Salama A, Mönnikes H, Klapp BF. Dipeptidyl peptidase IV (DPIV, CD26) in patients with inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1067-72.
  • 22. Tsuji T, Sugahara K, Tsuruda K, Uemura A, Harasawa H, Hasegawa H et al. Clinical and oncologic implications in epigenetic down-regulation of CD26/dipeptidyl peptidase IV in adult T-cell leukemia cells. Int J Hematol. 2004;80:254-60.
  • 23. Carbone A, Cozzi M, Gloghini A, Pinto A. CD26/dipeptidyl peptidase IV expression in human lymphomas is restricted to CD30-positive anaplastic large cell and a subset T- cell non-Hodgkin's lymphomas. Hum Pathol. 1994;25:1360-5.
  • 24. Bernengo MG, Novelli M, Quaglino P, Lisa F, De Matteis A, Savoia P et al. The relevance of the CD4+ CD26- subset in the identification of circulating Sezary cells. Br J Dermatol. 2001;144:125-35.
  • 25. Ho L, Aytac U, Stephens LC, Ohnuma K,Mills GB, McKee KS et al. In vitro and in vivo Antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30+ anaplastic large cell T-cell lymphoma Karpas 299. Clin Cancer Res. 2001;7:2031- 40.
  • 26. Cheng HC, Abdel-Ghany M, Elble RC, Pauli BU. Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface- associated fibronectin. J Biol Chem. 1998;273:24207-15.
  • 27. Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6:603-15.
  • 28. Asada Y, Aratake Y, Kotani T, Marutsuka K, Araki Y, Ohtaki S et al. Expression of dipeptidyl aminopeptidase IV activity in human lung carcinoma. Histopathology. 1993;23:265-70.
  • 29. Stecca BA, Nardo B, Chieco P, Mazziotti A, Bolondi L, Cavallari A. Aberrant dipeptidyl peptidase IV (DPP IV/CD26) expression in human hepatocellular carcinoma. J Hepatol. 1997;27:337-45.
  • 30. Sedo A, Malik R, Krepela E. Dipeptidyl peptidase IV in C6 rat glioma cell line differentiation. J Biol Chem. 1998;379:39-44.
  • 31. Wilson MJ, Ruhland AR, Quast BJ, Reddy PK, Ewing SL, Sinha AA. Dipeptidylpeptidase IV activities are elevated in prostate cancers and adjacent benign hyperplastic glands. J Androl. 2000;21:220-6.
  • 32. Kotani T, Aratake Y, Ogata Y, Umeki K, Araki Y, Hirai K et al. Expression of dipeptidyl aminopeptidase IV activity in thyroid carcinoma. Cancer Lett. 1991;57:203-8.
  • 33. Pethiyagoda CL,Welch DR,Fleming TP.Dipeptidyl peptidase IV(DPPIV) inhibits cellular invasion of melanoma cells. Clin Exp Metastasis. 2000;18:391-400.
  • 34. Kajiyama H, Kikkawa F, Suzuki T, Shibata K, Ino K, and Mizutani S. Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in metabolic control to cardiovascular protection. Curr Pharm Des. 2014;20:2387-94.
  • 35. Avogaro A, Kreutzenberg S, Fadini G. Dipeptidyl-peptidase 4 Inhibition: Linking in ovarian carcinoma. Cancer Res. 2002; 62:2753–7.
  • 36. Marguet D, Baggio L, Kobayashi T, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. PNAS. 2000;97:6874-79.
  • 37. Silva Junior WS, Gudoy-Matos AF, Kraemer-Aguiar LG. Dipeptidyl Peptidase 4: A new link between diabetes mellitus and atherosclerosis? BioMed Res Int. 2015;816164:1-10.
  • 38. Kim NH, Yu T, Lee DH. The nonglycemic actions of dipeptidyl peptidase-4 inhibitors. BioMed Res Int. 2014; 368703:1-10.
  • 39. Nongonierma AB, FitzGerald RJ. Features of dipeptidyl peptidase IV (DPP-IV) İnhibitory peptides from dietary proteins. J Food Biochem. 2017;12451:1-11.
  • 40. Nargis T, Kumar K, Ghosh AR, Sharma A, Rudra D, Sen D. KLK5 induces shedding of DPP4 from circulatory Th17 cells in Type 2 Diabetes Mol Met. 2017;9:4.
  • 41. Seliger E, Blumenauer V, Heins J, Neubert K, Kaltwasser P, Schöneich C. Detection of dipeptidyl peptidase IV in follicular fluid—initial report. Zentralbl Gynakol. 1988;110:1312-4.
  • 42. Shimomura Y, Ando H, Frugori K, Kajiyama H, Suzuki M, Iwase A. Possible involvement of crosstalk cell-adhesion mechanism by endometrial CD26/dipeptidyl peptidase IV and embryonal fibronectin in human blastocyst implantation. Mol Hum Reprod. 2006;12:491-5.
  • 43. Dolanbay EG, Yardımoğlu M, Yalçınkaya E, Hazır Y, Aksoy A, Karaöz E et al. Expression of trophinin and dipeptidyl peptidase IV in endometrial co-culture in the presence of an embryo:A comparative immunocytochemical study.Mol Med Rep.2016;13:3961-8.
  • 44. Tan CW, Eng B, Lee YH, Tan HH, Lau MSK, Choolani M. CD26/DPPIV down-regulation in endometrial stromal cell migration in endometriosis. Fertil Steril. 2014;102:167-77.
  • 45. Burden HP, Holmes CH, Persad R, Whittington K. Prostasomes-their effects on human male reproduction. Hum Reprod Update. 2006;12:283-92.
  • 46. Arienti G, Polci A, Carlini E, Palmerini CA. Transfer of CD26/dipeptidyl peptidase IV (E.C 3.5.4.4) from prostasomes to sperm. FEBS Letters. 1997;410:343-6.