Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Dipeptidyl Peptidase 4

  • Leona WagnerEmail author
Reference work entry
First Online:
DOI: https://doi.org/10.1007/978-3-319-67199-4_101580
How to cite

Synonyms

 ADABP;  CD26;  DPP4;  DPPIV

Historical Background

Nature has evolved a number of regulatory, neuronal, and immune peptides with a proline residue at the penultimate position determining their structural conformation and biological activity. Generally, the proline peptide bonds are resistant to proteolytic cleavage, yet an exclusive number of postproline-specific peptidases have emerged to regulate these peptides. The best-characterized one is dipeptidyl peptidase 4 (DPP4), though additional functional homologues of DPP4-like enzymes have been discovered, some structurally related, others without any structural homology. Since DPP4 is involved in glucose homeostasis and immune response, it is of medical and pharmaceutical interest to distinguish between these enzymes (Klemann et al. 2016; Lambeir et al. 2003; Wagner et al. 2016b).

DPP4 [EC 3.4.14.5] was first discovered in 1966 by Hopsu-Havu and Glenner and denoted with glycyl-prolyl-β-naphtylamidase. Other names include...
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References

  1. Aertgeerts K, et al. Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Sci. 2004;13(2):412–21.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bohm SK, et al. Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem J. 1995;311(Pt 3):835–43.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Chung KM, et al. The dimeric transmembrane domain of prolyl dipeptidase DPP-IV contributes to its quaternary structure and enzymatic activities. Protein Sci. 2010;19(9):1627–38. doi:10.1002/pro.443.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cynis H, Lichtenthaler S, Wagner L, Demuth H-U. Proteases in the nervous system. In: Brix K, Stöcker W, editors. Proteases: structures and functions. Wien: Springer; 2013. p. 319–71.CrossRefGoogle Scholar
  5. De Meester I, et al. CD26, let it cut or cut it down. Immunol Today. 1999;20(8):367–75.PubMedPubMedCentralCrossRefGoogle Scholar
  6. De Meester I, Durinx C, Proost P, Scharpe S, Lambeir AM. DP IV – Natural substrates of medical importance. In: Langner J, Ansorge S, editors. Ectopeptidases. New York: Kluwer Academic/Plenum Publishers; 2002. p. 223–57.CrossRefGoogle Scholar
  7. Elenkov IJ, et al. The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52(4):595–638.PubMedCentralPubMedGoogle Scholar
  8. Engel M, et al. The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci USA. 2003;100(9):5063–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Frerker N, et al. Neuropeptide Y (NPY) cleaving enzymes: structural and functional homologues of dipeptidyl peptidase 4. Peptides. 2007;28(2):257–68.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Frerker N, et al. Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions. Clin Chem Lab Med. 2009;47(3):275–87.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Harmar AJ. Family-B G-protein-coupled receptors. Genome Biol. 2001;2(12):3001–13.CrossRefGoogle Scholar
  12. Ikushima H, et al. Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci USA. 2000;97(15):8439–44.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ishii T, et al. CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO. Proc Natl Acad Sci USA. 2001;98(21):12138–43.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Klemann C, et al. Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol. 2016;185(1):1–21.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Lambeir AM, et al. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40(3):209–94.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Mortier A, et al. CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology. J Leukoc Biol. 2016;99(6):955–69.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Ohnuma K, et al. Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol. 2008a;29(6):295–301.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Ohnuma K, et al. Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008b;13:2299–310.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Ohnuma K, et al. Dipeptidyl peptidase in autoimmune pathophysiology. Adv Clin Chem. 2011;53:51–84.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Pacheco R, et al. CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc Natl Acad Sci USA. 2005;102(27):9583–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Rasmussen HB, et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol. 2003;10(1):19–25.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Rohrborn D, et al. Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells. FEBS Lett. 2014;588(21):3870–7.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Rohrborn D, et al. DPP4 in Diabetes. Front Immunol. 2015;6:386.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Sah R, et al. Interaction of NPY compounds with the rat glucocorticoid-induced receptor (GIR) reveals similarity to the NPY-Y2 receptor. Peptides. 2007;28(2):302–9.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Salgado FJ, et al. A role for IL-12 in the regulation of T cell plasma membrane compartmentation. J Biol Chem. 2003;278(27):24849–57.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Sherwood NM, et al. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev. 2000;21(6):619–70.PubMedCentralPubMedGoogle Scholar
  27. Wagner L, et al. Proteolytic degradation of neuropeptide Y (NPY) from head to toe: identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. J Neurochem. 2015;135(5):1019–37.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Wagner L, et al. Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation. Neuropeptides. 2016a;57:21–34.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Wagner L, et al. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin Exp Immunol. 2016b;184(3):265–83.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Wang Z, et al. Soluble DPP4 originates in part from bone marrow cells and not from the kidney. Peptides. 2014;57:109–17.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Waumans Y, et al. The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease including atherosclerosis. Front Immunol. 2015;6:387.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Waumans Y, et al. The dipeptidyl peptidases 4, 8, and 9 in mouse monocytes and macrophages: DPP8/9 inhibition attenuates M1 macrophage activation in mice. Inflammation. 2016;39(1):413–24.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Weihofen WA, et al. Crystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface. J Biol Chem. 2004;279(41):43330–5.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Weihofen WA, et al. Crystal structures of HIV-1 Tat-derived nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) bound to the active site of dipeptidyl-peptidase IV (CD26). J Biol Chem. 2005;280(15):14911–7.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Yu DM, et al. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J. 2010;277(5):1126–44.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Deutschsprachige Selbsthilfegruppe für Alkaptonurie e.VStuttgartGermany