Dipeptidyl peptidase-4

Function

The protein encoded by the DPP4 gene is an enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction, and apoptosis. It is a type II transmembrane glycoprotein, but a soluble form, which lacks the intracellular and transmembrane part, is present in blood plasma and various body fluids. DPP-4 is a serine exopeptidase that cleaves X-proline or X-alanine dipeptides from the N-terminus of polypeptides. Peptide bonds involving the cyclic amino acid proline cannot be cleaved by the majority of proteases and an N-terminal X-proline "shields" various biopeptides. Extracellular proline-specific proteases therefore play an important role in the regulation of these biopeptides.

DPP-4 is known to cleave a broad range of substrates including growth factors, chemokines, neuropeptides, and vasoactive peptides. The cleaved substrates lose their biological activity in the majority of cases, but in the case of the chemokine RANTES and neuropeptide Y, DPP-4 mediated cleavage leads to a shift in the receptor subtype binding.

DPP4 plays a major role in glucose metabolism. It is responsible for the degradation of incretins such as GLP-1. Furthermore, it appears to work as a suppressor in the development of some tumors.

DPP-4 also binds the enzyme adenosine deaminase specifically and with high affinity. The significance of this interaction has yet to be established.

Animal studies

Animal studies suggest its pathogenetic role in development of fibrosis of various organs, such as liver and kidney.

Clinical significance

CD26/DPPIV plays an important role in tumor biology, and is useful as a marker for various cancers, with its levels either on the cell surface or in the serum increased in some neoplasms and decreased in others.

A class of oral hypoglycemics called dipeptidyl peptidase-4 inhibitors works by inhibiting the action of this enzyme, thereby prolonging incretin effect in vivo.

Middle East respiratory syndrome coronavirus has been found to bind to DPP4. It is found on the surface of cells in the airways (such as the lungs) and kidneys. Scientists may be able to use this to their advantage by blocking the virus's entry into the cell.

DPP4, or its Mycobacterial homologue MtDPP, might play a role in the pathogenesis of tuberculosis via cleavage of the chemokine C-X-C motif chemokine ligand 10 (CXCL10).

References

References

1. (July 1993). "Direct association of adenosine deaminase with a T cell activation antigen, CD26". Science.
2. (1966). "A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide". Histochemie. Histochemistry. Histochimie.
3. (June 1995). "Proline motifs in peptides and their biological processing". FASEB Journal.
4. (November 1999). "Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides". Regulatory Peptides.
5. (2006). "Dipeptidyl Aminopeptidases".
6. (November 2006). "DPP-4 inhibitors and their potential role in the management of type 2 diabetes". International Journal of Clinical Practice.
7. (October 2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histology and Histopathology.
8. (December 2006). "DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells". Regulatory Peptides.
9. (February 2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Research.
10. (March 2004). "Dipeptidyl peptidase IV activity and/or structure homologues (DASH) and their substrates in cancer". The International Journal of Biochemistry & Cell Biology.
11. (March 2014). "Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats". Journal of Gastroenterology.
12. (June 2014). "Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction". Laboratory Investigation; A Journal of Technical Methods and Pathology.
13. (January 2008). "The role of CD26/dipeptidyl peptidase IV in cancer". Frontiers in Bioscience.
14. (April 2007). "Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus". Current Opinion in Endocrinology, Diabetes and Obesity.
15. "Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions". Front Immunol.
16. (Jan 2023). "The Mycobacterium tuberculosis prolyl dipeptidyl peptidase cleaves the N-terminal peptide of the immunoprotein CXCL-10". Biol Chem.