Deipeptidyl Peptidase information

Dipeptidyl Peptidase IV, or DPPIV, is an enzyme expressed in most human cells, and regulates cellular function through a variety of roles.  DPPIV is involved in immune regulation, signal transduction, apoptosis, glucose metabolism, and cancer suppression.  The diversity of substrates that DPPIV works on makes it not only extremely important physiologically, but an interesting protein to examine.  Substrates are proline and alanine containing peptides

Currently, DPPIV inhibitors are being developed as a treatment for Type 2 diabetes.  DPPIV rapidly degrades incretins (gastrointestinal hormones that cause more insulin to be released), preventing them from stimulating insulin release.  Degradation is caused by DPPIV cleaving two amino acids from the N-terminus of the incretins, resulting in severely decreased functionality to the incretins.  By inhibiting DPPIV, the incretins may remain active long enough to properly stimulate insulin release.  (1)  Interestingly, berberine inhibits DPPIV.  (2)

DPPIV is also important in cancer regulation.  In general, a higher level of DPPIV correlates with a lower level of cancerous cells.  Therefore, by checking the level of DPPIV it is possible to get an idea what the progress of a cancer is.  This has been shown true with many cancer types, including liver, skin, and lung.  Evidence suggests that DPPIV reduces cell growth once confluency has been reached.  Furthr evidence indicates that DPPIV plays a role in surface adhesion.

It should be noted, however, that in some cancer types (ovarian and thyroid cancer, for example) DPPIV has been shown to play a role in the cancer invasion.  This is most likely due to the specific glycoproteins that play a role in cell-cell adhesion.  As DPPIV is a transmembrane protein (with a solved crystal structure), it may intereact closely with the glycoproteins.  It is also thought that DPPIV may play a role in cancer cell migration.  DPPIV is therefore a potential target to combat specific cancers(3)

Crystal structures reveal that the active site of DPPIV contains a sodium ion and glycerol molecule. An in-depth analysis of the active site revealed that positively charged functional groups and conserved water molecules lead to enhanced ligand interactions.  This is useful for understanding how to design a molecule to inhibit DPPIV. (4)

1. Carolyn F Deacon, Bo Ahrén, and Jens J Holst, “Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes?,” Expert Opinion on Investigational Drugs 13, no. 9 (9, 2004): 1091-1102.  http://informahealthcare.com/doi/pdf/10.1517/13543784.13.9.1091
2. Al-Masri IM, Mohammad MK, Tahaa MO (July 2009). "Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine". Journal of Enzyme Inhibition and Medicinal Chemistry 0 (5): 090729101626017.  http://www.ncbi.nlm.nih.gov/pubmed/19640223
3. B. Pro and N.H. Dang, "CD26/dipeptidyl peptidase IV and its role in cancer," Cellular and Molecular Biology, (19,2004) 1345-1351  http://www.hh.um.es/Abstracts/Vol_19/19_4/19_4_1345.htm
4. Hajime Hiramatsu et al., “Crystal Structures of Human Dipeptidyl Peptidase IV in its Apo and Diprotin B-complexed Forms,” Acta Biochimica et Biophysica Sinica 39, no. 5 (May 1, 2007): 335 -343.  http://abbs.oxfordjournals.org/content/39/5/335.long