Tuesday, April 26, 2011

DPPIV is awesome!

I would like to convince you that Dipeptidyl Peptidase IV, or DPPIV, is the most awesome protein that you will encounter this year.  I think DPPIV deserves this title do to its beautiful structure, its catalytic mechanism, and its many cellular functions.  I will explain each in turn.

As you can see, there are four distinct subunits.  However, DPPIV functions as a dimer of dimers – essentially, two homodimer subunits, each one membrane-bound to the outside of a cell, come together to form a fully-functional tetramer. 

The active site is a large cavity in each subunit, in between the β-propeller domain and the α-helix domain.  The eight-bladed β-propeller domain can be seen here as the yellow anti-parallel beta sheets, while the alpha helix subunits are in red. 




The active site in each subunit can be accessed by the substrate from two different points: a small area in the middle of the β-propeller domain, or a larger area on the side of the protein in between the two domains.  DPPIV is shown here in its dimeric form.  


In short, the active site facilitates the cleavage of two peptides from the end of a protein, where the last amino acid is a proline (DPPIV also functions to a lesser extent when the last amino acid is an alanine).  DPPIV works as a typical serine protease (such as chymotrypsin), resulting in either the activation or inactivation of the substrate.  It is thought that the substrate generally leaves through the side opening, while the cleaved peptides leave through the β-propeller domain.  

DPPIV is regulated by glucose, with higher glycosylation decreasing enzyme activity.  The numerous sites help fine-tune the activity of the enzyme.  To get an idea of potential glycosylation sites, here’s a picture with the sugar shown as spheres:




Furthermore, DPPIV is regulated through gene expression and protein synthesis.  It should also be noted that DPPIV behaves differently when only one homodimer is bound to a cell.  Adenosine also down-regulates the expression of DPPIV on the surface of the cell.

So what does DPPIV do?  Well, it is expressed in most human cells and involved in many functions, some of which are good, and some of which are not as good.

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.  Interestingly, berberine inhibits DPPIV. 

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.  Further 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 interact 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.
DPPIV has also shown to be involved in immune regulation, signal transduction, and apoptosis.  Low levels of DPPIV have been correlated with depression, and it is thought that DPPIV activity is altered in patients with eating disorders.

In conclusion, then, DPPIV is a fantastic protein due to its structure, catalytic mechanisms, and cellular functions that are both diverse and important.


Saturday, April 9, 2011

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

Tuesday, March 1, 2011

Dipeptidyl peptidase IV

Here's some different views of the protein Dipeptidyl Peptidase IV:


The first image shows the protein as a homodimer without any ligands bound to it. (1PFQ)

The second image shows four subunits with ligands bound (Beta-D-Manose and N-Acetyl-D-Glucosamine). (1ORV)


This is a close-up of the N-Acetyl-D-Glucosamine on one of the subunits.  (1ORV)
Here's a space-filling model.  (1ORV)
And a mesh view with space-filling ligands (1ORV).

And finally, one more view to help visualize the four subunits and surrounding water molecules.  (1ORV)