DPP IV

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Introduction

Dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5) is a prolyl peptidase, which preferentially cleaves proteins and peptides after a proline residue. DPP IV can preferentially cleave the Xaa-Pro or Xaa-Ala dipeptide from the N-terminus of peptide (where Xaa is any amino acid except Pro). DPP IV is also a CD26 T cell activating antigen found in almost all human organs and tissues. It is strongly expressed in many tissues, including the exocrine pancreas, gastrointestional tract, kidney, biliary tract, thymus, lymph nodes, adrenal, sweat glands, uterus, placenta, prostate, salivary and mammary glands, etc. DPP IV is anchored to the plasma membrane of endothelial of almost all organs examined, and it has also been found solubilized in body fluids, such as cerebrospinal fluid and blood plasma. DPP IV can easily obtain endocrine peptides, neuropeptides, and a wide range of polypeptides.

Although DPP IV is a pleiotropic enzyme, it is known for its ability to inactivate two intestinal hormones called incretin, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP IV degrades GLP-1 and GIP very rapidly, and leads to the formation of metabolites lacking insulin-areleasing activity. Therefore, preventing the degradation of the incretin hormones by inhibiting DPP IV has become a potential therapeutic strategy. Research on the synthetic incretin analogs has spawned a series of DPP IV resistant analogs of GLP-1 and GIP. Some of these analogs are currently undergoing preclinical and clinical trials, and the GLP-1 mimic Byetta was introduced in the United States in 2005.

Figure 1. The two-pronged strategy for unlocking the therapeutic potential of the incretin hormones

Antidiabetic actions of the incretin hormones

Although GLP-1 and GIP were discovered and received attention as insulin-releasing peptide hormones, subsequent studies have shown that many other potential pancreatic and extra-pancreatic effects are also attributable to them. In the pancreatic islets, GLP-1 and GIP have very important effects on β cells, such as expanding β cell mass and increasing β cell survival. Extra-pancreatic effects include reducing hepatic insulin clearance and promoting glucose uptake and metabolism. The most notable are the inhibition of glucagon secretion, induction of satiety, tendency for weight loss and the reduced rate of gastric emptying associated with GLP-1.

Table 1. Key actions of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide)

Other members of the DPP IV enzyme family

Research on DPP IV discovered an enzyme family with DPP IV-like activity, re-opening the issue of inhibitor selectivity. Enzymes with DPP IV-like activity include fibroblast activation protein (FAP), dipeptidyl peptidase II (DPP II, also known as DPP 7 or quiescent cell proline dipeptidase [QPP]), dipeptidyl peptidase 8 (DPP 8) and dipeptidyl peptidase 9 (DPP 9). FAP is a membrane-bound protease with dipeptidyl peptidase activity and can cleave the N-terminal dipeptide from polypeptides. FAP also has collagen solubilizing activity to degrade gelatin and type I collagen. At present, the expression of FAP has been found in α cells of the pancreas and in serum. DPP II has been found to be expressed in a range of human tissues. DPP 8 and DPP 9 are widely distributed post-proline cleaving dipeptidases. Their ability to hydrolyze substrates derived from H-Ala-Pro and H-Gly-Pro proves their DPP IV-like activity. The selective inhibition of DPP 8/9 attenuated T cell activation indicates that these enzymes are involved in the immune system. The early observation that the plasma of DPPIV-deficient mice can cleave the substrate Gly-Pro pNA can predict the presence of other DPPIV-like enzymes.