Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders

Abstract

DP (dipeptidyl peptidase) IV is the archetypal member of its six-member gene family. Four members of this family, DPIV, FAP (fibroblast activation protein), DP8 and DP9, have a rare substrate specificity, hydrolysis of a prolyl bond two residues from the N-terminus. The ubiquitous DPIV glycoprotein has proved interesting in the fields of immunology, endocrinology, haematology and endothelial cell and cancer biology and DPIV has become a novel target for Type II diabetes therapy. The crystal structure shows that the soluble form of DPIV comprises two domains, an alpha/beta-hydrolase domain and an eight-blade beta-propeller domain. The propeller domain contains the ADA (adenosine deaminase) binding site, a dimerization site, antibody epitopes and two openings for substrate access to the internal active site. FAP is structurally very similar to DPIV, but FAP protein expression is largely confined to diseased and damaged tissue, notably the tissue remodelling interface in chronically injured liver. DPIV has a variety of peptide substrates, the best studied being GLP-1 (glucagon-like peptide-1), NPY (neuropeptide Y) and CXCL12. The DPIV family has roles in bone marrow mobilization. The functional interactions of DPIV and FAP with extracellular matrix confer roles for these proteins in cancer biology. DP8 and DP9 are widely distributed and indirectly implicated in immune function. The DPL (DP-like) glycoproteins that lack peptidase activity, DPL1 and DPL2, are brain-expressed potassium channel modulators. Thus the six members of the DPIV gene family exhibit diverse biological roles.

An Inhibitory Antibody against Dipeptidyl Peptidase IV Improves Glucose Tolerance in Vivo

“…DPP-IV activity is involved in many functions of the metabolic, endocrine, and immune systems and is implicated in regulating cell adhesion, cancer growth, and bone marrow mobilization (44). Its physiological substrates include GIP, GLP-1, substance P, and chemokines SDF1a (stromal cellderived factor 1 a) and SDF1b (45).…”

Sitagliptin induced splenic infarcts

“…DPP-4, also known as CD26, is expressed by microvascular endothelial cells in humans (i.e. in liver, spleen, lungs and brain) and in the hearts of rats [6,7]. DPP-4 has the potential to inhibit fibrin polymerization and clot formation [8,9].…”

Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2

“…Фермент представлен как мембрансвязанной, так и в небольшом количестве свободной формой. У человека ДПП-4 экспрессируется на эпителиальных клетках, эндотелии капилляров, лимфоцитах, в желудочно-кишечном тракте, в экзокринных ацинарных клетках поджелудочной железы, почках, тимусе, матке, плаценте, лимфатических узлах, предстательной железе, надпочечниках, паращитовидных, потовых, молочных железах, печени, селезенке, лёгких и головном мозге [6,7]. Фермент представляет собой белок из 766 аминокислот и состоит из двух доменов: N-терминального b-пропеллера и C-терминального a/b-гидролазного домена, которые формируют большую полость, содержащую активный сайт связывания.…”