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

2005 ◽  
Vol 108 (4) ◽  
pp. 277-292 ◽  
Author(s):  
Mark D. GORRELL
Keyword(s):  
Gene Family ◽  
Cell Biology ◽  
Cancer Biology ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Soluble Form ◽  
Peptidase Activity ◽  
Tissue Remodelling ◽  
Glucagon Like Peptide 1 ◽  
Novel Target

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 α/β-hydrolase domain and an eight-blade β-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.

scholarly journals Influence of dipeptidyl peptidase IV on enzymatic properties of adenosine deaminase.

2006 ◽  
Vol 53 (3) ◽  
pp. 539-546 ◽  
Author(s):  
Svetlana Sharoyan ◽  
Alvard Antonyan ◽  
Sona Mardanyan ◽  
Giulio Lupidi ◽  
Gloria Cristalli
Keyword(s):  
Adenosine Deaminase ◽  
Immune Cell ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Soluble Form ◽  
Kidney Cortex ◽  
Peptidase Activity ◽  
Extracellular Medium ◽  
Ph Profile ◽  
Enzyme Preparations

The importance of ADA (adenosine deaminase) in the immune system and the role of its interaction with an ADA-binding cell membrane protein dipeptidyl peptidase IV (DPPIV), identical to the activated immune cell antigen, CD26, has attracted the interest of researchers for many years. To investigate the specific properties in the structure-function relationship of the ADA/DPPIV-CD26 complex, its soluble form, identical to large ADA (LADA), was isolated from human blood serum, human pleural fluid and bovine kidney cortex. The kinetic constants (Km and Vmax) of LADA and of small ADA (SADA), purified from bovine lung and spleen, were compared using adenosine (Ado) and 2'-deoxyadenosine (2'-dAdo) as substrates. The Michaelis constant, Km, evidences a higher affinity of both substrates (in particular of more toxic 2'-dAdo) for LADA and proves the modulation of toxic nucleoside neutralization in the extracellular medium due to complex formation between ADA and DPPIV-CD26. The values of Vmax are significantly higher for SADA, but the efficiency, Vmax/Km, in LADA-catalyzed 2'-dAdo deamination is higher than that in Ado deamination. The interaction of all enzyme preparations with derivatives of adenosine and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was studied. 1-DeazaEHNA and 3-deazaEHNA demonstrate stronger inhibiting activity towards LADA, the DPPIV-CD26-bound form of ADA. The observed differences between the properties of the two ADA isoforms may be considered as a consequence of SADA binding with DPPIV-CD26. Both SADA and LADA indicated a similar pH-profile of adenosine deamination reaction with the optimum at pHs 6.5-7.5, while the pH-profile of dipeptidyl peptidase activity of the ADA/DPPIV-CD26 complex appeared in a more alkaline region.

scholarly journals Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs

2002 ◽  
Vol 172 (2) ◽  
pp. 355-362 ◽  
Author(s):  
CF Deacon ◽  
S Wamberg ◽  
P Bie ◽  
TE Hughes ◽  
JJ Holst
Keyword(s):  
Plasma Concentrations ◽  
Dipeptidyl Peptidase ◽  
Feedback Mechanism ◽  
Dipeptidyl Peptidase Iv ◽  
Biologically Active ◽  
Incretin Hormones ◽  
Dpp Iv ◽  
Incretin Secretion ◽  
Glucagon Like Peptide 1

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined. Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment. Total and intact incretin concentrations increased (P<0.0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P<0.01) than total peptide concentrations (22.6 +/- 1.2% intact GIP; 10.1 +/- 0.4% intact GLP-1). Following inhibitor treatment, the proportion of intact peptide increased (92.5 +/- 4.3% intact GIP, P<0.0001; 99.0 +/- 22.6% intact GLP-1, P<0.02). Active (intact) incretins increased after NVP-DPP728 (from 4797 +/- 364 to 10 649 +/- 106 pM x min for GIP, P<0.03; from 646 +/- 134 to 2822 +/- 528 pM x m in for GLP-1, P<0.05). In contrast, total incretins fell (from 21 632 +/- 654 to 12 084 +/- 1723 pM x min for GIP, P<0.002; from 5145 +/- 677 to 3060 +/- 601 pM x min for GLP-1, P<0.05). Plasma glucose, insulin and glucagon concentrations were unaltered by the inhibitor. We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.

scholarly journals Biosynthesis of intestinal microvillar proteins. Pulse-chase labelling studies on maltase-glucoamylase, aminopeptidase A and dipeptidyl peptidase IV

1983 ◽  
Vol 210 (2) ◽  
pp. 389-393 ◽  
Author(s):  
E M Danielsen ◽  
H Sjöström ◽  
O Norén
Keyword(s):  
Organ Culture ◽  
Membrane Fraction ◽  
Bound State ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Soluble Form ◽  
Membrane Bound ◽  
Aminopeptidase A ◽  
High Mannose ◽  
Small Intestinal

The biogenesis of three intestinal microvillar enzymes, maltase-glucoamylase (EC 3.2.1.20), aminopeptidase A (aspartate aminopeptidase, EC 3.4.11.7) and dipeptidyl peptidase IV (EC 3.4.14.5), was studied by pulse-chase labelling of pig small-intestinal explants kept in organ culture. The earliest detectable forms of the enzymes were polypeptides of Mr 225000, 140000 and 115000 respectively. These were found to represent the enzymes in a ‘high-mannose’ state of glycosylation, as judged by their susceptibility to treatment with endo-beta-N-acetylglucosaminidase H (EC 3.2.1.96). After about 40-60 min of chase, maltase-glucoamylase, aminopeptidase A and dipeptidyl peptidase IV were further modified to yield the mature polypeptides of Mr 245000, 170000 and 137000 respectively, which were expressed at the microvillar membrane after 60-90 min of chase. The fact that the enzymes before reaching the microvillar membrane were found in a Ca2+-precipitated membrane fraction (intracellular and basolateral membranes), but not in soluble form, indicates that during biogenesis maltase-glucoamylase, aminopeptidase A and dipeptidyl peptidase IV are transported and assembled in a membrane-bound state.

scholarly journals Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

2003 ◽  
Vol 31 (3) ◽  
pp. 529-540 ◽  
Author(s):  
BD Green ◽  
VA Gault ◽  
MH Mooney ◽  
N Irwin ◽  
CJ Bailey ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Biological Activities ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Glucose Lowering ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

scholarly journals Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV

2006 ◽  
Vol 396 (2) ◽  
pp. 391-399 ◽  
Author(s):  
Jais R. Bjelke ◽  
Jesper Christensen ◽  
Per F. Nielsen ◽  
Sven Branner ◽  
Anders B. Kanstrup ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Expression System ◽  
Baculovirus Expression System ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Dipeptidyl Peptidases ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dipeptidyl Peptidase Iv Inhibition

Dipeptidyl peptidases 8 and 9 have been identified as gene members of the S9b family of dipeptidyl peptidases. In the present paper, we report the characterization of recombinant dipeptidyl peptidases 8 and 9 using the baculovirus expression system. We have found that only the full-length variants of the two proteins can be expressed as active peptidases, which are 882 and 892 amino acids in length for dipeptidyl peptidase 8 and 9 respectively. We show further that the purified proteins are active dimers and that they show similar Michaelis–Menten kinetics and substrate specificity. Both cleave the peptide hormones glucagon-like peptide-1, glucagon-like peptide-2, neuropeptide Y and peptide YY with marked kinetic differences compared with dipeptidyl peptidase IV. Inhibition of dipeptidyl peptidases IV, 8 and 9 using the well-known dipeptidyl peptidase IV inhibitor valine pyrrolidide resulted in similar Ki values, indicating that this inhibitor is non-selective for any of the three dipeptidyl peptidases.

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