The Experts below are selected from a list of 14157 Experts worldwide ranked by ideXlab platform
Ingrid De Meester - One of the best experts on this subject based on the ideXlab platform.
-
the Dipeptidyl Peptidase family prolyl oligoPeptidase and prolyl carboxyPeptidase in the immune system and inflammatory disease including atherosclerosis
Frontiers in Immunology, 2015Co-Authors: Yannick Waumans, Anne-marie Lambeir, Lesley Baerts, Kaat Kehoe, Ingrid De MeesterAbstract:Research from over the past 20 years has implicated Dipeptidyl Peptidase (DPP) IV and its family members in many processes and different pathologies of the immune system. Most research has been focused on either DPPIV or just a few of its family members. It is, however, essential to consider the entire DPP family when discussing any one of its members. There is a substantial overlap between family members in their substrate specificity, inhibitors, and functions. In this review, we provide a comprehensive discussion on the role of prolyl-specific Peptidases DPPIV, FAP, DPP8, DPP9, Dipeptidyl Peptidase II, prolyl carboxyPeptidase, and prolyl oligoPeptidase in the immune system and its diseases. We highlight possible therapeutic targets for the prevention and treatment of atherosclerosis, a condition that lies at the frontier between inflammation and cardiovascular disease.
-
inhibition of Dipeptidyl Peptidase iv catalyzed peptide truncation by vildagliptin 2s 3 hydroxyadamantan 1 yl amino acetyl pyrrolidine 2 carbonitrile
Biochemical Pharmacology, 2005Co-Authors: Inger Brandt, Ingrid De Meester, Simon Scharpé, Jurgen Joossens, Xin Chen, M Maes, Anne-marie LambeirAbstract:Abstract Vildagliptin (NVP-LAF237/(2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile) was described as a potent, selective and orally bio-available Dipeptidyl-Peptidase IV (DPP IV, EC 3.4.14.5) inhibitor [Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, et al.1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable Dipeptidyl Peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003;46:2774–89]. Phase III clinical trials for the use of this compound in the treatment of Type 2 diabetes were started in the first quarter of 2004. In this paper, we report on (1) the kinetics of binding, (2) the type of inhibition, (3) the selectivity with respect to other Peptidases, and (4) the inhibitory potency on the DPP IV catalyzed degradation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and substance P. Vildagliptin behaved as a slow-binding DPP IV inhibitor with an association rate constant of 1.4 × 105 M−1 s−1 and a Ki of 17 nM. It is a micromolar inhibitor for Dipeptidyl-Peptidase 8 and does not significantly inhibit Dipeptidyl-Peptidase II (EC 3.4.11.2), prolyl oligoPeptidase (EC 3.4.21.26), aminoPeptidase P (EC 3.4.11.9) or aminoPeptidase M (EC 3.4.11.2). There was no evidence for substrate specific inhibition of DPP IV by Vildagliptin or for important allosteric factors affecting the inhibition constant in presence of GIP and GLP-1.
-
Kinetic investigation of human Dipeptidyl Peptidase II (DPPII)-mediated hydrolysis of dipeptide derivatives and its identification as quiescent cell proline diPeptidase (QPP)/Dipeptidyl Peptidase 7 (DPP7)
Biochemical Journal, 2005Co-Authors: Marie-berthe Maes, Kristel Senten, Pieter Van Der Veken, Koen Augustyns, Kambiz Gilany, Barbara Leiting, Anne-marie Lambeir, Simon Scharpé, Ingrid De MeesterAbstract:The presence of DPPII (Dipeptidyl Peptidase II; E.C. 3.4.14.2) has been demonstrated in various mammalian tissues. However, a profound molecular and catalytic characterization, including substrate selectivity, kinetics and pH-dependence, has not been conducted. In the present study, DPPII was purified from human seminal plasma to apparent homogeneity with a high yield (40%) purification scheme, including an inhibitor-based affinity chromatographic step. The inhibitor lysyl-piperidide (Ki~0.9 μM at pH 5.5) was chosen, as it provided a favourable affinity/recovery ratio. The human enzyme appeared as a 120 kDa homodimer. Mass spectrometric analysis after tryptic digestion together with a kinetic comparison indicate strongly its identity with QPP (quiescent cell proline diPeptidase), also called Dipeptidyl Peptidase 7. pH profiles of both kcat and kcat/Km clearly demonstrated that DPPII/QPP possesses an acidic and not a neutral optimum as was reported for QPP. Kinetic parameters of the human natural DPPII for dipeptide-derived chromogenic [pNA (p-nitroanilide)] and fluorogenic [4Me2NA (4-methoxy-2-naphthylamide)] substrates were determined under different assay conditions. DPPII preferred the chromogenic pNA-derived substrates over the fluorogenic 4Me2NA-derived substrates. Natural human DPPII showed high efficiency towards synthetic substrates containing proline at the P1 position and lysine at P2. The importance of the P1′ group for P2 and P1 selectivity was revealed, explaining many discrepancies in the literature. Furthermore, substrate preferences of human DPPII and Dipeptidyl Peptidase IV were compared based on their selectivity constants (kcat/Km). Lys-Pro-pNA (kcat/Km 4.1×106 s−1·M−1) and Ala-Pro-pNA (kcat/Km 2.6×106 s−1· M−1) were found to be the most sensitive chromogenic substrates for human DPPII, but were less selective than Lys-Ala-pNA (kcat/Km 0.4×106 s−1·M−1).
-
molecular characterization of Dipeptidyl Peptidase activity in serum soluble cd26 Dipeptidyl Peptidase iv is responsible for the release of x pro dipeptides
FEBS Journal, 2000Co-Authors: Christine Durinx, Anne-marie Lambeir, Simon Scharpé, Eugene Bosmans, Jeanbernard Falmagne, Raf Berghmans, Achiel Haemers, Ingrid De MeesterAbstract:Dipeptidyl Peptidase IV (DPPIV, EC 3.4.14.5) is a serine type protease with an important modulatory activity on a number of chemokines, neuropeptides and peptide hormones. It is also known as CD26 or adenosine deaminase (ADA; EC 3.5.4.4) binding protein. DPPIV has been demonstrated on the plasmamembranes of T cells and activated natural killer or B cells as well as on a number of endothelial and differentiated epithelial cells. A soluble form of CD26/DPPIV has been described in serum. Over the past few years, several related enzymes with similar Dipeptidyl Peptidase activity have been discovered, raising questions on the molecular origin(s) of serum Dipeptidyl Peptidase activity. Among them attractin, the human orthologue of the mouse mahogany protein, was postulated to be responsible for the majority of the DPPIV-like activity in serum. Using ADA-affinity chromatography, it is shown here that 95% of the serum Dipeptidyl Peptidase activity is associated with a protein with ADA-binding properties. The natural protein was purified in milligram quantities, allowing molecular characterization (N-terminal sequence, glycosylation type, CD-spectrum, pH and thermal stability) and comparison with CD26/DPPIV from other sources. The purified serum enzyme was confirmed as CD26.
Carolyn F Deacon - One of the best experts on this subject based on the ideXlab platform.
-
effects of Dipeptidyl Peptidase iv inhibition on glycemic gut hormone triglyceride energy expenditure and energy intake responses to fat in healthy males
American Journal of Physiology-endocrinology and Metabolism, 2014Co-Authors: Gabriella Heruc, Carolyn F Deacon, Michael Horowitz, Christine Feinlebisset, Christopher K Rayner, Natalie D Luscombemarsh, Tanya J LittleAbstract:Fat is the most potent stimulus for glucagon-like peptide-1 (GLP-1) secretion. The aims of this study were to determine whether Dipeptidyl Peptidase IV (DPP-IV) inhibition would enhance plasma acti...
-
Dipeptidyl Peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.
The international journal of biochemistry & cell biology, 2005Co-Authors: Carolyn F DeaconAbstract:Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic beta-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactivated by the serine Peptidase, Dipeptidyl Peptidase IV, so that the native peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally active Dipeptidyl Peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effective in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3-12 months duration in patients with type 2 diabetes, Dipeptidyl Peptidase IV inhibitors have proved efficacious, both as monotherapy and when given in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while beta-cell function was preserved. Current information suggests Dipeptidyl Peptidase IV inhibitors are body weight neutral and are well tolerated. A number of Dipeptidyl Peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
-
glucagon like peptide 1 and inhibitors of Dipeptidyl Peptidase iv in the treatment of type 2 diabetes mellitus
Current Opinion in Pharmacology, 2004Co-Authors: Carolyn F DeaconAbstract:Proof-of-concept for the efficacy of a glucagon-like peptide 1 (GLP-1)-based therapy of patients with type 2 diabetes was provided in 2002 by means of prolonged continuous subcutaneous infusion of native GLP-1. Since then, several long-acting analogues of GLP-1, as well as inhibitors of Dipeptidyl Peptidase IV, the enzyme that rapidly inactivates endogenous GLP-1, have demonstrated efficacy in long term clinical trials.
-
Dipeptidyl Peptidase iv resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological activity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, Liselotte Bjerre Knudsen, K Madsen, F C Wiberg, O JacobsenAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by Dipeptidyl Peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or α-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to Dipeptidyl Peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7–36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50 % of each analogue remained undegraded compared to 22.7 % for GLP-1 (7–36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3–3.9 min) than GLP-1 (7–36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to Dipeptidyl Peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy. [Diabetologia (1998) 41: 271–278]
-
Dipeptidyl Peptidase iv resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological activity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, K Madsen, F C Wiberg, Lotte Bjerre Knudsen, O JacobsenAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by Dipeptidyl Peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to Dipeptidyl Peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to Dipeptidyl Peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.
Mark D Gorrell - One of the best experts on this subject based on the ideXlab platform.
-
soluble cd26 Dipeptidyl Peptidase iv enhances human lymphocyte proliferation in vitro independent of Dipeptidyl Peptidase enzyme activity and adenosine deaminase binding
Scandinavian Journal of Immunology, 2011Co-Authors: L Slaitini, Geoffrey W Mccaughan, Catherine A Abbott, V Gysbers, A G M Riekhoff, Thilo Kahne, H M Knott, I De Meester, Mark D GorrellAbstract:Human CD26 has Dipeptidyl Peptidase-4 (DPP IV) enzyme activity and binds to adenosine deaminase (ADA). CD26 is costimulatory for lymphocytes and has a circulating soluble form (sCD26). DPP IV enzyme inhibition is a new successful type 2 diabetes therapy. We examined whether the ADA binding and catalytic functions of sCD26 contribute to its effects on T-cell proliferation. Wildtype soluble recombinant human CD26 (srhCD26), an enzyme inactive mutant (srhCD26E-) and an ADA non-binding mutant (srhCD26A-) were co-incubated in in vitro T-cell proliferation assays with peripheral blood mononuclear cells (PBMC) stimulated with phytohaemagglutinin (PHA), muromonab-CD3 or Herpes simplex virus antigen (HSV Ag). Both srhCD26 and srhCD26E- enhanced PHA-induced T-cell proliferation dose-dependently in all six subjects tested. srhCD26 and srhCD26A- had no overall effect on anti-CD3-stimulated PBMC proliferation in four of five subjects. srhCD26, srhCD26E- and srhCD26A- enhanced HSV Ag induced PBMC proliferation in low responders to HSV Ag, but had no effect or inhibited proliferation in HSV-high responders. Thus, effects of soluble human CD26 on human T-cell proliferation are mechanistically independent of both the enzyme activity and the ADA-binding capability of sCD26.
-
extraenzymatic functions of the Dipeptidyl Peptidase iv related proteins dp8 and dp9 in cell adhesion migration and apoptosis
FEBS Journal, 2006Co-Authors: Xin M Wang, Geoffrey W Mccaughan, Mark D GorrellAbstract:The Dipeptidyl Peptidase IV gene family contains the four Peptidases Dipeptidyl Peptidase IV, fibroblast activation protein, Dipeptidyl Peptidase 8 and Dipeptidyl Peptidase 9. Dipeptidyl Peptidase IV and fibroblast activation protein are involved in cell–extracellular matrix interactions and tissue remodeling. Fibroblast activation protein is upregulated and Dipeptidyl Peptidase IV is dysregulated in chronic liver disease. The effects of Dipeptidyl Peptidase 8 and Dipeptidyl Peptidase 9 on cell adhesion, cell migration, wound healing and apoptosis were measured by using green fluorescent protein fusion proteins to identify transfected cells. Dipeptidyl Peptidase 9-overexpressing cells exhibited impaired cell adhesion, migration in transwells and monolayer wound healing on collagen I, fibronectin and Matrigel. Dipeptidyl Peptidase 8-overexpressing cells exhibited impaired cell migration on collagen I and impaired wound healing on collagen I and fibronectin in comparison to the green fluorescent protein-transfected controls. Dipeptidyl Peptidase 8 and Dipeptidyl Peptidase 9 enhanced induced apoptosis, and Dipeptidyl Peptidase 9 overexpression increased spontaneous apoptosis. Mechanistic investigations showed that neither the catalytic serine of Dipeptidyl Peptidase 8 or Dipeptidyl Peptidase 9 nor the Arg-Gly-Asp integrin-binding motif in Dipeptidyl Peptidase 9 were required for the impairment of cell survival, cell adhesion or wound healing. We have previously shown that the in vitro roles of Dipeptidyl Peptidase IV and fibroblast activation protein in cell–extracellular matrix interactions and apoptosis are similarly independent of catalytic activity. Dipeptidyl Peptidase 9 overexpression reduced β-catenin, tissue inhibitor of matrix metalloproteinases 2 and discoidin domain receptor 1 expression. This is the first demonstration that Dipeptidyl Peptidase 8 and Dipeptidyl Peptidase 9 influence cell–extracellular matrix interactions, and thus may regulate tissue remodeling.
-
fibroblast activation protein a cell surface Dipeptidyl Peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis
Hepatology, 1999Co-Authors: Miriam T Levy, Geoffrey W Mccaughan, Catherine A Abbott, John Edward Park, Anne M Cunningham, Erika Muller, Wolfgang J Rettig, Mark D GorrellAbstract:Fibroblast activation protein (FAP) is a cell surface-bound protease of the prolyl oligoPeptidase gene family expressed at sites of tissue remodelling. This study aimed to delineate the expression of FAP in cirrhotic human liver and examine its biochemical activities. Seventeen cirrhotic and 8 normal liver samples were examined by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). Hepatic stellate cells (HSC) were isolated and immunostained. Recombinant FAP and immunopurified, natural FAP were analyzed for protease activities and similarities to Dipeptidyl Peptidase IV (DPPIV), a structurally related enzyme. FAP-specific messenger RNA and immunoreactivity were detected in cirrhotic, but not normal, livers. FAP immunoreactivity was most intense on perisinusoidal cells of the periseptal regions within regenerative nodules (15 of 15 cases); this pattern coincides with the tissue remodelling interface. In addition, human FAP was expressed by cells within the fibrous septa (10 of 15 cases). Cell morphology, location, and colocalization with glial fibrillary acidic protein (GFAP) indicated that FAP is present on HSC in vivo. Similarly, isolated HSC expressed FAP in vitro. Both natural FAP from cirrhotic liver and recombinant FAP were shown to have gelatinase and Dipeptidyl Peptidase activities. FAP is a cell-bound, dual-specificity Dipeptidyl Peptidase and gelatinase expressed by activated HSC at the tissue remodelling interface in human cirrhosis. FAP may contribute to the HSC-induced extracellular matrix (ECM) changes of cirrhosis.
Anne-marie Lambeir - One of the best experts on this subject based on the ideXlab platform.
-
the Dipeptidyl Peptidase family prolyl oligoPeptidase and prolyl carboxyPeptidase in the immune system and inflammatory disease including atherosclerosis
Frontiers in Immunology, 2015Co-Authors: Yannick Waumans, Anne-marie Lambeir, Lesley Baerts, Kaat Kehoe, Ingrid De MeesterAbstract:Research from over the past 20 years has implicated Dipeptidyl Peptidase (DPP) IV and its family members in many processes and different pathologies of the immune system. Most research has been focused on either DPPIV or just a few of its family members. It is, however, essential to consider the entire DPP family when discussing any one of its members. There is a substantial overlap between family members in their substrate specificity, inhibitors, and functions. In this review, we provide a comprehensive discussion on the role of prolyl-specific Peptidases DPPIV, FAP, DPP8, DPP9, Dipeptidyl Peptidase II, prolyl carboxyPeptidase, and prolyl oligoPeptidase in the immune system and its diseases. We highlight possible therapeutic targets for the prevention and treatment of atherosclerosis, a condition that lies at the frontier between inflammation and cardiovascular disease.
-
inhibition of Dipeptidyl Peptidase iv catalyzed peptide truncation by vildagliptin 2s 3 hydroxyadamantan 1 yl amino acetyl pyrrolidine 2 carbonitrile
Biochemical Pharmacology, 2005Co-Authors: Inger Brandt, Ingrid De Meester, Simon Scharpé, Jurgen Joossens, Xin Chen, M Maes, Anne-marie LambeirAbstract:Abstract Vildagliptin (NVP-LAF237/(2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile) was described as a potent, selective and orally bio-available Dipeptidyl-Peptidase IV (DPP IV, EC 3.4.14.5) inhibitor [Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, et al.1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable Dipeptidyl Peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003;46:2774–89]. Phase III clinical trials for the use of this compound in the treatment of Type 2 diabetes were started in the first quarter of 2004. In this paper, we report on (1) the kinetics of binding, (2) the type of inhibition, (3) the selectivity with respect to other Peptidases, and (4) the inhibitory potency on the DPP IV catalyzed degradation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and substance P. Vildagliptin behaved as a slow-binding DPP IV inhibitor with an association rate constant of 1.4 × 105 M−1 s−1 and a Ki of 17 nM. It is a micromolar inhibitor for Dipeptidyl-Peptidase 8 and does not significantly inhibit Dipeptidyl-Peptidase II (EC 3.4.11.2), prolyl oligoPeptidase (EC 3.4.21.26), aminoPeptidase P (EC 3.4.11.9) or aminoPeptidase M (EC 3.4.11.2). There was no evidence for substrate specific inhibition of DPP IV by Vildagliptin or for important allosteric factors affecting the inhibition constant in presence of GIP and GLP-1.
-
Kinetic investigation of human Dipeptidyl Peptidase II (DPPII)-mediated hydrolysis of dipeptide derivatives and its identification as quiescent cell proline diPeptidase (QPP)/Dipeptidyl Peptidase 7 (DPP7)
Biochemical Journal, 2005Co-Authors: Marie-berthe Maes, Kristel Senten, Pieter Van Der Veken, Koen Augustyns, Kambiz Gilany, Barbara Leiting, Anne-marie Lambeir, Simon Scharpé, Ingrid De MeesterAbstract:The presence of DPPII (Dipeptidyl Peptidase II; E.C. 3.4.14.2) has been demonstrated in various mammalian tissues. However, a profound molecular and catalytic characterization, including substrate selectivity, kinetics and pH-dependence, has not been conducted. In the present study, DPPII was purified from human seminal plasma to apparent homogeneity with a high yield (40%) purification scheme, including an inhibitor-based affinity chromatographic step. The inhibitor lysyl-piperidide (Ki~0.9 μM at pH 5.5) was chosen, as it provided a favourable affinity/recovery ratio. The human enzyme appeared as a 120 kDa homodimer. Mass spectrometric analysis after tryptic digestion together with a kinetic comparison indicate strongly its identity with QPP (quiescent cell proline diPeptidase), also called Dipeptidyl Peptidase 7. pH profiles of both kcat and kcat/Km clearly demonstrated that DPPII/QPP possesses an acidic and not a neutral optimum as was reported for QPP. Kinetic parameters of the human natural DPPII for dipeptide-derived chromogenic [pNA (p-nitroanilide)] and fluorogenic [4Me2NA (4-methoxy-2-naphthylamide)] substrates were determined under different assay conditions. DPPII preferred the chromogenic pNA-derived substrates over the fluorogenic 4Me2NA-derived substrates. Natural human DPPII showed high efficiency towards synthetic substrates containing proline at the P1 position and lysine at P2. The importance of the P1′ group for P2 and P1 selectivity was revealed, explaining many discrepancies in the literature. Furthermore, substrate preferences of human DPPII and Dipeptidyl Peptidase IV were compared based on their selectivity constants (kcat/Km). Lys-Pro-pNA (kcat/Km 4.1×106 s−1·M−1) and Ala-Pro-pNA (kcat/Km 2.6×106 s−1· M−1) were found to be the most sensitive chromogenic substrates for human DPPII, but were less selective than Lys-Ala-pNA (kcat/Km 0.4×106 s−1·M−1).
-
molecular characterization of Dipeptidyl Peptidase activity in serum soluble cd26 Dipeptidyl Peptidase iv is responsible for the release of x pro dipeptides
FEBS Journal, 2000Co-Authors: Christine Durinx, Anne-marie Lambeir, Simon Scharpé, Eugene Bosmans, Jeanbernard Falmagne, Raf Berghmans, Achiel Haemers, Ingrid De MeesterAbstract:Dipeptidyl Peptidase IV (DPPIV, EC 3.4.14.5) is a serine type protease with an important modulatory activity on a number of chemokines, neuropeptides and peptide hormones. It is also known as CD26 or adenosine deaminase (ADA; EC 3.5.4.4) binding protein. DPPIV has been demonstrated on the plasmamembranes of T cells and activated natural killer or B cells as well as on a number of endothelial and differentiated epithelial cells. A soluble form of CD26/DPPIV has been described in serum. Over the past few years, several related enzymes with similar Dipeptidyl Peptidase activity have been discovered, raising questions on the molecular origin(s) of serum Dipeptidyl Peptidase activity. Among them attractin, the human orthologue of the mouse mahogany protein, was postulated to be responsible for the majority of the DPPIV-like activity in serum. Using ADA-affinity chromatography, it is shown here that 95% of the serum Dipeptidyl Peptidase activity is associated with a protein with ADA-binding properties. The natural protein was purified in milligram quantities, allowing molecular characterization (N-terminal sequence, glycosylation type, CD-spectrum, pH and thermal stability) and comparison with CD26/DPPIV from other sources. The purified serum enzyme was confirmed as CD26.
Loretta M Byrne - One of the best experts on this subject based on the ideXlab platform.
-
interactive hemodynamic effects of Dipeptidyl Peptidase iv inhibition and angiotensin converting enzyme inhibition in humans
Hypertension, 2010Co-Authors: Annis M Marney, Siri Kunchakarra, Loretta M ByrneAbstract:Dipeptidyl Peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl Peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that Dipeptidyl Peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum Dipeptidyl Peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P ≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner ( P P =0.02) and augmented the hypotensive response to 5 mg of enalapril ( P =0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril ( P= 0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of Dipeptidyl Peptidase-IV and ACE inhibition in humans.
-
interactive hemodynamic effects of Dipeptidyl Peptidase iv inhibition and angiotensin converting enzyme inhibition in humans
Hypertension, 2010Co-Authors: Annis M Marney, Siri Kunchakarra, Loretta M ByrneAbstract:Dipeptidyl Peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl Peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that Dipeptidyl Peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum Dipeptidyl Peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of Dipeptidyl Peptidase-IV and ACE inhibition in humans.