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PubMed1981

Immunoelectrophoretic studies on human small intestinal brush border proteins--the longitudinal distribution of peptidases and disaccharidases.

The longitudinal distribution of different brush border enzymes along the human small intestine was studied by crossed immunoelectrophoresis. The results are based on biopsies taken every 50 cm in three intestines obtained at autopsy and on peroral or peroperative biopsies from the ligament of Treitz, proximal jejunum and distal ileum from 11 patients undergoing jejunoileal bypass operation for obesity. Lactase-phlorizin hydrolase (EC 3.2.1.23-62) and sucrase-isomaltase(EC 3.2.1.48-10) had their highest level in jejunum with decreasing activity towards the proximal and distal ends of the intestine, while maltase (EC 3.2.1.20) increased along the intestine and reached its highest activity in the distal ileum. A carboxypeptidase (EC 3.4.12.X) is demonstrated as an enzymatic entity of the human intestine. This enzyme had a rather flat distribution curve while microvillus aminopeptidase (EC 3.4.11.2), dipeptidyl peptidase IV (EC 3.4.14.X) and aspartate aminopeptidase (EC 3.4.11.7) all increased along the length axis and reached maximum values in distal ileum.

Aminopeptidases↗

PubMed1988

Dipeptidyl peptidase III and alanyl aminopeptidase in the human seminal plasma: origin and biochemical properties.

Human seminal plasma contained two distinct enzyme activities hydrolysing ArgArgNA. The enzymes were separated by anion exchange chromatography and further purified by gel filtration and/or hydrophobic interaction chromatography. The enzyme eluting at the lower NaCl concentration (0.26 mol/l) displayed an optimum at pH 5.7-6.0 (enzyme A), while the other enzyme eluted at 0.32 mol/l NaCl and showed an optimum at pH 8.5-9.0 (enzyme B). Enzyme A was found to coelute with an aminopeptidase which hydrolysed various amino acid derivatives as well as dipeptide naphthylamides sequentially. Both enzymes were sensitive to heavy metal ions (Cd, Cu, Hg, Pb) and chelating agents (EDTA, o-phenanthroline) and moderately sensitive to di-isopropylfluorophosphonate (DFP) or phenylmethylsulfonylfluoride (PMSF). After EDTA suppression both activities were partially reactivated by divalent metal ions, particularly by Co2+. Enzyme A was highly sensitive to amastatin, bestatin and puromycin, while enzyme B was not markedly influenced. With different substrates the modifier characteristics of enzyme A were equal. High concentrations of some substrates suppressed the hydrolysis rates of both enzymes. Enzyme B was much more sensitive to the thermal treatment than enzyme A. Tentative molecular masses of 110 kD and 80 kD were obtained for enzymes A and B, respectively. Enzyme B was found in all male reproductive tissues (testis, epididymis, vas deferens, ampulla, seminal vesicles, prostate), while enzyme A was only detected in the prostatic homogenate. Thus, ArgArgNA in the human seminal plasma is hydrolysed by dipeptidyl peptidase III, which may originate from different reproductive organs, while the prostate is responsible for the secretion of an aminopeptidase with a wide substrate spectrum including dipeptidyl derivatives.

Aminopeptidases↗

PubMed1985

Identification of dipeptidyl peptidase IV as a protein shared by the plasma membrane of hepatocytes and liver biomatrix.

The histotypic organization of liver parenchyma involves specific intercellular contacts and interaction of hepatocytes with supporting biomatrix. Evidence from this laboratory identified a peptide (Hep105, apparent Mr 105 000) that is shared by the plasma membrane of rat hepatocytes and rat liver biomatrix. This report identifies Hep105 as a peptide component of dipeptidyl peptidase IV (DPPIV; EC 3.4.14.-). A monoclonal antibody (MAb 236.3) was shown to immunoprecipitate DPPIV from non-ionic detergent extracts of surface-labeled 125I hepatocytes. The immunoprecipitate contained two 125I-labeled peptides: Hep105 and a peptide of apparent Mr 150000 (Hep150). Proteolysis of 125I-labeled Hep105 and Hep150 by Staphylococcus aureus V8 protease yielded essentially identical patterns of 125I-labeled peptide degradation products, indicating that Hep105 and Hep150 are structurally related. Only Hep150 exhibited DPPIV activity on transblot analysis, an observation that is consistent with the interpretation that it is the monomeric form of the enzyme. Heating (100 degrees C, 5 min) of purified Hep150 in the presence of sodium dodecylsulfate (SDS) resulted in its conversion to Hep105 and the disappearance of any demonstrable enzymatic activity. 3H-labeled diisopropyl fluorophosphate was incorporated into Hep105, indicating that Hep105 contains the active site for DPPIV. Purified rat liver biomatrix was shown to possess significant DPPIV activity. Taken together, these data indicate that Hep105 s a peptide component of DPPIV.

Animals↗

PubMed1991

The isolation and some properties of dipeptidyl peptidases II and III from porcine spleen.

1. Dipeptidyl peptidases (DPP) II and III from porcine spleen have been purified to homogeneity as assessed by disc gel electrophoresis, HPLC and chromatofocusing. 2. The enzyme are both inhibited by diisopropylfluorophosphate suggesting that the active site contains an essential serine residue, but they are also inhibited by a variety of other reagents. 3. The pI of DPP II is 4.8, that of DPP III, 4.0. 4. The former enzyme has a molecular weight of 97,000, the latter 66,000 and both are glycoproteins. 5. The enzymes are compared with those from other sources.

Amino Acids↗

PubMedDate not supplied

Biochemical studies on dipeptidyl peptidases I to IV of the human placenta.

Homogenates of human term placentae were utilized to demonstrate the presence of four dipeptidyl peptidases (DPP I to IV) after sequential fractionations with gel filtration and anion-exchange chromatography. DPP I was assayed with SerTyrNA as substrate and showed the characteristics of a thiol-dependent serine enzyme with optimum at pH 4.5 and a molecular weight of 210,000. DPP II, analysed with LysAlaNA as substrate, had an optimum at pH 5.5 and a molecular weight of 130,000 with no dependence on thiol groups or divalent ions. DPP III was studied with ArgArgNA as substrate. It was optimally hydrolysed at pH 8.8 and had a molecular weight of 84,000. The enzyme was highly suppressed by chelating agents but could be reactivated by Co2+ and some other divalent ions. DPP IV, with GlyProNA as substrate, displayed an optimum at pH 8.2. The fractionations displayed multiple forms of the enzyme, possibly indicating the presence of proto- and polymeric DPP IV activities. The protomer had a molecular weight of 260,000 and showed no dependence on thiol groups but was sensitive to Zn2+.

Chromatography, Gel↗

PubMed1983

Purification and properties of dipeptidyl peptidase II from rat kidney.

Dipeptidyl peptidase II (EC 3.4.14.2) from rat kidney was purified to a specific activity of 66.2 mumol/min per mg protein by a series of column chromatographic techniques. The purified enzyme was apparently homogeneous as judged by disc gel electrophoresis. Gel filtration on a calibrated column indicated an apparent molecular weight of 130 000 for the native enzyme. Gel electrophoresis of the denatured enzyme in the presence of sodium dodecyl sulfate in a constant acrylamide concentration resulted in the appearance of a single component for which a molecular weight of 64 000 was calculated. The pH optima for dipeptidyl arylamides and for tripeptides were pH 5.5 and 4.5, respectively, and the isoelectric point was 4.8. Substrate specificity studies indicated that the purified enzyme hydrolyzes specifically N-terminal X-alanine or X-proline from their respective arylamides and from tri- or tetrapeptides, but not from pentapeptides.

Animals↗

PubMed1985

Peptidase-containing neurons in rat striatum.

The effects of surgical lesions on peptidase activity have been studied in the striatonigral system of the rat brain. Knife cuts separating the anterior part of the caudate putamen from the globus pallidus resulted in a decrease in the activity of angiotensin-converting enzyme and alanyl aminopeptidase in both the globus pallidus and substantia nigra. The activity of nigral prolyl endopeptidase and leucyl aminopeptidase was also decreased. An increase in dipeptidyl aminopeptidase and arginyl endopeptidase activity was observed in both the caudate putamen and globus pallidus. These results suggest that the striatal neurons containing angiotensin-converting enzyme or alanyl aminopeptidase project to both the globus pallidus and substantia nigra, and the neurons containing prolyl endopeptidase and/or leucyl aminopeptidase project to the substantia nigra. Dipeptidyl aminopeptidase and arginyl endopeptidase are probably associated with glial function.

Aminopeptidases↗

PubMed1993

Dipeptidyl peptidase I from goat brain: purification, characterization and its action on Leu-enkephalin.

Brain dipeptidyl peptidase (DPP) I has been purified 2990-fold to apparent homogeneity shown by a single protein band in electrophoreses at pH 4.5, 8.4 and in SDS-PAGE at pH 7.2. The purification techniques included homogenization of brain acetone powder, autolysis at pH 4.2, 30-80% (NH4)2SO4 fractionation. Sephadex G-100 column chromatography, heat treatment at 65 C. organomercurial affinity chromatography. CM-Sephadex cation-exchange chromatographies at pH 5.6 and 5.0 and anion-exchange chromatography on DEAE-Sephadex at pH 6.8. The enzyme hydrolysed synthetic substrate Gly-Arg-4-methoxy-beta-naphthyl-amide maximally at pH 6.0. The Km values for Gly-Arg-beta-naphthylamide and Gly-Arg-4-methoxy-beta-naphthylamide substrates were 0.10 mM and 0.14 mM respectively. The enzyme was inhibited by thiol inhibitors like p-chloromercuribenzoic acid, iodoacetic acid, iodoacetamide and microbial inhibitors leupeptin and antipain. Molecular weight estimations on a calibrated Sephadex G-200 column afforded a value of 180,000 Da while in denaturing conditions on sodium dodecyl sulphate polyacrylamide gel electrophoresis, the subunit molecular weight was 22,000 Da. The subunit structure of the native enzyme was unfolded in presence of different concentrations of urea. In 8 M urea, the enzyme dissociated completely into monomers of 25,000 Da but 6, 5 and 4 M urea concentrations revealed the existence of dimers, tetramers and hexamers. Leu-enkephalin. Tyr-Gly-Gly-Phe-Leu was degraded by DPPI into Tyr-Gly and Gly-Phe-Leu with no further degradation of the newly generated tripeptide.

Amino Acid Sequence↗

PubMed1988

Neonatal rat brain astroglial dipeptidyl peptidase II activity regulation by cations and anions.

Astrocytic glial cells from neonatal rat brains were grown in primary culture. Dipeptidyl peptidase II (DPP-II) enzyme activity was measured in cells disrupted by nonionic detergent. The rate of enzyme activity was measured in the presence of various ions, under isosmotic conditions adjusted using mannitol and NaCl. DPP-II activity was not affected by the candidate metal co-factors (2 mM) Co2+, Mg2+, and Mn2+, nor by the metal chelators EDTA and o-phenanthroline. However, selected cations (50 mM Cl- salts) significantly inhibited DPP-II activity compared to Na+ control; the relative inhibition ranking was Rb+ less than K+ less than Zn2+ less than Hg2+. Many test anions (50 mM Na+ salts) also inhibited DPP-II activity compared to Cl- control: SO4(2-) less than NO3- less than F- less than SO3(2-). Surprisingly, the anion S2O3(2-) was the only test agent which strongly stimulated activity. The data are consistent with the concept that specific ion species interact with the glial DPP-II enzyme to affect catalytic activity.

Animals↗

PubMed1995

Transforming growth factor beta 1 and parathyroid hormone-related protein control the secretion of dipeptidyl peptidase II by rat astrocytes.

Meninges synthesize parathyroid hormone-related protein (PTHrP) and transforming growth factor (TGF beta 1). Both factors control the activity of the glial enzyme dipeptidyl peptidase II (DPP II): TGF beta 1 induces the secretion of enzyme activity by cultivated astrocytes in a dose dependent manner. The maximal effect is achieved with a concentration of 10 ng/ml and is dependent on the time of incubation. PTHrP itself has no effect on the release of DPP II activity but considerably reduces the effect of TGF beta 1. It is assumed that DPP II influences the course of cicatrization after penetrating injuries of the brain and thus, meninges control glial scarring by the release of TGF beta 1 and PTHrP.

Acid Phosphatase↗

PubMed2006

Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.

Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is a zinc-hydrolase with an indicated role in the mammalian pain modulatory system. In order to find a potent antagonist of this enzyme, we synthesized and screened the effect of a small set of benzimidazole derivatives on its activity. To improve the inhibitory potential, a cyclobutane ring was introduced as rigid conformation support to the diamidino substituted dibenzimidazoles. Two such compounds (1' and 4') from the group of cyclobutane derivatives containing amidino-substituted benzimidazole moieties, obtained by photochemical cyclization in water and by respecting rules of the "green chemistry" approach, were found to be strong DPP III inhibitors, with IC(50) value below 5 microM. Compound 1' displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924+/-549 M(-1)min(-1) (K(i)=0.20 microM). The peptide substrate valorphin protected the enzyme from inactivation by 1'.

Adamantane↗

PubMed2003

Tripeptidyl-peptidase II (TPP II) inhibitory activity of (S)-2,3-dihydro-2-(1H-imidazol-2-yl)-1H-indoles, a systematic SAR evaluation. Part 2.

We have systematically explored the structure-activity relationship (SAR) for a series of compounds 2 as inhibitors of tripeptidyl-peptidase II (TPP II), a serine protease responsible for the degradation of cholecystokinin-8 (CCK-8). This SAR evaluation of the core structure 2 suggest a fairly restrictive pharmacophore for such related structures, but has yielded a limited set of compounds (2b, 2c, 2d, 2s, and 2t) with potent TPP II inhibitory activity (IC(50) 4-11 nM).

Aminopeptidases↗

PubMed2006

Synthesis and dipeptidyl peptidase inhibition of N-(4-substituted-2,4-diaminobutanoyl)piperidines.

In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.

Amination↗

PubMed2006

Xanthine mimetics as potent dipeptidyl peptidase IV inhibitors.

A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV K(i)=2nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines.

Animals↗

PubMed2006

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.

Animals↗

PubMed2005

Dipeptidyl-peptidase IV in patients with short bowel syndrome.

BACKGROUND & AIMS: The aim of this study was to determine serum dipeptidyl peptidase IV (DPP IV) levels in a population of short bowel syndrome (SBS) patients, who had achieved intestinal adaptation. METHODS: DDP IV reference values were determined in a healthy population (n=47). The SBS study group consisted of 30 patients (17 men, 13 women; 53.2+/-13.2 years). The criteria for inclusion were a remnant small bowel <200cm with or without colon resection. The time interval between resection and DPP IV measurement was >24 months except in 4 patients, in which it was 13-24 months (total mean: 64.7+/-47.3 months). Nutritional support was exclusively oral in 17 patients, oral plus cyclic TPN in 12 and TPN alone in one patient. RESULTS: The reference range for DPP IV was 10-23U/l (mean: 16.01+/-3.2). In the group of SBS patients, mean serum DPP IV was 14.02+/-3.6U/l and mean body mass index 22.07+/-4.1kg/m(2). Eleven patients (36.6%) had hyperphagia and mean DPP IV in this group was 15.2+/-4.9U/l. CONCLUSIONS: Measurement of DPP IV levels in this limited series of SBS patients who had reached intestinal adaptation showed normal levels and did not provide additional clinical information. Further analysis in the earlier postoperative period will determine whether this enzyme has a role as an indicator of evolution in these patients.

Adaptation, Physiological↗

PubMed2006

Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1.

GLP-1 and GIP are insulin-releasing 'incretin' hormones inactivated following degradation by dipeptidyl peptidase IV. Incretin hormone analogues resistant to degradation by DPP IV, as well as, inhibitors of DPP IV are in development as novel treatments for type 2 diabetes. The biguanide metformin is an oral agent commonly prescribed to treat type 2 diabetes. Antidiabetic actions of metformin involve the reduction of hepatic glucose production and/or insulin resistance. Recent reports indicate that metformin may have the additional property of inhibiting DPP IV activity. Here we examine the effects of metformin on plasma DPP IV activity of normal and ob/ob diabetic mice. DPP IV activity present in mouse plasma was concentration-dependently inhibited by metformin generating IC(50) values of 38 microM for normal mice and 29 microM for ob/ob mice. In vivo metformin lowered plasma DPP IV activity in ob/ob mice, and improved glucose-lowering and insulin-releasing effects of exogenous GLP-1 administration. This was associated with increased circulating concentrations of active GLP-1(7-36)amide. In contrast metformin had minor effects on in vitro GLP-1-stimulated insulin release from clonal beta cells. Long-term (12 day) oral metformin administration to ob/ob mice resulted in lower DPP IV activity but had no effect on basal glucose and insulin levels. These findings indicate that metformin decreases the plasma DPP IV activity, limiting the inactivation of exogenously administered GLP-1 and improving glycaemic control.

Analysis of Variance↗

PubMed2006

E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase-IV inhibitor.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, which is a novel imidazopyridazinone-derived DPP-IV inhibitor. E3024 inhibited recombinant human and mouse DPP-IV with IC50 values of approximately 100 nM. E3024 inhibited DPP-IV in human, mouse, rat and canine plasma with IC50 values of 140 to 400 nM. In contrast, E3024 did not inhibit DPP-8 or DPP-9 activity. Kinetic analysis indicated that E3024 is a competitive DPP-IV inhibitor. In Zucker fa/fa rats, E3024 (1 mg/kg) reduced glucose excursion after glucose load, with increases in plasma insulin and active glucagon-like peptide-1 levels. In fasted rats, this compound did not cause hypoglycemia. In a rat 4-week toxicological study, no notable changes were found at doses up to 750 mg/kg. The present preclinical studies indicate that E3024 is a novel selective DPP-IV inhibitor with anti-diabetic effects and a good safety profile.

Animals↗