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PubMed2000

Role of hepatocyte nuclear factor 1alpha and 1beta in the transcriptional regulation of human dipeptidyl peptidase IV during differentiation of Caco-2 cells.

Caco-2 cells undergo differentiation to an enterocytic-like cell when maintained in a post-confluent state for 1-2 weeks. During this period Caco-2 cells begin to express high levels brush border membrane associated enzymes such as dipeptidyl peptidase IV. Using the dipeptidyl peptidase IV gene promoter in electrophoretic mobility shift assays, we have shown for the first time that levels of hepatocyte nuclear factor 1alpha increase three- to fourfold during Caco-2 cell differentiation. Transient cotransfection experiments with 3T3 cells using dipeptidyl peptidase IV promoter constructs and expression vectors containing hepatocyte nuclear factor 1alpha and beta show that the ratio of alpha and beta modulates reporter gene expression. These results suggest that the increase in levels of hepatocyte nuclear factor 1alpha that occur during intestinal cell differentiation, are important for expression of dipeptidyl peptidase IV and other intestinal proteins.

Caco-2 Cells↗
PubMed2000

Enhancement of brush border membrane peptidase activity in rat jejunum induced by starvation.

Conflicting results have been obtained in previous studies concerning the adaptation of intestinal blush border membrane enzymes to starvation. This study was designed to clarity the changes in these enzymes under starvation conditions, using a molecular biological approach. Sprague-Dawley rats were starved or given total parenteral nutrition (TPN) for 5 days. Rats allowed free access to food were used as controls. Changes in the activity and expression of jejunal brush border membrane enzymes were compared between three groups. In the starved group, aminopeptidase N and dipeptidyl peptidase IV activity was significantly elevated to 177% and 166%, respectively, of control values. In contrast, sucrase and maltase activity was significantly decreased. The activity of these peptidases also tended to be increased at the renal brush border membrane. Up-regulation of peptidase activity was not evident in the TPN group. Western and Northern blot analysis revealed that the changes in aminopeptidase N activity were attributable to increases in the protein and mRNA level. The activity and expression of brush border membrane peptidases in rat jejunum is up-regulated during starvation, and these changes are considered to be an effect of whole-body malnourishment, rather than an absence of luminal nutrition.

Aminopeptidases↗
PubMed2006

Synthesis, kinetic evaluation, and utilization of a biotinylated dipeptide proline diphenyl phosphonate for the disclosure of dipeptidyl peptidase IV-like serine proteases.

In this study, we report on the synthesis, kinetic characterisation, and application of a novel biotinylated and active site-directed inactivator of dipeptidyl peptidase IV (DPP-IV). Thus, the dipeptide-derived proline diphenyl phosphonate NH(2)-Glu(biotinyl-PEG)-Pro(P)(OPh)(2) has been prepared by a combination of classical solution- and solid-phase methodologies and has been shown to be an irreversible inhibitor of porcine DPP-IV, exhibiting an over all second-order rate constant (k(i)/K(i)) for inhibition of 1.57 x 10(3) M(-1) min(-1). This value compares favourably with previously reported rates of inactivation of DPP-IV by dipeptides containing a P(1) proline diphenyl phosphonate grouping [B. Boduszek, J. Oleksyszyn, C.M. Kam, J. Selzler, R.E. Smith, J.C. Powers, Dipeptide phophonates as inhibitors of dipeptidyl peptidase IV, J. Med. Chem. 37 (1994) 3969-3976; B.F. Gilmore, J.F. Lynas, C.J. Scott, C. McGoohan, L. Martin, B. Walker, Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha), Biochem, Biophys. Res. Commun. 346 (2006) 436-446.], thus demonstrating that the incorporation of the side-chain modified (N-biotinyl-3-(2-(2-(3-aminopropyloxy)-ethoxy)-ethoxy)-propyl) glutamic acid residue at the P(2) position is compatible with inhibitor efficacy. The utilisation of this probe for the detection of both purified dipeptidyl peptidase IV and the disclosure of a dipeptidyl peptidase IV-like activity from a clinical isolate of Porphyromonas gingivalis, using established electrophoretic and Western blotting techniques previously developed by our group, is also demonstrated.

Affinity Labels↗
PubMed2004

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum.

The discovery of a potentially novel proline-specific peptidase from bovine serum is presented which is capable of cleaving the dipeptidyl peptidase IV (DPIV) substrate Gly-Pro-MCA. The enzyme was isolated and purified with the use of Phenyl Sepharose Hydrophobic Interaction, Sephacryl S-300 Gel Filtration, and Q-Sephacryl Anion Exchange, producing an overall purification factor of 257. SDS PAGE resulted in a monomeric molecular mass of 158kDa while size exclusion chromatography generated a native molecular mass of 328kDa. The enzyme remained active over a broad pH range with a distinct preference for a neutral pH range of 7-8.5. Chromatofocusing and isoelectric focusing (IEF) revealed the enzyme's isoelectric point to be 4.74. DPIV-like activity was not inhibited by serine protease inhibitors but was by the metallo-protease inhibitors, the phenanthrolines. The enzyme was also partially inhibited by bestatin. Substrate specificity studies proved that the enzyme is capable of sequential cleavage of bovine beta-Casomorphin and Substance P. The peptidase cleaved the standard DPIV substrate, Gly-Pro-MCA with a K(M) of 38.4 microM, while Lys-Pro-MCA was hydrolysed with a K(M) of 103 microM. The DPIV-like activity was specifically inhibited by both Diprotin A and B, non-competitively, generating a K(i) of 1.4 x 10(-4) M for both inhibitors. Ile-Thiazolidide and Ile-Pyrrolidide both inhibited competitively with an inhibition constant of 3.7 x 10(-7) and 7.5 x 10(-7) M, respectively. It is concluded that bovine serum DPIV-like activity share many biochemical properties with DPIV and DPIV-like enzymes but not exclusively, suggesting that the purified peptidase may play an important novel role in bioactive oligopeptide degradation.

Animals↗
PubMed2004

K579, a slow-binding inhibitor of dipeptidyl peptidase IV, is a long-acting hypoglycemic agent.

Dipeptidyl peptidase IV inhibitors are expected to be categorized in a new type of antidiabetic drugs. We had developed a long-acting dipeptidyl peptidase IV inhibitor, K579 [(S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidinecarbonitrile]. The aim of present study was to characterize the pharmacological profiles of K579. In normal rats, K579 suppressed the blood glucose elevation after an oral glucose tolerance test with the increment of plasma insulin and active forms of glucagon-like peptide-1 (GLP-1). During repetitive glucose loading using Zucker fatty rats, pretreatment with K579 attenuated the glucose excursion after the second glucose loading as well as the first glucose loading without inducing hypoglycemia. The kinetic study using cell extract revealed that K579 was a more potent and slower binding inhibitor than the existing dipeptidyl peptidase IV inhibitor (NVP-DPP728, 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine). These profiles of K579 might be advantageous over the existing dipeptidyl peptidase IV inhibitor with respect to less dosing frequency.

Administration, Oral↗
PubMed1999

Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV.

The tetrapeptide, endomorphin-2 (Tyr-Pro-Phe-PheNH2) possesses high affinity for mu opioid receptors, and produces potent analgesia in mice. Its structure appears to satisfy the substrate requirements of the proteinase, dipeptidyl peptidase IV which removes dipeptides from the amino terminus of peptides containing proline as the penultimate amino acid. A potent, stable and specific inhibitor of this enzyme, Ala-Pyrrolidonyl-2-nitrile, has been described which should potentiate endomorphin-2-induced analgesia. Further, since dipeptidyl peptidase IV has an absolute requirement for l-Pro, a more metabolically-stable d-Pro2-endomorphin-2 analog should produce longer analgesic actions at lower doses. The present study found that endomorphin-2 was degraded approximately twice as fast than the chromogenic substrate, Ala-Pro-2naphthylamide, by dipeptidyl peptidase IV, whereas d-Pro2-endomorphin-2 was totally resistant to this enzyme's action. d-Pro2-endomorphin-2 (ED50=0.05 microg) was more potent than endomorphin-2 (ED50=30 microg) in significantly increasing tail-flick latencies with longer durations of action. Both the peptide and analogue were equipotent (ED50=0.5 microg) in significantly increasing jump thresholds. Ala-Pyrrolidonyl-2-nitrile (10-75 nmol) elicited a dose-dependent analgesia, and potentiated the analgesic actions of endomorphin-2, particularly on the tail-flick test. Whereas systemic naltrexone (2.5, 10 mg/kg) dose-dependently eliminated each of the three forms of analgesia on the jump test as well as the peak (15 min) effect on the tail-flick test, analgesia elicited by either endomorphin-2, d-Pro2-endomorphin-2 or Ala-Pyrrolidonyl-2-nitrile returned after 30-60 min in naltrexone-treated rats on the tail-flick test. These data strongly suggest that dipeptidyl peptidase IV plays a role in the inactivation of endomorphin-2 in vivo, and thereby modulates its central analgesic actions.

Analgesics, Opioid↗
PubMed2000

Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice.

We explored whether inhibition of the enzyme dipeptidyl peptidase IV (DPP IV) increases endogenous levels of glucagon-like peptide-1 (GLP-1) and improves glucose tolerance and insulin secretion in mice. Glucose (150 mg) was administered through a gastric gavage with or without the inhibitor of dipeptidyl peptidase IV, valine-pyrrolidide (100 micromol/kg), in high-fat fed glucose intolerant or control C57BL/6J mice. The increase in plasma GLP-1 after gastric glucose was potentiated by dipeptidyl peptidase IV inhibition (P<0.05). Valine-pyrrolidide also potentiated the plasma insulin response to gastric glucose and improved the glucose tolerance in both groups of mice (P<0.001). In contrast, valine-pyrrolidide did not affect glucose-stimulated insulin secretion from isolated islets. This suggests that valine-pyrrolidide improves insulin secretion and glucose tolerance through indirect action, probably through augmentation of levels of GLP-1 and other incretin hormones. Therefore, inhibition of dipeptidyl peptidase IV activity is feasible to exploit as a treatment for glucose intolerance and type 2 diabetes.

Animals↗
PubMed1988

Occurrence of pyroglutamyl peptidase II, a specific TRH degrading enzyme in rabbit retinal membranes and in human retinoblastoma cells.

Pyroglutamyl peptidase II, a highly specific thyrotropin releasing hormone (TRH)-degrading enzyme is found in highest concentration in brain where it is localized to synaptic membranes. Retina contains relatively high concentrations of both immunoreactive TRH and TRH receptors. We report that the specific activity of pyroglutamyl peptidase II in rabbit retinal membranes exceeds that of all non-CNS tissues thus far studied. Nine clonal cell lines were screened for this enzymatic activity. The specific activity of pyroglutamyl peptidase II in Y79 retinoblastoma cells was greater than the highest activity found in other cell lines by approximately one order of magnitude. These studies further support a functional relationship between pyroglutamyl peptidase II and TRH and identify a cell line suitable for studies on the regulation of this enzyme.

Aminopeptidases↗
PubMed2002

Mitochondrial processing peptidases.

Three peptidases are responsible for the proteolytic processing of both nuclearly and mitochondrially encoded precursor polypeptides targeted to the various subcompartments of the mitochondria. Mitochondrial processing peptidase (MPP) cleaves the vast majority of mitochondrial proteins, while inner membrane peptidase (IMP) and mitochondrial intermediate peptidase (MIP) process specific subsets of precursor polypeptides. All three enzymes are structurally and functionally conserved across species, and their human homologues begin to be recognized as potential players in mitochondrial disease.

Amino Acid Sequence↗
PubMed2006

Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts.

Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a k(cat)/K(m) value of 0.5 and 0.1 s(-1) x microM(-1) respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.

Amino Acid Sequence↗
PubMed1999

Comparison of the effect of native glucagon-like peptide 1 and dipeptidyl peptidase IV-resistant analogues on insulin release from rat pancreatic islets.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and may improve glycaemic control in type 2 diabetes. Therapeutic use is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. MATERIALS AND METHODS: Five GLP-1 analogues with alterations at cleavage positions were synthesized according to the Fmoc strategy and tested for metabolic stability by incubation with rat kidney membranes containing dipeptidyl peptidase IV activity. Their insulinotropic effect was compared in isolated rat pancreatic islets after 24 h maintenance in tissue culture. Ten islets per vial were incubated for 30 min; insulin was measured radioimmunologically. Each analogue was compared with GLP-1 in the same experiment. RESULTS: All analogues were biologically active in isolated islets in the potency order da2d8 = da2 > d2d9 > da2ds8 > desamino. At 16.7 mmol L-1 glucose, GLP-1 and GLP-1 analogues altered as position 2, or 2 and 8 significantly (P < 0.05) increased insulin release at 10(-9) mol L-1. N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation in rat kidney membranes in vitro. CONCLUSIONS: The analogues tested are biologically active and resistant to degradation by dipeptidyl peptidase IV. Their greater metabolic stability may help to realize the potential of GLP-1 analogues in diabetes therapy.

Amino Acid Sequence↗
PubMed2001

Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family.

Chemokines coordinate many aspects of leukocyte migration. As chemoattractants they play an important role in the innate and acquired immune response. There is good experimental evidence that N-terminal truncation by secreted or cell surface proteases is a way of modulating chemokine action. The localization of CD26/dipeptidyl peptidase IV on cell surfaces and in biological fluids, its primary specificity, and the type of naturally occurring truncated chemokines are consistent with such a function. We determined the steady-state catalytic parameters for a relevant selection of chemokines (CCL3b, CCL5, CCL11, CCL22, CXCL9, CXCL10, CXCL11, and CXCL12) previously reported to alter their chemotactic behavior due to CD26/dipeptidyl peptidase IV-catalyzed truncation. The results reveal a striking selectivity for stromal cell-derived factor-1alpha (CXCL12) and macrophage-derived chemokine (CCL22). The kinetic parameters support the hypothesis that CD26/dipeptidyl peptidase IV contributes to the degradation of certain chemokines in vivo. The data not only provide insight into the selectivity of the enzyme for specific chemokines, but they also contribute to the general understanding of CD26/dipeptidyl peptidase IV secondary substrate specificity.

Amino Acid Sequence↗
PubMed1998

Importance of residues carboxyl terminal relative to the cleavage site in substrates of mitochondrial processing peptidase for their specific recognition and cleavage.

We previously identified distal and proximal arginine residues in the N-terminal portion and an aromatic amino acid at position 1 (P1' site3) relative to the cleavage site as important recognition signals in substrates of mitochondrial processing peptidase [Niidome, T., Kitada, S., Shimokata, K., Ogishima, T., and Ito, A. (1994) J. Biol. Chem. 269, 24714-24722; Ogishima, T., Niidome, T., Shimokata, K., Kitada, S., and Ito, A. (1995) ibid. 270, 30322-30326]. To further elucidate the elements required for the specific recognition and cleavage by the enzyme, we synthesized synthetic peptides that possessed only the distal and proximal arginine residues and phenylalanine at the P1' site in a poly alanine sequence, and analyzed the processing reaction toward them. They were not cleaved by the peptidase although they inhibited the peptidase activity. However, when serine was introduced into the C-terminal portions of the sequence, processing was observed. The efficiency of the resultant peptides improved as the number of serine residues was increased. A peptide with serine or histidine at P2' and threonine at P3' was processed most efficiently. These results indicate that the processing reaction catalyzed by the peptidase depends not only on the N-terminal portion but also on the C-terminal portion from the cleavage site in the substrates.

Amino Acid Sequence↗
PubMed2004

N-linked glycosylation of dipeptidyl peptidase IV (CD26): effects on enzyme activity, homodimer formation, and adenosine deaminase binding.

The type II transmembrane serine protease dipeptidyl peptidase IV (DPPIV), also known as CD26 or adenosine deaminase binding protein, is a major regulator of various physiological processes, including immune, inflammatory, nervous, and endocrine functions. It has been generally accepted that glycosylation of DPPIV and of other transmembrane dipeptidyl peptidases is a prerequisite for enzyme activity and correct protein folding. Crystallographic studies on DPPIV reveal clear N-linked glycosylation of nine Asn residues in DPPIV. However, the importance of each glycosylation site on physiologically relevant reactions such as dipeptide cleavage, dimer formation, and adenosine deaminase (ADA) binding remains obscure. Individual Asn-->Ala point mutants were introduced at the nine glycosylation sites in the extracellular domain of DPPIV (residues 39-766). Crystallographic and biochemical data demonstrate that N-linked glycosylation of DPPIV does not contribute significantly to its peptidase activity. The kinetic parameters of dipeptidyl peptidase cleavage of wild-type DPPIV and the N-glycosylation site mutants were determined by using Ala-Pro-AFC and Gly-Pro-pNA as substrates and varied by <50%. DPPIV is active as a homodimer. Size-exclusion chromatographic analysis showed that the glycosylation site mutants do not affect dimerization. ADA binds to the highly glycosylated beta-propeller domain of DPPIV, but the impact of glycosylation on binding had not previously been determined. Our studies indicate that glycosylation of DPPIV is not required for ADA binding. Taken together, these data indicate that in contrast to the generally accepted view, glycosylation of DPPIV is not a prerequisite for catalysis, dimerization, or ADA binding.

Adenosine Deaminase↗
PubMed2000

Subcellular distribution of pyroglutamyl-peptidase I activity in the developing rat cerebellum.

In this work we analyzed the activity of pyroglutamyl (pGlu)-peptidase I in several subcellular fractions of the rat cerebellum during its development. The aim of this study is to determine if there is a developmental redistribution of this enzyme activity and if this fact could indicate changes in the role of the enzyme as age progresses. Results show that pGlu-peptidase I is widely distributed, but not homogeneously, in all the subcellular fractions that were studied, in both soluble and particulate forms. Significantly the distribution of the enzyme changes with development. Thus, in the soluble synaptosomal fraction, the pGlu-peptidase I activity is low until PD9 and the activity increases significantly from PD9 to PD15, when it reaches adult levels. In contrast, in the cytosolic fraction, the pGlu-peptidase I activity is high from fetal day 22 to postnatal day 6, and then decreases significantly until postnatal day 90.

Animals↗
PubMed1999

Specific localization of membrane dipeptidase and dipeptidyl peptidase IV in secretion granules of two different pancreatic islet cells.

Endocrine cells require several protein convertases to process the precursors of hormonal peptides that they secrete. In addition to the convertases, which have a crucial role in the maturation of prohormones, many other proteases are present in endocrine cells, the roles of which are less well established. Two of these proteases, dipeptidyl peptidase IV (EC 3.4.14.5) and membrane dipeptidase (EC 3.4.13.19), have been immunocytochemically localized in the endocrine pancreas of the pig. Membrane dipeptidase was present exclusively in cells of the islet of Langerhans that were positive for the pancreatic polypeptide, whereas dipeptidyl peptidase IV was restricted to cells positive for glucagon. Both enzymes were observed in the content of secretory granules and therefore would be released into the interstitial space as the granules undergo exocytosis. At this location they could act on secretions of other islet cells. The relative concentration of dipeptidyl peptidase IV was lower in dense glucagon granules, where the immunoreactivity to glucagon was higher, and vice versa for light granules. This suggests that, in A-cells, dipeptidyl peptidase IV could be sent for degradation in the endosomal/lysosomal compartment during the process of granule maturation or could be removed from granules for continuous release into the interstitial space. The intense proteolytic activity that takes place in the endocrine pancreas could produce many potential dipeptide substrates for membrane dipeptidase. (J Histochem Cytochem 47:489-497, 1999)

Animals↗
PubMed1991

Inhibition of pyroglutamyl peptidase II synthesis by phorbol ester in the Y-79 retinoblastoma cell.

Pyroglutamyl peptidase II (EC 3.4.19.-), a highly specific membrane-bound TRH-degrading enzyme, is inactivated in Y-79 human retinoblastoma cells by exposure to 12-O-tetradecanoyl phorbol-13-acetate (TPA) in a biphasic manner. We have previously demonstrated a rapid decrease in pyroglutamyl peptidase II activity to 10% of the control level within 15 min, which returns to 70% of the control level by 1 h. This decrease results from enzyme phosphorylation by TPA-activated protein kinase-C. We now report a second phase of inactivation after longer exposure of cells to TPA. After 1 h, enzymatic activity slowly and progressively declined. By 7 h, only 15% of control activity remained. Cotreatment of cells with H-7, a protein kinase-C inhibitor, prevented this second phase of inactivation. Immunoblot experiments demonstrated a reduction in the amount of pyroglutamyl peptidase II in Y-79 membranes after long term exposure to TPA. Y-79 cells were labeled with [35S]methionine, and pyroglutamyl peptidase II was immunoprecipitated. A decreased incorporation of [35S]methionine paralleled the decrease in enzyme activity. These studies demonstrate that the second phase of inactivation after exposure to TPA is due to an inhibition of enzyme synthesis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Structural requirement for recognition of the precursor proteins by the mitochondrial processing peptidase.

We examined the structural characteristics of the extension peptides responsible for the recognition by the mitochondrial processing peptidase by using preadrenodoxin, which has a long extension peptide of 58 amino acid residues, as the substrate. The deletion of various parts of the extension peptide of pre-adrenodoxin indicated that more than 40 amino acid residues and the presence of basic amino acid residues in the distal portion (20-40 amino acid residues upstream of the cleavage site) were necessary for the recognition of the precursor by the peptidase. The processing of preadrenodoxin was strongly inhibited by the synthetic peptide corresponding to the middle portion of the extension peptide, whereas the peptide corresponding to the amino-terminal portion exhibited weak inhibition of the processing. The replacement of arginine residues in the middle portion of the extension peptide with neutral amino acids resulted in a great decrease in the processing. We conclude that basic amino acids at a position distal to the cleavage site are necessary for the recognition of the precursor proteins by the processing peptidase and that basic amino acids required for the mitochondrial targeting and those for the recognition by the peptidase are separately located in the extension peptide of pre-adrenodoxin.

Adrenodoxin↗