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At least 1,207 records · Page 67Linked to original sources

PubMed1977

Activity of arginine aminopeptidases and phosphatases in inflamed palatal mucosa in denture stomatitis: a histochemical and biochemical study.

Aminopeptidase and phosphatase activity of denture stomatitis mucosa was studied histochemically and biochemically. Stomatitis clearly increased the activity of these enzymes. An enzyme resembling the chloride-activated aminopeptidase B, usually involved in inflammatory processes, was recognized in the inflamed tissue in higher concentrations than in the control tissue.

Acid Phosphatase↗

PubMed2004

Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis.

Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) plays an important role in angiogenesis by regulating the proliferation and migration of endothelial cells (ECs). Here we characterize the mechanism by which PILSAP regulates the vascular endothelial growth factor (VEGF)-stimulated proliferation of ECs. The specific elimination of PILSAP expression or its enzymatic activity inhibited VEGF-stimulated G1/S transition in ECs. This G1 arrest correlated with reduced cyclin dependent kinase 4/6 (CDK4/6) activity and retinoblastoma (Rb) protein phosphorylation. Analyses of signaling molecules upstream of CDK4/6 revealed that S6 kinase (S6K) activation was affected by PILSAP, whereas that of phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal-related kinase 1/2 (ERK1/2) was not. We further demonstrated that PILSAP bound phosphatidylinositol-dependent kinase 1 (PDK1) and removed 9 amino acids from its N-terminus, which allowed S6K to associate with PDK1 and PILSAP upon VEGF stimulation. We constructed mutant PILSAP, which lacked the aminopeptidase activity but bound PDK1. Mutant PILSAP abrogated S6K activation upon VEGF stimulation in a dominant-negative manner. An N-terminal truncated form of PDK1 abolished the dominant-negative effect of mutant PILSAP. Finally, the introduction of a mutated PILSAP gene in ECs inhibited angiogenesis and retarded tumor growth in vivo. These results indicate that PILSAP plays a crucial role in the cell cycle progression of ECs and angiogenesis via the binding and modification of PDK1.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2002

A mouse orthologue of puromycin-insensitive leucyl-specific aminopeptidase is expressed in endothelial cells and plays an important role in angiogenesis.

Using polymerase chain reaction-coupled subtractive hybridization, we have isolated genes expressed during the in vitro differentiation of murine embryonic stem cells into endothelial cells (ECs). Among the genes obtained, we identified one gene that was inducible by vascular endothelial growth factor (VEGF) in the murine EC line MSS31. Analysis of the nucleotide and deduced amino acid sequences revealed that the protein was composed of 930 amino acids, including an HEXXH(X)18E consensus sequence of the M1 aminopeptidase family, and is thought to be a mouse orthologue of puromycin-insensitive leucyl-specific aminopeptidase (mPILSAP). The recombinant protein hydrolyzed N-terminal leucyl and methionyl residues from synthetic substrates. Immunohistochemical analysis revealed that mPILSAP was expressed in ECs during postnatal angiogenesis. Specific elimination of mPILSAP expression by antisense oligodeoxynucleotide (AS-ODN) attenuated VEGF-stimulated proliferation, migration, and network formation of ECs in vitro. Moreover, AS-ODN to mPILSAP inhibited angiogenesis in vivo. These results suggest a novel function of mPILSAP, which is expressed in ECs and plays an important role in angiogenesis.

Animals↗

PubMed2006

The puromycin-sensitive aminopeptidase PAM-1 is required for meiotic exit and anteroposterior polarity in the one-cell Caenorhabditis elegans embryo.

In the nematode Caenorhabditis elegans, sperm entry into the oocyte triggers the completion of meiosis and the establishment of the embryonic anteroposterior (AP) axis. How the early embryo makes the transition from a meiotic to a mitotic zygote and coordinates cell cycle changes with axis formation remains unclear. We have discovered roles for the C. elegans puromycin-sensitive aminopeptidase PAM-1 in both cell cycle progression and AP axis formation, further implicating proteolytic regulation in these processes. pam-1 mutant embryos exhibit a delay in exit from meiosis: thus, this peptidase is required for progression to mitotic interphase. In addition, the centrosomes associated with the sperm pronucleus fail to closely associate with the posterior cortex in pam-1 mutants, and the AP axis is not specified. The meiotic exit and polarity defects are separable, as inactivation of the B-type cyclin CYB-3 in pam-1 mutants rescues the meiotic exit delay but not the polarity defects. Thus PAM-1 may regulate CYB-3 during meiotic exit but presumably targets other protein(s) to regulate polarity. We also show that the pam-1 gene is expressed both maternally and paternally, providing additional evidence that sperm-donated gene products have important roles during early embryogenesis in C. elegans. The degradation of proteins through ubiquitin-mediated proteolysis has been previously shown to regulate the cell cycle and AP axis formation in the C. elegans zygote. Our analysis of PAM-1 requirements shows that a puromycin-sensitive aminopeptidase is also required for proteolytic regulation of the oocyte to embryo transition.

Amino Acid Sequence↗

PubMed2004

Marginal involvement of pyroglutamyl aminopeptidase I in metabolism of thyrotropin-releasing hormone in rat brain.

On thyrotropin-releasing hormone (TRH) metabolism, pyroglutamyl aminopeptidase II (PAP-II), a zinc-dependent ectoenzyme primarily located in the central nervous system, is believed to play a predominant role. Recently we cloned pyroglutamyl aminopeptidase I (PAP-I) which is known for specifically removing a L-pyroglutamate (L-pGlu) residue from the amino terminus of proteins and peptides including TRH. To investigate possible contribution of PAP-I toward TRH metabolism, we conducted biochemical and immunohistochemical characterization using recombinant rat, mouse and human PAP-Is and an antibody raised against rat PAP-I. The Km values toward TRH by the recombinant PAP-Is were about 0.05 mM, being similar value to the reported value of recombinant PAP-II. The L-pGlu-cleaving activities toward TRH in rat brain homogenate were inhibited by a PAP-II specific inhibitor 1,10-phenanthroline, but not inhibited by the antibody against rat PAP-I. Immunohistochemical study in rats revealed heterogeneous distribution of PAP-I in the pituitary, the target tissue of TRH, but the distribution was cytosolic. Taken together, these results suggested that PAP-I might not be dominantly involved in the degradation of TRH in rats. Additionally, we found that PAP-I was localized in the renal proximal tubules. Further investigations are needed for elucidating the function of PAP-I in these restricted sites.

Aminopeptidases↗

PubMed2004

Role of aminopeptidases in the blood pressure regulation.

In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.

Amino Acid Sequence↗

PubMed2003

Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton.

Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.

Aminopeptidases↗

PubMed1984

The role of bestatin-sensitive aminopeptidase, angiotensin converting enzyme and thiorphan-sensitive "enkephalinase" in the potency of enkephalins in the guinea-pig ileum.

The role of each enkephalin-hydrolyzing peptidase in the inhibitory potency of exogenously added enkephalins in the myenteric plexus-longitudinal muscle preparation of guinea-pig ileum was studied by using the relatively specific inhibitor of each enzyme. Results showed that three distinct enzymes, bestatin-sensitive aminopeptidase(s), angiotensin converting enzyme, and thiorphan-sensitive "enkephalinase", played a critical role in the inactivation of enkephalins. Additionally, these enzymes are likely to be located close to opioid receptors, since they produce a significant concentration difference of enkephalin between the surrounding organ bath and the vicinity of opioid receptors. In contrast to these three enzymes, both L-tyrosyl-L-tyrosine-sensitive dipeptidyl aminopeptidase and D-phenylalanine-sensitive carboxypeptidase are indicated not to be involved significantly in the degradation of exogenously added enkephalins in the guinea-pig ileum.

Amino Acids, Sulfur↗

PubMed2004

Substrate specificity of aminopeptidase from the mid-gut gland of the scallop (Patinopecten yessoensis).

An action for various peptides and a kinetic study for amino acid p-nitroanilides (pNAs) and 4-methylcoumaryl-7-amides (MCAs) were performed with purified aminopeptidase from the mid-gut of the scallop. The enzyme preferred dipeptides having Ala, Met, and Phe in the amino-terminal or the penultimate position from the amino-termini. The catalytic efficiencies, k(cat)/K(m) values for Ala-pNA and MCA were the highest in the tested substrates, and those for pNA and MCA substrates having Met or Phe were the next highest. The enzyme was found to be a new alanine-specific aminopeptidase.

Aminopeptidases↗

PubMed1981

N-Acetylalanine aminopeptidase, a new enzyme from human erythrocytes.

A new enzyme liberating N-acetylalanine from N-acetylalanine peptides with high specificity has been isolated from the cytosol of human erythrocytes. The N-acetylalanine aminopeptidase was purified by ammonium sulfate precipitation at 60% saturation, followed by chromatography on columns of Sephadex G-200, SP-Sephadex C-50, and DEAE-Sephadex A-50. About 2 000-fold enrichment was achieved from hemolyzed erythrocytes. The enzyme was homogeneous according to polyacrylamide disc electrophoresis and had a specific activity of 18.1 U/A280 unit. An apparent molecular weight of 300 000 +/- 15 000 was obtained from gel filtrations and was confirmed in the ultracentrifuge in "an active enzyme centrifugation" giving a corrected sedimentation value, s20w of 12 S. The pH optimum in triethanolamine/HCl buffer was around pH 8.3 with N-acetylalanine-4-nitroanilide as substrate, the Km was 0.616 mmol/l. The enzyme was stable between pH 6.0 to 8.0, but lost enzymic activity rapidly below pH 5 and with organic solvents. It is stabilized in a 0.1 M solution of ammonium sulfate. The activity was destroyed by high concentrations of chloromercuribenzoate and di(2-pyridyl)disulfide in an unspecific manner and could not be restored by cysteine. Various protein endoproteinase inhibitors are without influence on the enzymic activity. The enzyme exhibits an aminopeptidase-like activity with release of N-acetylalanine in order of decreasing activity from N-acetylalanine-4-nitroanilide, N-acetylalanyl-alanylalanine, N-acetylalanyl-tyrosyl-isoleucine, N-acetylalanylalanine, N-acetylalanyl-alanyl-alanylalanine, and N-acetylalanine ethyl ester. Several unacetylated peptides and alanine-4-nitroanilide as well as protein substrates were not hydrolyzed. The enzymic activity has not been found in the cytosolic compartment of highly purified human leucocytes. Its physiological function in erythrocytes is still unknown.

Aminopeptidases↗

PubMed1982

Separation of the human leucocyte enzymes alanine aminopeptidase, cathepsin G, collagenase, elastase and myeloperoxidase.

A simple and rapid procedure is described for the separation of the human leucocyte enzymes alanine aminopeptidase, cathepsin G, collagenase, elastase and myeloperoxidase. The enzymes are prepared from leucocytes, obtained from buffy coat, by repeated extraction with buffer A(1 M salt concentration). The pooled extracts are successively subjected to batch adsorption on concanavalin A-Sepharose, gel filtration on Sephacryl S-300, affinity chromatography on collagen-Sepharose 4-B, batch adsorption on CM-Sephadex C-50 and adsorption chromatography on hydroxyapatite. The yields of the isolated enzymes of a typical preparation are 47% alanine aminopeptidase, 9% cathepsin G, 90% latent and active collagenase, 23% elastase and approximately 100% myeloperoxidase with respect to the pooled extracts. The cathepsin G, collagenase and elastase preparations are essentially free from other proteolytic enzymes and may be used without further purifications.

Aminopeptidases↗

PubMed1982

Improved adsorbents for the affinity chromatography of aminopeptidases.

In order to develop efficient and, at the same time, economical aminopeptidase adsorbents, derivatives of 3-amino-2-hydroxy-4-phenylbutanoic acid (Ahp) were examined in view of a prospective use as immobilized ligands. In addition, some methods of linking these compounds to aminohexyl-Sepharose were critically compared. It turned out that highest yields can be obtained by carbodiimide coupling of unprotected tripeptides containing C-terminal glycine. A material of this type, (2S,3S)-Ahp-Val-Gly-aminohexyl-Sepharose, proved to be an excellent affinity absorbent for two rather dissimilar aminopeptidases from yeast. The enzymes were strongly bound, even under unfavourable conditions, but were readily eluted again by low concentrations of Zn2+.

Aminopeptidases↗

PubMed1984

Interaction of the (2S,3S)-isomer of bestatin with yeast aminopeptidase I. Kinetic and binding studies.

Inhibition of yeast aminopeptidase I by N-[(2S,3S)-3-amino-2-hydroxyl-1-oxo-4-phenylbutyl]-L-leucine [(2S,3S)-Ahp-Leu];a stereoisomer of natural bestatin, is a slow process with half-times in the minute range. Action of the inhibitor is non-competitive with respect to the substrate. Up to 1 mol of (2S,3S)-Ahp-Leu is bound per mol of enzyme subunit. Inhibitor binding does not interfere with binding of essential metal ions but completely suppresses allosteric activation by chloride and high Zn(II)-concentrations. These and other findings suggest that (2S,3S)-Ahp-Leu inhibits aminopeptidase I by stabilizing a weakly active enzyme conformation.

Aminopeptidases↗

PubMed1987

Interaction of chloride with yeast aminopeptidase I. Equilibrium binding studies.

The effect of chloride on metal binding by yeast aminopeptidase I, as well as the binding of chloride to various enzyme forms were studied by means of a micro-centrifugation technique using radioactive 36Cl- as a ligand. Chloride did not significantly alter the binding of activating Zn2+, or binding of Co2+ to the essential metal sites. Both the native Zn2+ enzyme and Co2+-substituted aminopeptidase I bind stoichiometric amounts of C1- (1 Cl-/subunit) with apparent dissociation constants of 0.1-0.2 mM. Additional Cl- was bound at higher concentrations. In contrast to the metal-containing enzyme forms the apoenzyme did not express the high-affinity chloride binding site.

Aminopeptidases↗

PubMed1992

Distribution of proline-specific aminopeptidases in human tissues and body fluids.

The proline-specific peptidases, aminopeptidase P (EC 3.4.11.9) and dipeptidyl peptidase IV (EC 3.4.14.5), were measured in human tissue homogenates and physiological fluids. All tissues examined contained measurable aminopeptidase P and dipeptidyl peptidase IV activities. High specific activities for both enzymes under study were found in benign prostatic hypertrophy. Normal prostate and prostatic adenocarcinoma had a much lower activity. This difference, however, is not reflected in the serum values of the patients. The most striking finding is the extremely high activity of dipeptidyl peptidase IV in prostatosomes, prostate-derived organelles, which occur freely in human seminal plasma, and which are important for enhancement of sperm forward motility.

Adenocarcinoma↗

PubMed1982

Yeast aminopeptidase II: rapid purification using affinity chromatography of the periplasmic enzyme.

Periplasmic aminopeptidase II of yeast was isolated from protoplast supernatants by ammonium sulfate precipitation, DEAE-Sephacel chromatography and affinity chromatography on immobilized bestatin. This isolation method is more rapid than conventional procedures and, in addition, avoids contact of the enzyme with yeast proteinases. Thus the preparation obtained is likely to represent the native periplasmic from of aminopeptidase II.

Aminopeptidases↗

PubMed1994

Brain Lys-aminopeptidase activity. Changes during cycle and pregnancy.

Lys-aminopeptidase activity levels during the estrous cycle (estrous and proestrous, in the morning and afternoon) and the pregnancy (2nd, 7th, 14th and 20th day postinsemination and the parturition day), in several areas of the rat brain, were studied in this research. The selected brain regions were the frontal, parietal and occipital cortices, olphactory bulbus, thalamus, hypothalamus, hippocampus, amygdala, striatum and pituitary gland. The most significant changes were shown in the hypothalamus and the pituitary gland. Thus, in these areas, the higher cyclic enzyme levels were found in the proestrous stage. During pregnancy, there was a rise on the 7th and 14th days, with a decrease on the 20th day. Also, similar changes in the occipital cortex, striatum, hippocampus and amygdala were appreciated, but fewer than those observed in the hypothalamus and the pituitary. In conclusion, the activity of the aminopeptidase under study fluctuates during the estrous cycle and during pregnancy, as well as in the hypothalamic-pituitary axis and also in several extrahypothalamic areas of the rat brain.

Aminopeptidases↗

PubMed1985

Ocular aminopeptidase activity and distribution in the albino rabbit.

Ocular aminopeptidase activity in the albino rabbit was determined using L-leucine-, L-alanine-, and L-arginine-4-methoxy-2-naphthylamide as substrates. The corneal epithelium and the iris-ciliary body were found to be the most active, followed by, in turn, conjunctiva and corneal stroma, lens and aqueous humor, and lastly tears. The pattern of substrate hydrolysis suggests that a common dominant aminopeptidase is present in these tissues except the conjunctiva. While the role of these peptidases in ocular physiology is unknown, they may play a role in limiting the entry of topically applied peptides into the eye.

Aminopeptidases↗