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PubMed1976

Partial characterization of hog renin purified by affinity chromatography.

A method has been set up to purify renin on a large scale by affinity chromatography using Pepstatin, a potent inhibitor of renin, as a ligand. Pepstatin was covalently coupled to Sepharose via six different spacer 'arms'. The Sepharose-hexamethylenediamino-Pepstatin appeared to be the better derivative for renin purification even at a concentration as low as 160 nmol of Pepstatin/ml of moist gel. Renin was extracted from 100 kg of hog kidneys and semi-purified by ammonium sulfate precipitations and chromatography on DEAE-cellulose. The active fraction (48.5 g of proteins) was applied on a 500-ml affinity column. Renin was eluted in the starting buffer containing 6 M urea. Renin was purified 120-fold by the affinity chromatography step with a 79% recovery. Physico-chemical characterization of highly purified renin was performed. Isoelectrofocusing on a pH gradient from 3 to 6 showed a major peak with an isoelectric point (pI) of 4.95 and a minor peak (pI = 4.70). Polyacrylamide gel electrophoresis, pH 7.8, at different gel concentrations, showed a single peak of renin activity which was found in the major protein band. Molecular size estimated on agarose-acrylamide gel filtration was 40 000. All these physical parameters were similar before and after purification.

Animals↗
PubMed1992

Lymphoproliferative activity of Pseudomonas exotoxin A is dependent on intracellular processing and is associated with the carboxyl-terminal portion.

Pseudomonas aeruginosa exotoxin A (PE) represents a microbial superantigen that requires processing by accessory cells in order to induce the proliferation of V beta 8-bearing murine T lymphocytes. In this study, we have observed that PE requires intracellular processing by a protease in order to induce lymphoproliferation. Pepstatin A, an inhibitor of acid proteases, inhibited PE-induced lymphoproliferation, whereas leupeptin, an inhibitor of serine and thiol proteases, had no effect on PE-induced lymphoproliferation. A number of mutant forms of PE were examined for their ability to induce lymphoproliferation. The mutant form which lacks amino acids 5 to 224 of the receptor-binding domain, PE43, was capable of inducing murine thymocytes to proliferate in the presence of accessory cells. However, neither PEgly276, a mutant toxin which undergoes a different intracellular processing pattern than wild-type PE, nor PE589, a mutant toxin which lacks amino acids 590 to 613 at the carboxyl terminus, was able to induce thymocyte proliferation. In addition, the lymphoproliferation induced by the PE43 mutant form of PE could also be inhibited by pepstatin A. Therefore, our data indicate that intracellular processing by a proteolytic enzyme which is inhibited by pepstatin A is critical for PE-induced lymphoproliferation. Furthermore, the lymphoproliferative activity of PE is associated with the carboxyl-terminal portion of PE.

ADP Ribose Transferases↗
PubMed1988

Influence of culture medium pH and proteinase inhibitors on extracellular proteinase activity and cell growth of Sporothrix schenckii.

Sporothrix schenckii produces two extracellular proteinases in albumin- or collagen-supplemented unbuffered liquid medium. Proteinase I had an optimal pH of 6.0, and its activity was strongly inhibited by chymostatin. Proteinase II had an optimal pH of 3.5, and its activity was strongly inhibited by pepstatin. Speculating that these two proteinases are key enzymes for fungal growth, we investigated the influences of culture medium pH and either or both of the proteinase inhibitors pepstatin and chymostatin on the cell growth of S. schenckii. In buffered medium at a pH of 3.5, an optimal pH for proteinase II, only proteinase II activities were observed, while at pH 6.0, an optimal pH for proteinase I, only proteinase I activities were observed. However, there was no cell growth inhibition. These results suggested that the regulation of the production of the two proteinases is dependent on environmental pH. The addition of pepstatin or chymostatin to the culture medium did not inhibit the cell growth of S. schenckii, but the addition of both inhibitors at a concentration of 10 micrograms/ml strongly inhibited growth. These results suggested that at least one of the two proteinases was expressed to allow fungal growth in albumin-supplemented media. The indirect fungistatic action of the proteinase inhibitors, which inhibit proteolysis, may be applied to a topical therapeutic agent in vivo.

Chymotrypsin↗
PubMed1985

Lysosomal digestion of thyroglobulin: role of cathepsin D and thiol proteases.

Purified hog thyroid lysosomes, prepared by a procedure previously developed in this laboratory, were used to study lysosomal digestion of [131I]thyroglobulin [131I]Tg). The lysosomal proteases were solubilized with 0.1% Triton X-100. Rates of proteolytic digestion, measured by the release of ethanol-ammonium acetate-extractable 131I, were greatly stimulated by thiol reagents. The pH optimum was also affected by the presence of thiols. In the absence of a thiol reagent, a broad pH optimum was observed, ranging from 3.5-4.5. However, in the presence of 1 mM mercaptoethanol, the maximum rate of digestion occurred at pH 5.0, very close to reported values for the internal pH of lysosomes. Pepstatin, an inhibitor of cathepsin D, markedly inhibited lysosomal digestion of [131I]Tg at concentrations as low as 0.01 micrograms/ml. Its inhibitory effect was greater at pH 3.5 (pH optimum of cathepsin D) than at pH 5.0. Leupeptin, an inhibitor of thiol proteases, was not as potent as pepstatin, but it was significantly inhibitory at a concentration of 1 microgram/ml. In contrast to pepstatin, leupeptin displayed a greater inhibitory effect at pH 5.0 than at pH 3.5. The pH optimum of hog thiol proteases has been reported to range from 5.5-6.5. The effects of the two inhibitors were additive at pH 5.0. We conclude from these results that both cathepsin D and thiol proteases play a role in lysosomal digestion of Tg. Cathepsin D appears to be quantitatively more important than thiol protease in the initial phase of the digestion. The stimulatory effect of thiols on lysosomal digestion of [131I]Tg probably involves two separate effects: 1) stimulation of thiol proteases, and 2) reduction of S-S bonds in Tg, making the protein more susceptible to attack by proteolytic enzymes. Poorly iodinated [131I]Tg was more rapidly hydrolyzed than well iodinated [131I]Tg, based on the release of ethanol-ammonium acetate-extractable 131I. However, there was little or no difference in the rate of total peptide bond cleavage between poorly iodinated and well iodinated Tg. These results suggest that the first sites of iodination of Tg are preferentially attacked by lysosomal proteases. Long term (24-h) digestion of [131I]Tg with solubilized thyroid lysosomes at pH 5.0 in the presence of thiol compounds was just as effective as digestion with pronase at pH 8.0 in liberating free 131I-labeled iodothyronines and 131I-labeled iodotyrosines. Thus, thyroid lysosomes contain the full complement of proteases and peptidases required for cleaving free iodoamino acids from Tg.

Animals↗
PubMed1994

Bestatin, a potent aminopeptidase-N inhibitor, inhibits in vitro decidualization of human endometrial stromal cells.

We have reported that human endometrial stromal cells (ESC) express a cluster of differentiation-13 antigen/aminopeptidase-N, and the expression of this peptidase antigen was shown to increase with the decidualization of ESC. To clarify the role of this peptidase in human endometrium, the effect of bestatin ([(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-(S)-leucine), an inhibitor of aminopeptidase-N, on the decidualization of ESC in vitro was examined. Purified human ESC were cultured for 12 days in the presence of 10(-6) mol/L progesterone with or without bestatin. Decidualization was assessed by PRL production and morphological transformation. The effects of a stereoisomer of bestatin and of pepstatin were similarly examined using the same culture system. Bestatin inhibited progesterone-induced PRL production in a dose-dependent manner, with no effect on cell number or viability, whereas neither its stereoisomer nor pepstatin inhibited aminopeptidase activity or PRL production. The morphological transformation of ESC was also inhibited by bestatin, but not by its stereoisomer or pepstatin. These findings demonstrate that the inhibition of aminopeptidase-N activity blocks the in vitro decidualization of ESC and suggest an important role for this peptidase in the functional differentiation of human ESC.

Adult↗
PubMed1988

In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells.

It has been proposed that proteases secreted by cancer cells facilitate metastasis by degrading extracellular matrix. Estrogen receptor-positive breast cancer cells secrete a Mr 52,000 pro-cath-D under estrogen stimulation, whereas this protease is produced constitutively by estrogen receptor-negative cancer cells. We report on the degradation in vitro of extracellular matrix by purified Mr 52,000 cathepsin D (cath-D) and by conditioned media prepared from different cell lines. The purified Mr 52,000 pro-cath-D was autoactivated at pH 4.5 into a Mr 51,000 cath-D and found to digest the extracellular matrix of endothelial bovine corneal cells labeled with [3H]proline or [35S]methionine. Culture medium conditioned by estrogen-treated MCF7 cells had a similar effect at pH 4.5 but not at pH 7.4. Matrix degradation was totally inhibited by pepstatin. Other breast cancer cells (BT20, MDA-MB231, T47D cells, etc.) and other cancer cells also secreted a pepstatin-sensitive proteinase able to degrade extracellular matrix. By contrast, the U2 variant of MCF7 cells, which lacks the Mr 52,000 cath-D gene, and the nontumoral epithelial mammary cells secreted a negligible amount of this proteinase. In all conditioned media, the pepstatin-dependent extracellular matrix degrading activity was highly correlated to the Mr 52,000 cath-D concentration measured by immunoenzymatic assay. We conclude that the Mr 52,000 cath-D is the major acidic protease secreted by mammary cancer cells. We suggest that this protease may degrade basement membrane and consequently facilitate tumor invasion when it is released in an acidic microenvironment.

Breast Neoplasms↗
PubMedDate not supplied

[Action of lysosomotropic modulators on the thyroid cells of rats].

Hydrocortisone, ammonium chloride, pepstatin and contrykal have been studied for their effect on incubated and cultured fragments of rat thyroid gland. It is found that the radioactive iodine uptake by thyroid gland cells is inhibited by hydrocortisone, ammonium chloride and pepstatin. Pepstatin induces formation of vacuoles with nonhydrolyzed thyroglobulin in thyrocytes.

Ammonium Chloride↗
PubMed1976

Effect of a pepsin-inhibitory pentapeptide upon the peptic activity and acidity of gastric secretion.

The effect of a pepsin-inhibiting pentapeptide, pepstatin, upon the peptic activity and gastric acidity was investigated in 9 men with ulcer dyspepsia and a high acid output. Subtotal inhibition of peptic activity was obtained, basally as well as after broth stimulation, as early as 15 minutes after the method of administration, and the inhibition remained almost unchanged during the 60 minutes of the experimental period. The acidity was not affected by pepstatin. No side-effects occurred. The results confirm preliminary reports on the pepsin-inhibitory activity of the drug. It is concluded that pepstatin ought to be investigated with regard to its clinical effect upon peptic ulcer.

Adult↗
PubMed1983

Isolation, partial purification and some properties of two acid proteases from adult Dirofilaria immitis.

Two acid proteases were isolated from the soluble extracts of adult Dirofilaria immitis, the filarial heartworm of canines. Activity of these proteases was detected using 3H-labeled bovine alpha-casein as substrate, and they were designated Fp-I and Fp-II in order of their elution from a CM-cellulose column. The molecular weight of partially purified Fp-I was approximately 170000, and it was active between pH 4.6-5.8. The activity of Fp-I doubled in the presence of various sulfhydryl reagents at 5 mM, and it was inhibited 50-60% by the sulfhydryl inhibitors p-hydroxymercuribenzoate and iodoacetate at 1 mM, the heavy metal chelating agent o-phenanthroline at 1 mM and the peptide aldehyde protease inhibitors pepstatin (10 microM), leupeptin, antipain and chymostatin (50 microM). The molecular weight of the more extensively purified Fp-II is approximately 48000. This protease was active between pH 2.6-3.4 and was highly sensitive to inhibition by pepstatin (80% inhibition at 10 nM). Fp-II was not significantly affected by sulfhydryl reagents, sulfhydryl inhibitors, metal chelating agents or peptide aldehyde protease inhibitors other than pepstatin. These properties of dirofilarial Fp-II resemble those of mammalian cathepsin D.

Animals↗
PubMed1998

A probarley lectin processing enzyme purified from Arabidopsis thaliana seeds.

An aspartic proteinase was purified from the seeds of Arabidopsis thaliana (ecotype RLD) using affinity chromatography on pepstatin-agarose and ion exchange chromatography. The purified enzyme is optimally active at pH 3.5 and completely inhibited by pepstatin A. The purified Arabidopsis aspartic proteinase contains four subunits (apparent molecular weights 31, 28.5, 15 and 6 kDa), two of which are probably linked by disulfide bridges. These properties are similar to the aspartic proteinase previously isolated from barley seeds. The amino acid sequence of the peptide subunits corresponds exactly with the sequence of the previously isolated cDNA for the Arabidopsis aspartic proteinase. The Arabidopsis enzyme processed probarley lectin in vitro at the carboxy-terminus between phenylalanine and alanine, the same place where the barley enzyme cleaves the lectin in vitro. The aspartic proteinase appears to be the major enzyme processing the lectin in seeds as pepstatin A inhibited this activity in a crude seed extract.

Amino Acid Sequence↗
PubMed2003

Systemic peptide delivery via the stomach: in vivo evaluation of an oral dosage form for salmon calcitonin.

It was the aim of this study to investigate the potential of stomach targeted delivery systems for systemic peptide administration using salmon calcitonin as a model drug. Chitosan was modified by the immobilization of thiol groups utilizing 2-iminothiolane in order to obtain a chitosan-4-thiobutylamidine conjugate (chitosan-TBA). Furthermore, a chitosan-pepstatin A conjugate was synthesized by a carbodiimide mediated linkage of the pepsin inhibitor to the polymer. The protective effect of this novel conjugate for calcitonin towards pepsin was evaluated in vitro. Minitablets (5 mg) were generated by direct compression of calcitonin, chitosan, chitosan-TBA, chitosan-pepstatin A conjugate and glutathione (GSH), respectively (A, 1:0:69:20:10; B, 1:79:0:20:0; C, 1:99:0:0:0). The drug release was investigated in an artificial gastric fluid. Biofeedback studies were performed in rats by determining the decrease in plasma calcium level after oral administration. The novel chitosan-pepstatin A conjugate displayed 291+/-58 nmol inhibitor per gram polymer (mean+/-S.D., n = 5). The chitosan-inhibitor conjugate showed a very strong protective effect for salmon calcitonin towards pepsinic degradation. A controlled drug release was provided by all tested dosage forms-A, B and C. Dosage form B led only to a slight reduction of the plasma calcium level, displaying a pharmacological efficacy versus i.v. injection of 0.41%, while dosage form C did not lead to any significant effect. In contrast, dosage form A led to a decrease in the plasma calcium level of 10% for at least 12 h. The pharmacological efficacy of this formulation was determined to be 1.35%. The study suggests that stomach targeted oral delivery might be a promising novel approach for noninvasive systemic peptide administration.

Administration, Oral↗
PubMed1998

Stored renin isoforms in the developing rat kidney.

Fetal rat kidney contains renin in renal microvasculature, whereas adult rat kidney contains renin predominantly in juxtaglomerular cells. It is hypothesized that renin isoforms stored within these renal tissues may differ chemically and functionally. To test this hypothesis, stored renin isoforms in fetal and adult rat kidney were compared by isolating renin from adult and fetal kidney homogenate with pepstatin agarose. Pepstatin-eluted renin isoforms were separated by relative molecular size using one-dimensional polyacrylamide gel electrophoresis (SDS-PAGE), or by isoelectric point (pI) and size using two-dimensional (2D) gel electrophoresis. Isoforms were identified either by silver staining or immunoblotting. One-dimensional polyacrylamide gel electrophoresis of pepstatin-treated kidney homogenates showed a silver-stained band in the range of approximately 45 kDa, which corresponded to a silver-stained spot consistently seen on 2D gels. In fetal kidney homogenate, the approximately 45 kDa band had a pI of 5.3 +/- 0.1, whereas the corresponding band in adult samples had a basic pI of 6.0 +/- 0.05. Angiotensin I generation was measured to assess renin enzymatic activity. There was significantly more inactive renin in fetal kidney homogenate than in adult kidney homogenate (60.2 +/- 22.4 v 9.6 +/- 4.0 ng AI/mg protein/h, P < .05). There was significantly less active renin in fetal kidney homogenate than in adult kidney homogenate (5.4 +/- 0.4 v 36.5 +/- 14.2 ng AI/mg protein/h, P < .05). The average total renin activity in fetal kidney homogenate was significantly higher than in adult kidney homogenate (65.6 +/- 22.3 v 46.0 +/- 15.2, P < .05). These results demonstrate major differences in the physical and enzymatic forms of stored renin found in fetal and adult kidney. It is speculated that these variations in stored renin isoforms play a role in the developmental differential regulation of the intrarenal renin angiotensin system.

Animals↗
PubMed2000

Tripeptidyl-peptidase I deficiency in classical late-infantile neuronal ceroid lipofuscinosis brain tissue. Evidence for defective peptidase rather than proteinase activity.

Brain tissue from patients with classical late-infantile neuronal ceroid lipofuscinosis (LINCL, an infantile form of Batten disease) is deficient in the lysosomal enzyme tripeptidyl-peptidase I (EC 3.4.14.9). The activities of other lysosomal enzymes are either increased or decreased. Tripeptidyl-peptidase I is a pepstatin-insensitive exo-tripeptidase, with little or no endo-proteolytic activity, that is active on small peptides but not on large proteins. Using haemoglobin and casein as substrates for proteolytic activity, we were unable to demonstrate any significant defect in pepstatin-sensitive or pepstatin-insensitive proteinase activity in brain tissue or cultured skin fibroblasts of LINCL patients. These observations suggest that the lysosomal storage of undegraded, small peptides in LINCL results from the absence of peptidase rather than proteinase activity.

Adult↗
PubMed1981

Glucose-induced inactivation of mitochondrial enzymes in the yeast Saccharomyces cerevisiae.

1. Addition of glucose induced an inactivation of mitochondrial enzymes in the yeast Saccharomyces cerevisiae containing normal mitochondrial particles. 2. The glucose-induced inactivation of mitochondrial enzymes was inhibited by the presence of cycloheximide. 3. Pepstatin also inhibited the inactivation, but phenylmethanesulphonyl fluoride accelerated the inactivation. 4. The specific activities of fructose 1,6-bisphosphatase and cytoplasmic malate dehydrogenase were decreased on the exposure to glucose, as well as those of the mitochondrial enzymes. However, the glucose-induced inactivation of cytoplasmic enzymes was not inhibited by the presence of pepstatin. 5. The specific activities of hexokinase and phosphofructokinase, which are cytoplasmic enzymes were increased by the addition of glucose, and this effect was not affected by pepstatin. 6. Addition of glucose resulted in an increase in the synthesis of proteins of the mitochondria and the cytosol, and simultaneously in degradation of these mitochondrial and cytoplasmic proteins.

Cycloheximide↗
PubMed1990

Substrate and inhibitor studies with human gastric aspartic proteinases.

The separation of pepsin isoenzymes 1, 2, 3 and 5 (gastricsin) in human gastric juice was effected by chromatography on Mono Q ion-exchanger, and slow-moving proteinase was purified to homogeneity by using a modified procedure incorporating a novel affinity-chromatography step. The pH-activity profiles of these enzymes with mucus glycoprotein and basement-membrane substrates were determined; the profiles for pepsin 2 were noticeably different, and, in general, the pH optima for the hydrolysis of basement membrane were more acidic. Pepsin 1 expressed larger specificity constants (kcat./Km) than pepsin 3 with a series of synthetic peptide substrates, reflecting greater binding (smaller Km) by pepsin 1. Inhibitor studies at pH 1.7 and 4.5 with a series of P2-substituted lactoyl-pepstatins implied that valine at position P2 was optimal for inhibiting pepsins 1, 2 and 3 but detrimental for pepsin 5, whereas lysine at position P2 was tolerated well by pepsin 5 but not by pepsins 1, 2 and 3. The potency of lactoyl-pepstatin with lysine at position P2 did not increase as a function of pH. P2-substituted lactoyl-pepstatins failed to show any inhibitory selectivity among pepsins 1, 2 and 3.

Basement Membrane↗
PubMed2000

Lysosomal cathepsin B plays an important role in antigen processing, while cathepsin D is involved in degradation of the invariant chain inovalbumin-immunized mice.

We previously reported that CA074, a specific inhibitor of cathepsin B, modulates specific immune responses from the T helper 2 (Th2) type to Th1 type in BALB/c mice infected with Leishmania major. In the present study, we found that a similar type of immune deviation was also induced in mice immunized with ovalbumin (OVA). However, treatment of mice with pepstatin A, a specific cathepsin D inhibitor, suppressed the OVA-specific proliferation of lymphocytes and blocked the development of both Th1 and Th2 cellular responses. These inhibitors did not appear to have any direct influence in vitro on functions of naive lymphocytes. OVA antigen (47 000 MW) was digested mainly into 40 000 MW protein in vitro by lysosomal proteases from naive BALB/c mice, and its digestion was markedly inhibited by the addition of CA074, but not by addition of pepstatin A, during incubation. However, pepstatin A strongly suppressed the degradation of the major histocompatibility complex class II-associated invariant chain (Ii) molecule in vivo and in vitro. Thus, cathepsin B appears to process antigens directed to preferential activation of Th2 cells, while cathepsin D may be responsible for the degradation of Ii, the processing of which is essential in initiating the antigen-specific activation of Th1 and Th2 CD4+ T cells. These lysosomal proteases may have different functions in regulating immune responses.

Animals↗
PubMed1999

gamma-Secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid beta peptides of varying length.

gamma-Secretase activity is the final cleavage event that releases the amyloid beta peptide (Abeta) from the beta-secretase cleaved carboxyl-terminal fragment of the amyloid beta protein precursor (APP). No protease responsible for this highly unusual, purportedly intramembranous, cleavage has been definitively identified. We examined the substrate specificity of gamma-secretase by mutating various residues within or adjacent to the transmembrane domain of the APP and then analyzing Abeta production from cells transfected with these mutant APPs by enzyme-linked immunosorbent assay and mass spectrometry. Abeta production was also analyzed from a subset of transmembrane domain APP mutants that showed dramatic shifts in gamma-secretase cleavage in the presence or absence of pepstatin, an inhibitor of gamma-secretase activity. These studies demonstrate that gamma-secretase's cleavage specificity is primarily determined by location of the gamma-secretase cleavage site of APP with respect to the membrane, and that gamma-secretase activity is due to the action of multiple proteases exhibiting both a pepstatin- sensitive activity and a pepstatin-insensitive activity. Given that gamma-secretase is a major therapeutic target in Alzheimer's disease these studies provide important information with respect to the mechanism of Abeta production that will direct efforts to isolate the gamma-secretases and potentially to develop effective therapeutic inhibitors of pathologically relevant gamma-secretase activities.

Amino Acid Sequence↗
PubMed1992

Effect of a human immunodeficiency virus protease inhibitor on human monocyte function.

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Presenting Cells↗