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PubMed1978

The preparation and purification of individual human pepsins by using diethylaminoethyl-cellulose.

A procedure was devised for isolating human pepsins 1, 2, 3 and 5 from gastric juice by repetitive column chromatography on DEAE-cellulose. The combined yields in four different experiments varied from 14% to 90% of the total peptic activity of the starting material. The isolated individual pepsins were shown to behave as single homogeneous proteins on agar-gel electrophoresis at pH 5.0 and on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. There is preliminary evidence, requiring further study, of two other pepsins, one migrating between pepsins 1 and 2 and the other a pepsin-3 component associating closely with pepsin 5 on chromatography.

Chromatography, DEAE-Cellulose↗

PubMed1977

The effects of somatostatin and metiamide on tachyphylaxis of pentagastrin stimulated gastric acid and pepsin secretion in the conscious cat.

1. Pentagastrin stimulated gastric acid and pepsin secretions show parallel rates of tachyphylaxis in the conscious cat. The responses to histamine show only slight tachyphylaxis. 2. Somatostatin 10 microng.kg(-1).hr(-1) inhibits pentagastrin but not histamine stimulated acid secretion and inhibits pentagastrin stimulated pepsin secretion. 3. The inhibition of pentagastrin stimulated acid and pepsin secretion by Somatostatin delays the tachyphylaxis of these responses, but the rates of tachyphylaxis when they do subsequently occur are identical. 4. Metiamide 10 mg-kg(-1)-hr(-1) equally inhibits histamine and pentagastrin stimulated acid secretion but does not inhibit pentagastrin stimulated pepsin secretion. 5. Inhibiton of acid secretion during metiamide infusion neither prevents nor delays acid nor pepsin tachyphylaxis. 6. It is suggested that tachyphylaxis of acid and pepsin secretion is a gastrin receptor phenomenon and that Somatostatin occupies or modifies the behaviour of these receptors, preventing tachyphylaxis. Metiamide, however, exerts its action only on the histmine H2-receptor and not the gastrin receptor mechanism, and this apparently does not prevent or delay acid tachyphylaxis.

Animals↗

PubMed1977

Pepsin immobilized on inorganic supports for the continuous coagulation of skim milk.

The milk-clotting enzyme pepsin was immobilized onto beads of alumina, titania, glass, stainless steel, iron oxide, and Teflon for treating skim milk in a fluidized-bed reactor. Two covalent attachment procedures using silanized supports and glutaraldehyde and two adsorption procedures were evaluated. The three best catalysts were titania and glass, using the covalent attachment procedure, and alumina, using the adsorption procedure at pH 1.2. The pepsin adsorbed on alumina catalyst has commercial potential compared to the previously used glass catalyst. Attempts to increase the stability of pepsin adsorbed on alumina by cross-linking with glutaraldehyde were unsuccessful owing to the low pH necessary for optimum pepsin adsorption; Desorption of pepsin from alumina during reactor operation was determined. Regeneration of spent catalysts was only partially successful.

Alum Compounds↗

PubMed1979

Inhibition of pepsin secretion by metiamide and atropine in the conscious rat.

The inhibition of pepsin secretion by metiamide and atropine has been studied in the gastric fistula rat and the Heidenhain pouch rat. A comparison of the effectiveness of metiamide and atropine in inhibiting pepsin secretion was made by using doses of the antagonists which produced a similar level of inhibition of acid secretion. In the gastric fistula rat both atropine and metiamide inhibited the basal pepsin output, but atropine was more effective than metiamide in this respect. In the Heidenhain pouch rat a large dose of metiamide which inhibited bethanechol-stimulated acid secretion had no significant effect on the corresponding output of pepsin. In this preparation atropine inhibited both acid and pepsin secretion. Possible reasons for the differences in the two preparations are discussed.

Animals↗

PubMed1978

Properties of the activation by pepsin of inactive renin in human amniotic fluid.

1. The renin present in human amniotic fluid was found to have an apparent Mr of 58 000 by gel filtration and is thus bigger than renin in untreated kidney extracts and plasma (Mr approximately 40 000). 2. Treatment with pepsin (40 microgram/ml pH 4.8, 2 h, 22 degrees C) caused a 6-fold increase in activity of this renin species, although Mr was not very different (57 000). 3. Unlike renal renin, renin in human amniotic fluid was not a glycoprotein and behaved similarly on concanavalin A-Sepharose before and after activation by pepsin. 4. Ion-exchange chromatography demonstrated a small change in the ionization properties of human amniotic fluid renin after activation by pepsin. 5. Pepsin-mediated activation resulted in a five-fold increase in V, but only a small decrease in the Km of renin to 39% of normal, so that the increase in activity observed was not due to an increase in the affinity of the enzyme for its substrate. The kinetic data were consistent with the theory of noncompetitive inhibition. 6. The activation of human amniotic fluid renin by pepsin may be caused by a change in the tertiary structure of the molecule subsequent to a proteolytic action that does not remove detectable polypeptide components.

Amniotic Fluid↗

PubMed1975

Kinetic studies on the mechanism of pepsin action.

The linear noncompetitive inhibition of the pepsin-catalyzed hydrolysis of Ac-Phe-Phe-Gly at pH 2.1 by L-Ac-Phe, L-Ac-Phe-NH2, and L-Ac-Phe-OEt has been claimed to substantiate the ordered release of products specified by the amino-enzyme mechanism for pepsin action. According to this interpretation, the binding of inhibitor to free enzyme and the amino-enzyme intermediate (Scheme I) generates the observed inhibition pattern. The proposition is valid only if a simple alternative explanation for the kinetic data, Scheme II, can be disproved. Scheme II attributes the inhibition pattern to the binding of inhibitor to free enzyme and the enzyme-substrate (Michaelis) complex. The experiments reported here have enabled us to distinguish between the two mechanisms. The pepsin-catalyzed hydrolyses of Ac-Phe-Trp, Z-H'IS-Phe-Trp, Z-Gly-His-Phe-Trp, and Z-Ala-His-Phe-Trp at pH 1.8 occur exclusively at the Phe-Trp bond and must yield the same amino-enzyme, E-Trp, if it is implicated. Under these circumstances, Scheme I requires that a plot of 1/kc vs. (I)o for the four substrates and a given noncompetitive inhibitor provide a set of four parallel lines. Scheme II predicts that the four lines generally will not be parallel. L-Ac-Phe, L-Ac-Phe-NH2, L-Ac-Phe-OMe, and D-Ac-Phe act as linear noncompetitive inhibitors for the pepsin-catalyzed hydrolysis of the four Trp-containing substrates. The plot of 1/kc vs. (I)o for each inhibitor results in a set of four nonparallel lines. Therefore Scheme II must be correct and the detection of noncompetitive inhibition accompanying the pepsin-catalyzed hydrolysis of peptides offers no insight into the merits of the amino-enzyme hypothesis.

Binding, Competitive↗

PubMed1979

Action of human pepsins 1,2,3 and 5 on the oxidized B-chain of insulin.

Human pepsins 1 and 2 attack the B-chain of oxidized insulin at pH 1.7 at the same bonds as does human pepsin 3. At pH 3.5, pepsins 1 and 2 attack insulin B-chain at essentially the same bonds as at pH 1.7, but more slowly. For all three enzymes, the first bond to be hydrolysed is Phe(25)-Tyr(26), followed simultaneously by Glu(13)-Ala(14), Leu(15)-Tyr(16) and Tyr(16)-Leu(17). Human pepsin 5, however, attacks Phe(24)-Phe(25) first of all, followed by Leu(15)-Tyr(16) and Tyr(16)-Leu(17). The results suggest that each pepsin has only one active site. Acid hydrolysis indicates that the sites of enzymic cleavage are not bonds with an inherent instability at low pH.

Amino Acid Sequence↗

PubMed1977

The effect of serotonin on pepsin inhibition by duodenal fat.

The purpose of these studies was to evaluate the possible role of serotonin on pepsin secretion. The results of our data suggest that serotonin is a stimulator of pepsin secretion since (a) pretreatment with reserpine (which depletes serotonin stores) abolished the stimulatory effect of histamine on pepsin secretion; (b) pretreatment with UML-491 (a serotonin blocking agent at the effector level) augmented the pepsin inhibition induced by the intraduodenal infusion of fat, and (c) 5-hydroxytryptophan (a serotonin precursor) caused a significant stimulation of pepsin secretion. The mode of action of serotonin is probably by a direct hormonal action on the gastric chief cells.

Animals↗

PubMed1976

Electron paramagnetic resonance studies on spin-labelling of pepsin: effects of temperature, pH and urea on its conformation.

Pepsin was spin-labelled with N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidyl) bromoacetamide, possibly at the active site, at a beta-catboxyl group of a reactive aspartic acid. The spectrum of the spin-labelled pepsin showed that the spin probe was strongly immobilized (correlation time is greater than or equal to 10(-8) sec). Spin-labelled pepsin was thermally denatured at various temperatures and electron paramagnetic resonance (e.p.r.) spectra were taken at various times. Rates of denaturation estimated from the e.p.r. spectra at various temperatures showed that the enthalpy and entropy of thermal denaturation of spin-labelled pepsin at pH 3.5 were 48.0+/-4.9 kcal/mole and 214.7+/-14.5 e.u. respectively. Addition of conc. NaOH or 1 M acetate buffer at pH 6.0 sharpened e.p.r. spectra of the spin-labelled pepsin, indicating that the spin probe became mobilized by alkaline denaturation. Addition of urea caused unfolding of the protein which increased with the urea concentration, although only slight transition of conformational changes was observed in the e.p.r. spectra.

Electron Spin Resonance Spectroscopy↗

PubMed1979

Hereditary aspects of duodenal ulceration: pepsin 1 secretion in relation to ABO blood groups and ABH secretor status.

Pepsin 1, the ulcer-associated pepsin, occurred significantly more frequently in the gastric juice of those patients with duodenal ulcer who did not secrete A, B, or H antigens into gastric juice than in those secreting these antigens. This observation may explain the increased proportion of such non-secretors among patients with duodenal ulceration. In patients with gastric ulcer and non-ulcer dyspepsia, and in a miscellaneous group of patients, there was no association of pepsin 1 secretion with secretor status, suggesting that the association noted in duodenal ulceration is an indirect rather than a direct one. No increase of pepsin 1 occurred in group O patients with peptic ulcer, so that the increased proportion of such patients in peptic ulcer does not arise from differences in pepsin 1 secretion.

ABO Blood-Group System↗

PubMed1977

Role of intragastric pressure, pH, and pepsin in gastric ulceration in the rat.

A method of continuous gastric perfusion with "artificial gastric juice" was used in a study of individual factors (intragastric pressure, pH, and pepsin) known to participate in the pathogenesis of peptic ulcers. This method allowed change of only one factor at a time, while the other two remained constant. The gastric mucosa of normal rats, fasted for 48 hr, was found to be resistant to the ulcerogenic effects of artificial gastric juice perfused through the stomach for 6 hr without increasing the intragastric pressure. Perfusion of hydrochloric acid (pH 1.3) under increasing pressure produced ulceration of the corpus as well as forestomach portion of the stomach. The degree of gastric ulceration paralleled increases in intragastric pressure, acidity, and pepsin proteolytic activity. Inhibition of pepsin activity by a pepsin inhibitor protected the gastric mucosa even at the very low pH of 1.3. These results demonstrate that under the experimental conditions used, hydrochloric acid alone in the absence of pepsin does not produce ulceration of the rat stomach.

Animals↗

PubMed1977

Pepsin and acid secretions during and after gastric operations in patients with duodenal ulcer.

Measurement of gastric pepsin and acid secretion was performed before, during and after selective vagotomy with antrectomy (SVA) and Billroth I gastrectomy (B-I) in 20 patients with a duodenal ulcer. Preoperative pepsin concentration increased during operation and decreased gradually 72 hours after SVA and 1 to 3 months after B-I. Although the pepsin concentration decreased substantially, it was never less than 70% of the preoperative level in both groups. Acid concentration decreased immediately after vagotomy in the SVA group and decreased gradually after 72 hours in the B-I group. Although there was a notable increase in the pH in both groups after operation, a pH of 5 was never reached. Decrease in gastric secretory volume (about 50%) was approximately equal in both groups. It appears that any increase in acid secretion occurring after vagotomy or gastrectomy may be sufficient to activate high-and low-pH-acting pepsins. Extravagal and extraantral stimulation of gastric pepsin secretion after operation should be considered an important etiologic factor in the pathogenesis of recurrent ulcer.

Duodenal Ulcer↗

PubMedDate not supplied

[The fluorescence of pepsin conjugates with DNS-chloride].

Parameters of rotational relaxation of pepsin conjugated in neutral and slightly alkaline solutions with a fluorescent label 1-dimethylaminonaphthalene-5-sulphonyl chloride (DNS-Cl) are measured by a fluorescence polarization method. It is shown that the globule of pepsin denatured and loose at lakaline pH values converts into a compact form after transfer to acidic solution. The compactness of this new form is close to that of native inhibited pepsin. A new globule is distinguished from the native by the absence of segmental flexibility. Conjugated with a DNS at pH less than or equal to 7.0 pepsin relaxes in solution as catalytically active dansylated aminopepsin (DNS-3-aminotyrosine pepsin). Evidence is presented that these conjugates are also characterized by segmental flexibility.

Animals↗

PubMed1977

New data on pepsin mechanism and specificity.

New data on the specificity and mechanism of action of porcine pepsin are presented, including statistical analysis of protein cleavage by the enzyme, kinetics of synthetic substrates, enzyme inhibition and activation, kinetics of transpeptidation reaction, and 180 exchange studies. From these data it was concluded that pepsin has an extended active site being able to accomodate specifically five amino acid residues of the substrate. The orientation of the substrate molecule relative to the ethanol binding loci in pepsin crystals has been determined. Pepsin mechanism includes "amino-enzyme" formation which chemically is not an amide, formed by the enzyme carboxyl with the amino fragment of the substrate.

Amino Acid Sequence↗

PubMed1978

Clinical study on gastric secretion with special reference to pepsin secretion.

The stimulating effect of AOC-tetragastrin, caerulein, Histalog and secretin on human gastric acid and pepsin secretion was studied in gastric ulcer patients. The pattern of gastric acid and pepsin secretion after the administration of caerulein was closely resembled to that of gastrin. Slight increase of pepsin secretion after gastrin or caerulein could be based on "wash-out" action caused by the increase of acid secretion after the stimulants. Stimulating effect on gastric pepsin secretion of histalog and secretin would be independent of gastric acid secretion.

Ceruletide↗

PubMed1976

Isolation, by partial pepsin digestion, of the three collagen-like regions present in subcomponent Clq of the first component of human complement.

1. Digestion of human subcomponent C1q with pepsin at pH4.45 for 20h at 37 degrees C fragmented most of the non-collagen-like amino acid sequences in the molecule to small peptides, whereas the entire regions of collagen-like sequence that comprised 38% by weight of the subcomponent C1q were left intact. 2. The collagen-like fraction of the digest was eluted in the void volume of a Sephadex G-200 column, was was showm to be composed of two major fragments when examined by electrophoresis on polyacrylamide gels run in buffers containing sodium dodecyl sulphate. These fragments were separated on CM-cellulose at pH4.9 in buffers containing 7.5M-urea. 3. Human subcomponent C1q on reduction and alkylation yields equimolar amounnts of three chains, which have been designated A, B and C [Reid et al. (1972) Biochem. J. 130, 749-763]. One of the pepsin fragments was shown to be composed of the N-terminal 95 residues of the A chain linked, via residue A4, by a single disulphide bond to a residue in the sequence B2-B6 in the N-terminal 91 residues of the B chain. The second pepsin fragment was shown to be composed of a disulphide-linked dimer of the N-terminal 94 residues of the C chain, the only disulphide bond being located at residue C4.4. The mol. wts. of the unoxidized and oxidized pepsin fragments were estimated from their amino acid compositions to be 20 000 and 18 200 for the A-B and C-C dimers and 11 400, 8800 and 9600 for the collagen-like fragments of the A, B and C chains respectively. Estimation of the molecular weights of the peptic fragments by polyacrylamide-gel electrophoresis run in the presence of sodium dodecyl sulphate gave values that were approx. 50% higher than expected from the amino acid sequence data. This is probably due to the high collagen-like sequence content of these fragments.

Alkylation↗

PubMed1977

Inhibition of the reconstitution of the haemolytic activity of the first component of human complement by a pepsin-derived fragment of subcomponent C1q.

1. A fragment of subcomponent C1q, which contained all the collagen-like features present in the intact molecule, was isolated by pepsin digestion as described by Reid [Biochem. J. (1976) 155, 5-17]. 2. The pepsin-derived fragment of subcomponent C1q did not bind to antibody-coated erythrocytes under conditions where complete binding of sub-component C1q took place. 3. The peptic fragment blocked the reconstitution of C1 haemolytic activity by competing with intact subcomponent C1q in the utilization of a mixture of the other two subcomponents, C1r and C1s. 4. Reduction and alkylation of the interchain disulphide bonds in the pepsin fragment did not markedly affect its inhibitory effect, whereas heating at 56 degrees C for 30min completely abolished the effect. 5. Lathyritic rat skin collagen and CNBr-derived peptides of pig type II collagen showed no ability to mimic the inhibitory effect of the pepsin fragment when tested over the same concentration range as used for the peptic fragment. 6. The peptic fragment was unable to block efficiently the reconstitution of C1 haemolytic activity unless it was added to the mixture of subcomponents C1r and C1s before the attempt to reconstitute C1 haemolytic activity, in solution, or on the surface of antibody-coated erythrocytes. 7. Evidence was obtained that suggested that subcomponent C1q bound the subcomponent C1r-C1s complex more efficiently when the subcomponent C1q was bound to antibody than when it was free in solution.

Binding Sites, Antibody↗

PubMed1977

Inhibition of hydrochloric acid and pepsin secretion from gastric pouches by antral pouch acidification in sheep.

1. Secretion of acid and pepsin from separated pouches of the body of the abomasum was studied in sheep during perfusion of antral pouches with acid solutions. 2. Resting secretion of acid and pepsin was reduced by acidification of antral pouches to pH 2.7 or less. 3. Increases in the secretion of HCl and pepsin normally obtained on feeding were reduced or abolished by perfusion of antral pouches with solutions at pH 1.3--2.0. 4. Perfusion of antral pouches with acetylcholine at pH 2.5 failed to stimulate acid secretion as it did at a higher pH. 5. Pentagastrin stimulated acid and pepsin secretion during the inhibition of secretion produced by antral pouch acidification. 6. Increases in reticular motility occurred on antral pouch acidification with solutions of pH 1.1--1.3. 7. The contribution of antral pH in regulating abomasal acid secretion is discussed.

Abomasum↗