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At least 19 recordsLinked to original sources
PubMed1980

Monkey pepsinogens and pepsins. Monkey pepsinogens and pepsins. V. Purification, Characterization, and amino-terminal sequence determination of crab-eating monkey pepsinogens and pepsins.

Pepsinogens were purified from the gastric mucosa of the crab-eating monkey, Macaca fascicularis. Eight pepsinogens were shown to be present disc-electrophoretically and they were termed pepsinogens I-a, I-b, III-1-a, III-1-b, III-2-a, III-2-b, III-3, and C, based on the nomenclature used for Japanese monkey pepsinogens. The molecular weights were 43,000 for pepsinogens I-a and I-b, 40,000 for pepsinogens III-1-a, III-1-b, III-2-a, III-2-b, and III-3, and 38,000 for pepsinogen C, as determined by sodium dodecyl sulfate-polyacrylamide disc gel electrophoresis. Pepsinogens I-a and I-b contained carbohydrate amounting to about 4-5% by weight. Each was activated to pepsin by acidification at pH 2.0. Pepsinogen III-1 (a mixture of III-1-a and III-1-b) yielded a single pepsin, i.e. pepsin III-1, and pepsinogen III-2 (a mixture of III-2-a and III-2-b) also gave a single pepsin, i.e. pepsin III-2. The molecular weights were estimated to be 38,000 for pepsins I-a and I-b, 35,000 for pepsins III-1, III-2, and III-3, and 34,000 for pepsin C. Optimal pHs toward acid-denatured hemoglobin were 1.9, 2.3, 2.0, 2.0, and 2.3 for pepsins I-a, III-1, III-2, III-3, and C, respectively. Pepstatin, diazoacetyl-DL-norleucine methyl ester (DAN), 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP), and p-bromophenacyl bromide inhibited each pepsin. Amino acid compositions of the pepsinogens and pepsins were determined. Pepsinogen C and pepsin C were distinct from the other pepsinogens and pepsins in their high ratios of glutamic acid to aspartic acid, and leucine to isoleucine. Amino acid sequences of the amino (N)-terminal 14 residues of pepsinogens were determined by the manual Edman procedure. One to three substitutions of amino acids were observed in the 14-residue segments among the pepsinogens except for pepsinogen C. There were 7 amino acid substitutions between pepsinogens C and III-3. These results suggest that the amino acid substitutions in the N-terminal region contribute considerably to the heterogeneity of pepsinogens.

Amino Acid Sequence↗
PubMed1995

[Effects of pepsinogen C gene polymorphisms on serum pepsinogen I and serum pepsinogen II levels].

Recently pepsinogens have been considered to be effective markers of terminal differentiation of stomach mucosa, and also good markers of preneoplastic and neoplastic changes of the stomach mucosa. Not a few studies concerning polymorphisms of pepsinogen A and C genes have been reported, however, as far as the authors are aware, no study was performed as to the relation between polymorphisms and serum pepsinogen I and II levels. Polymorphisms of the pepsinogen C (PGC) gene were identified by PCR, which amplifies DNA in the region within the intron between exon 7 and exon 8, and 6% polyacrylamide gel (no urea) electrophoresis. Six alleles were observed in the Japanese population. Frequencies for these alleles in 221 unrelated Japanese individuals were 0.077, 0.036, 0.328, 0.240, 0.009 and 0.310, respectively. The association between the PGC genotype and serum pepsinogen was investigated. A higher serum pepsinogen II level was observed in individuals homozygous for allele 6 than in those with other genotypes. This result indicates that careful attention should be paid to the genetic background of serum pepsinogen in screening of stomach cancer by this method.

Adult↗
PubMed1989

Radioimmunoassay of human pepsinogen A and pepsinogen C.

We describe the development of radioimmunoassays to measure both human pepsinogen A and pepsinogen C concentrations in serum. The antibodies were raised in goats by immunization with purified pepsinogen A or C. The affinity constants of the respective antibodies were 20.10(10) l/mol and 7.10(10) l/mol. Pepsinogens A and C were labeled with Na 125I by the chloramine T method. The binding between labels and antibodies was inhibited by 0.50 at 0.82 ng pepsinogen A per tube and 2.1 ng pepsinogen C per tube. The detection limits of the assay of pepsinogen A and C were 0.12 microgram/l and 1.8 micrograms/l, respectively. Pepsinogen A and C were purified and added to a patient serum, showing a good recovery in the radioimmunoassays. Serial dilution of another patient serum, which contained a high concentration of both antigens, showed curves parallel to the standard curves. The intra- and interassay variations of these radioimmunoassays were evaluated. The intra-assay coefficients of variation for pepsinogen A were found to vary from 0.03 to 0.102 at concentrations in serum in the normal range, while the inter-assay coefficient of variation ranged from 0.118 to 0.194 at the same concentrations in serum. For the pepsinogen C radioimmunoassay we found intra-assay coefficients of variation between 0.126 and 0.147 at concentrations in serum in the normal range, while the inter-assay coefficient of variation ranged from 0.174 to 0.325 for the same sera. In 201 blood donors we found a mean serum concentration of pepsinogen A of 59 micrograms/l and a mean serum concentration of pepsinogen C of 15 micrograms/l. There was a significant relationship between these values (r = 0.779, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Achlorhydria↗
PubMed1983

Purification and characterization of pepsinogens and pepsins from Asiatic black bear, and amino acid sequence determination of the NH2-terminal 60 residues of the major pepsinogen.

Five pepsinogens were purified to homogeneity from the gastric mucosa of Asiatic black bear and termed pepsinogens I-1, I-2, II-1, II-2, and III. Pepsinogen II-1 was the major component and accounted for more than half of the total pepsinogens. Their molecular weights were estimated to be 40,000 for pepsinogens I-1 and I-2, 38,000 for pepsinogens II-1 and II-2, and 42,000 for pepsinogen III. They resembled each other in amino acid composition, except that pepsinogens I-1 and I-2 contained larger numbers of basic residues than the others. Pepsinogen III was a glycoprotein containing about 3.7% carbohydrate. Each was activated to the corresponding pepsin and their enzymatic characteristics were investigated. The optimal pH against hemoglobin was about 2.2 for pepsin I-1, and about 2.5 for pepsins II-1, II-2, and III. Each pepsin was inhibited by pepstatin as well as porcine pepsin and also by diazoacetyl-DL-norleucine methyl ester, 1,2-epoxy-3-(p-nitrophenoxy)-propane, and p-bromophenacyl bromide. Each pepsin could hydrolyze N-acetyl-L-phenylalanyl-3,5-diiodo-L-tyrosine, but the specific activity was much lower than that of porcine pepsin. Activation peptides corresponding to residues 1-43, 1-25, and 26-43 were isolated from an activation mixture of pepsinogen II-1. The amino acid sequences of these peptides and of the NH2-terminal portions of pepsinogen II-1 and pepsin II-1 were determined, resulting in the complete NH2-terminal 60-residue sequence of pepsinogen II-1.

Amino Acid Sequence↗
PubMed1976

Mechanism of intramolecular activation of pepsinogen. Evidence for an intermediate delta and the involvement of the active site of pepsin in the intramolecular activation of pepsinogen.

Intramolecular pepsinogen activation is inhibited either by pepstatin, a potent pepsin inhibitor, or by purified globin from hemoglobin, a good pepsin substrate. Also, pepsinogen at pH 2 can be bound to a pepstatin-Sepharose column and recovered as native zymogen upon elution in pH 8 buffer. Kinetic studies of the globin inhibition of pepsinogen activation show that globin binds to a pepsinogen intermediate. This interaction gives rise to competitive inhibition of intramolecular pepsinogen activation. The evidence presented in this paper suggests that pepsinogen is converted rapidly upon acidification to the pepsinogen intermediate delta. In the absence of an inhibitor, the intermediate undergoes conformational change to bind the activation peptide portion of this same pepsinogen molecule in the active center to form an intramolecular enzyme-substrate complex (intermediate theta). This is followed by the intramolecular hydrolysis of the peptide bond between residues 44 and 45 of the pepsinogen molecule and the dissociation of the activation peptide from the pepsin. Intermediate delta apparently does not activate another pepsinogen molecule via an intermolecular process. Neither does intermediate delta hydrolyze globin substrate.

Amino Acids↗
PubMed1987

Clinical significance of pepsinogen A isozymogens, serum pepsinogen A and C levels, and serum gastrin levels.

Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (less than 25 micrograms/l), a low serum pepsinogen A/pepsinogen C ratio (less than 1.5), and a high serum gastrin level (greater than 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ratio less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes.

Adult↗
PubMed1988

Cell-specific hypomethylation of the pepsinogen gene in pepsinogen-producing cells.

The pepsinogen gene is hypomethylated in the stomach, in which it is expressed. For demonstration that this hypomethylation of the pepsinogen gene in the stomach reflects pepsinogen-producing cells, we analyzed fractions of dispersed mucosal cells with various contents of pepsinogen-producing cells prepared from guinea pig stomach by centrifugal elutriation. mRNA expression and the extent of hypomethylation of the pepsinogen gene in each fraction was closely correlated with the content of pepsinogen-producing cells. These results suggested hypomethylation of the pepsinogen gene in pepsinogen-producing cells and differential pepsinogen gene methylation in cell subpopulations in the stomach.

Animals↗
PubMedDate not supplied

Relations between serum pepsinogen levels, pepsinogen phenotypes, ABO blood groups, age and sex in blood donors.

Serum pepsinogen A (pepsinogen I) levels and urinary pepsinogen A phenotypes were studied in relation to ABO blood group, age and sex in 700 healthy blood donors. There was no relation between urinary pepsinogen A phenotypes and serum pepsinogen A levels. It is concluded that serum PGA levels and PGA phenotypes are independent factors in predisposition to gastroduodenal disorders. Serum pepsinogen A levels were higher in males than in females and rose with increasing age. The ABO blood groups were not related to pepsinogen A phenotypes. Blood group O individuals showed higher serum pepsinogen A levels compared with blood group A. Pepsinogen A phenotypes with intensity of fraction 5 were more frequent in males compared with females.

ABO Blood-Group System↗
PubMed1982

Monkey pepsinogens and pepsins. VI. One-step activation of Japanese monkey pepsinogen to pepsin.

When Japanese monkey pepsinogen was activated at pH 2.0 in the absence of pepstatin, the activation segment of the amino(N)-terminal 47 residues was released as a single intact polypeptide. This clearly shows that the pepsinogen was activated to pepsin directly. This direct activation was called a 'one-step' process. On the other hand, when pepsinogen was activated at pH 2.0 in the presence of pepstatin, an appreciable amount of pepsinogen was converted to an intermediate form between pepsinogen and pepsin, although a part of pepsinogen was activated directly to pepsin. The intermediate form was generated by releasing the N-terminal 25 residues of pepsinogen. This activation through the intermediate form is thought to be a 'two-step' or 'stepwise-activating' process involving a bimolecular reaction between pepstatin-bound pepsinogen and free pepsin.

Animals↗
PubMed1992

Enzymic activities of two-chain pepsinogen, two-chain pepsin, and the amino-terminal lobe of pepsinogen.

In order to study the relationships of aspartic proteases, we have modified pepsin, a single-chain eukaryotic enzyme, to a two-chain heterodimer, which resembles aspartic proteases from retrovirus, including human immunodeficiency virus. Two fragments of pepsinogen, residues 1P-172 and 173-326, were expressed separately in Escherichia coli. Mixtures of chains were refolded from urea solutions to generate an active two-chain pepsinogen, which was converted to two-chain pepsin in acid solutions. The intramolecular and bimolecular activation constants (k1 and k2) of two-chain pepsinogen are about 1.5-fold and one-sixth, respectively, of those for pepsinogen. Structural evidence suggests that the faster k1 of two-chain pepsinogen is due to decreased interaction of the propeptide with the pepsin moiety, implying that the rate-limiting step in the intramolecular activation of pepsinogen is the "conformational dissociation" of its propeptide. Two-chain pepsin has the same Km but only one-sixth of the kcat of pepsin. Both pepsinogen chains are capable of independent refolding. The refolding of the NH2-terminal chain, which contains the propeptide and the NH2-terminal lobe, generated a small amount of proteolytic activity which is likely derived from the homodimer of the NH2-terminal lobe. It has been postulated that mammalian aspartic proteases, which contain two structurally homologous lobes, are derived in evolution from a homodimer enzyme by gene duplication and fusion (Tang, J., James, M. N. G., Hsu, I.-N., Jenkins, J. A., and Blundell, T. L. (1978) Nature 271, 618-621). The observation of the homodimer activity of the NH2-terminal lobe of pepsinogen suggests that the interface of the lobes is conservative in evolution.

Base Sequence↗
PubMed1981

Purification and characterization of embryonic chicken pepsinogen, a unique pepsinogen with large molecular weight.

An embryo-specific pepsinogen was isolated from the proventriculi of 15-day-old chicken embryos and purified by means of fractionation with ammonium sulfate, filtration on Sephadex G-100, and chromatography on DEAE-Sepharose CL-6B and hydroxyapatite. The properties of this pepsinogen and pepsin derived from it were compared with those of an adult-specific chicken pepsinogen and its pepsin. Though the optimal pH and alkali-stability were similar in the two pepsinogens, molecular weight, sensitivity to pepstatin, and antigenicity were quite different. Among the properties of this embryo-specific pepsinogen, the large molecular weight (56,000 for pepsinogen and 53,000 for pepsin) is especially noteworthy, since the molecular weights of the known pepsinogens of mammals and birds fall into the range of 35,000-48,000.

Animals↗
PubMed1988

Analysis of the activation of pepsinogen in the presence of protein substrates and estimation of the intrinsic proteolytic activity of pepsinogen.

Monkey pepsinogen A, monkey progastricsin, and porcine pepsinogen A were activated in the presence of two different protein substrates, namely, reduced and carboxymethylated lysozyme and hemoglobin. In each case, an extensive delay in activation was observed. The intermolecular activation reaction required for the generation of pepsin or gastricsin was strongly inhibited and this inhibition was essentially responsible for the delay. However, the intramolecular reaction required for the generation of the intermediate forms of the proenzymes was scarcely affected. The delay was longer at pH 3.0 than at pH 2.0. Irrespective of the delay in activation of pepsinogen, the digestion of substrates proceeded rapidly, evidence of the significant proteolytic activity of pepsinogen itself. Kinetic experiments demonstrated that pepsinogen changed from an enzymatically inactive species to an active species before the release of the activation segment. The proteolytic activity of the active pepsinogen was highest at pH 2.0, at 37 degrees C and the activity under these conditions was comparable to that of pepsin.

Amino Acid Sequence↗
PubMed1980

Monkey pepsinogens and pepsins. IV. The amino acid sequence of the activation peptide segment of Japanese monkey pepsinogen.

The complete amino acid sequence of the activation peptide segment of the major component of Japanese monkey pepsinogens was determined. The pepsinogen was converted to pepsin by incubation at pH 2.0 and 14 degrees C for 17 min. The activation peptides were separated from the resulting pepsin and purified by chromatography on columns of sulfopropyl (SP)-Sephadex. One 25-residue peptide and two 22-residue peptides were isolated and their amino acid sequences were determined. The results showed that the former peptide was derived from the amino-terminal half (residues no. 1 to 25) and the latter peptides from the carboxyl-terminal half (residues no. 26 to 47) of the activation segment. The latter two peptides were identical except for a single amino acid replacement. The complete amino acid sequence of the whole activation peptide segment was thus deduced as follows: Ile1-Ile-Tyr-Lys-Val-Pro-Leu-Val-Arg-Lys10-Lys-Ser-Leu-Arg-Arg-Asn-Leu-Ser-Glu- His20-Gly-Leu-Leu-Lys-Asp-Phe-Leu-Lys-Lys-His30-Asn-Leu-Asn-Pro-Ala-Ser-Lys-Tyr -Phe-Pro40-LysGln-Ala-Glu-Ala-Pro-Thr-Leu47. The whole chain was composed of 47 residues, and cleaved into two polypeptides by the cleavage of Asp25-Phe26 bond during activation. Two amino acids were detected at residue-41, i.e., glutamine and lysine, indicating the presence of two closely related pepsinogens in the sample used. The total number of residues (47) of the whole activation peptide segment is 3 and 2 residues larger than those of porcine pepsinogen and bovine pepsinogen, respectively. The differences are 15 and 22 residues as compared with porcine pepsinogen and bovine pepsignogen, respectively.

Amino Acid Sequence↗
PubMed1985

Monkey pepsinogens and pepsins. VII. Analysis of the activation process and determination of the NH2-terminal 60-residue sequence of Japanese monkey progastricsin, and molecular evolution of pepsinogens.

Japanese monkey progastricsin was shown to be activated to gastricsin exclusively by a two-step process through an intermediate form. The occurrence of this process was substantiated by the isolation of the intermediate form and released peptides. By NH2-terminal sequence analyses of these protein and peptide species, the amino acid sequence of the 43-residue activation segment (propart) was determined to be as follows: (Formula: see text) The NH2-terminal 26-residue peptide was released first, resulting in generation of the intermediate form. The subsequent release of peptides, residues Nos. 27-40 and 27-43, generated two gastricsins as the final products. This two-step process of activation of Japanese monkey progastricsin is in striking contrast to the one-step activation process occurring exclusively for pepsinogen A of the same monkey species. The course of molecular evolution of pepsinogens including progastricsins was deduced from the amino acid sequences of their activation segments by constructing phylogenic trees. The trees divided pepsinogens into 3 clusters, i.e., pepsinogens A, progastricsins and prochymosin, showing that these three groups diverged from one another very early on in the course of the evolution of pepsinogens.

Amino Acid Sequence↗
PubMed1981

Induction of changes in the pepsinogen content and the pepsinogen isoenzyme pattern of the pyloric mucosa of the rat stomach by short-term administration of stomach carcinogens.

Changes in pepsinogen isoenzyme patterns were examined in the pyloric mucosae of the stomachs of noninbred male Wistar rats after short-term administration of gastric carcinogens. N-Methyl-N-nitro-N-nitrosoquanidine, N-ethyl-N1-nitro-N-nitrosoguanidine, and N-propyl-N-nitro-N-nitrosoguanidine, which induce stomach cancer in rats, decreased the content of pepsinogen isoenzyme 1 )Pg 1), which was separated by poly-acrylamide gel electrophoresis. They also decreased the pepsingoen content of the pyloric mucosa. 4-Nitroguinoline 1-oxide, which induces a low incidence of stomach cancer in rats, rarely decreased the Pg 1 content or the pepsinogen content of the pyloric mucosa, and the incidence of such decreases was not statistically significant. However, diethylnitrosamine and dimethylnitrosamine, which do not induce stomach cancer in rats, did not cause any decrease in pepsinogen content. Ethyl methanesulfonate, a direct-acting carcinogen used as a control, also did not decrease the pepsinogen content.

4-Nitroquinoline-1-oxide↗
PubMed1990

Pharmacology of pepsinogen secretion: influence of pentagastrin on pepsinogen secretion in man.

To investigate the effect of pentagastrin on serum and urinary pepsinogens and gastric pepsin, eight healthy male volunteers were studied twice during continuous intragastric perfusion with either NaCl 0.9% or 0.1 M HCl in random order. To the perfusate 3 mg/ml phenol red was added as inert recovery marker. Gastric content was aspirated in 15-minute samples, 4 basally and subsequently 6 during continuous i.v. infusion of pentagastrin 1.5 micrograms/kg/h. Furthermore, serum and urine samples were collected immediately before and after each test. Gastric pepsin output increased after pentagastrin. There were no differences in basal or stimulated pepsin output during saline or HCl perfusion despite marked differences in intra-gastric acidity and acid delivery to the duodenum. In addition, no significant changes in serum pepsinogen levels or urinary pepsinogen excretion were observed after pentagastrin infusion. It is concluded that pentagastrin stimulates gastric pepsin secretion directly, but does not stimulate the release of pepsinogens into the systemic circulation.

Adult↗
PubMed1988

Seminal pepsinogen C is not identical with, but is very similar to gastric pepsinogen C.

Human seminal pepsinogen C has been purified and compared with gastric pepsinogen C. The two zymogens cannot be distinguished by amino acid compositions and sequences of the first 28 N-terminal amino acid residues are identical. Apparent immunological identity is observed with polyclonal antisera. Monoclonal antibodies toward seminal pepsinogen C have been produced. One is able to recognize a non-carbohydrate antigenic determinant only present in seminal pepsinogen C.

Amino Acids↗