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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↗
PubMed1997

Fast detection of phosphorylation of human pepsinogen A, human pepsinogen C and swine pepsinogen using a combination of reversed-phase high-performance liquid chromatography and capillary zone electrophoresis for peptide mapping.

A combination of reversed-phase high-performance liquid chromatography (RP-HPLC) and capillary zone electrophoresis (CZE) was used for characterization of alpha-chymotryptic digests of human pepsinogen A, human pepsinogen C (both isolated from stomach mucosa of patients suffering from gastric cancer), swine pepsinogen and their dephosphorylated forms. Combining RP-HPLC and CZE for peptide mapping allowed to detect phosphorylations in molecules of the above mentioned gastric zymogens. We have found one phosphate group in the molecule of human pepsinogen A and two phosphate groups in the molecule of human pepsinogen C. The investigated sample was obtained from stomach mucosa of a patient suffering from gastric cancer. An increased number of phosphate groups in molecules of human pepsinogen seems to be associated with gastric cancer. The developed method represent a suitable tool for studying relationships between specific phosphorylations of proteins and cancerogenesis or potentially could serve for early diagnosis of gastric cancer.

Animals↗
PubMedDate not supplied

Serum pepsinogen I and pepsinogen II, and the ratio of pepsinogen I/pepsinogen II in peptic ulcer diseases: with special emphasis on the influence of the location of the ulcer crater.

To investigate the effect of the location of the ulcer crater on the serum levels of pepsinogen I (PGI), pepsinogen II (PGII) and the ratio of PGI/PGII, these parameters were determined in 161 healthy controls, 29 patients with gastric ulcer in the gastric body (GU-I), 65 with coexistent gastroduodenal ulcer (GU-II), 104 with gastric ulcer in the prepyloric region (GU-III), and 116 with duodenal ulcer (DU). Serum PGI levels were significantly higher (P < 0.01) in patients with GU-III (110.6 +/- 65.1 ng/mL), GU-II (100.0 +/- 46.6 ng/mL), and DU (92.2 +/- 35.2 ng/mL) than in the controls (77.4 +/- 31.4 ng/mL), while there were no significant differences between GU-I (82.5 +/- 36.3 ng/mL) and the controls. Patients with gastric ulcer in any region had significantly higher (P < 0.01) serum PGII levels (GU-I, 20.0 +/- 15.7 ng/mL; GU-II, 15.5 +/- 10.9 ng/mL; GU-III, 14.3 +/- 10.0 ng/mL) than the controls (10.6 +/- 6.0 ng/mL) and the patients with DU (10.0 +/- 5.5 ng/mL), whereas no significant differences existed between the latter two. The ratio of PGI/PGII in GU-I (5.86 +/- 3.90) was significantly lower (P < 0.01) than any other group (controls, 8.83 +/- 4.70; GU-II, 8.33 +/- 4.99; GU-III; 9.64 +/- 6.13; DU, 10.45 +/- 4.49), while patients with DU it was significantly higher (P < 0.01) than any other groups. These findings indicate that peptic ulcer is comprised of a heterogeneous group of diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Amphibian pepsinogens: purification and characterization of xenopus pepsinogens, and molecular cloning of Xenopus and bullfrog pepsinogens.

Two pepsinogens (Pg C and Pg A) were isolated from the stomach of adult Xenopus laevis by Q-Sepharose, Sephadex G-75, and Mono-Q column chromatographies. Autolytic conversion and activation of the purified Pgs into the pepsins were examined by acid treatment. We determined the amino acid sequences from the NH2-termini of Pg C, pepsin C, Pg A, and pepsin A. Based on the sequences, the cDNAs for Pg C and Pg A were cloned from adult stomach RNA, and the complete amino acid sequences of the Pg C and Pg A were predicted. In addition, a Pg A cDNA was cloned from the stomach of adult bullfrog Rana catesbeiana, and the primary structure of the Pg A was predicted. Molecular phylogenetic analysis showed that such anuran Pg C and Pg A belong to the Pg C group and the Pg A group in vertebrates, respectively. The molecular properties of Pg C and Pg A, such as size, sequences of the activation peptide and active site, profile of autolytic activation, and pH dependency of proteolytic activity of the activated forms, pepsin C and pepsin A, resemble those of Pgs found in other vertebrates. However, the hemoglobin-hydrolyzing activity of Xenopus pepsin C is completely inhibited in the presence of equimolar pepstatin, an inhibitor of aspartic proteinases. Thus, the Xenopus pepsin C differs significantly from other vertebrate pepsins C in its high susceptibility to pepstatin, and closely resembles A-type pepsins.

Amino Acid Sequence↗
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↗
PubMed1998

Advantages of serum pepsinogen A combined with gastrin or pepsinogen C as first-line analytes in the evaluation of suspected cobalamin deficiency: a study in patients previously not subjected to gastrointestinal surgery.

OBJECTIVES: Since there is a significant overlap in serum cobalamin concentrations between healthy and cobalamin-deficient individuals, we wanted to compare two different principles for use as supplementary tests to serum cobalamin concentration in patients with suspected cobalamin malabsorption and deficiency. DESIGN: Clinical study of consecutive patients. SETTING: The catchment area of Sahlgrenska University Hospital, Göteborg. SUBJECTS: A total of 112 patients with suspected cobalamin deficiency who had not previously undergone gastrointestinal surgery. INTERVENTIONS: Gastroduodenoscopy with biopsies taken from the gastric body and the duodenum, Schilling test, and measurement of serum methylmalonic acid (MMA), total homocysteine (Hcy), pepsinogens A and C, and gastrin. MAIN OUTCOME MEASURES: Number of patients with gastric body atrophy identified with the combination of MMA and Hcy, and pepsinogen A combined with pepsinogen C or gastrin. RESULTS: About 95% of the patients with severe gastric body atrophy had abnormal concentrations of serum pepsinogen A and/or gastrin or pepsinogen A/C ratio, whereas 65% had abnormal metabolite concentrations. Serum pepsinogen A combined with pepsinogen C identified 100%, and combined with gastrin 88%, of the patients with gastric body atrophy and elevated metabolite tests, and 67 and 75%, respectively, of those who had not yet developed elevated metabolite tests. CONCLUSIONS: Pepsinogen A, combined with pepsinogen C or gastrin, should be the first option in evaluating patients with suspected cobalamin deficiency who have not previously undergone gastrointestinal surgery.

Adult↗
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↗
PubMed1993

Diagnostic value of serum pepsinogen C in patients with raised serum concentrations of pepsinogen A.

Hypopepsinogenaemia A is often found in patients with gastric atrophy and gastric surgery. In these conditions serum pepsinogen C provides additional diagnostic information, especially when expressed as pepsinogen A:C ratio. Hyperpepsinogenaemia A has been shown in patients with duodenal ulcer disease, Zollinger-Ellison syndrome, hypertrophic gastropathy, chronic renal failure, and during omeprazole treatment. As patients with hyperpepsinogenaemia A often overlap in symptoms, endoscopical findings, and serum gastrin values, this study has evaluated whether measurement of serum pepsinogen C in subjects with hyperpepsinogenaemia A can help in differentiating clinical conditions. Serum concentrations of pepsinogen A and C were measured in serologically Helicobacter pylori negative blood transfusion donors (127) as reference population, and in patients with Zollinger-Ellison syndrome (24), duodenal ulcer (50), hypertrophic gastropathy (5), and chronic renal failure (50), and also in reflux oesophagitis patients on longterm omeprazole treatment (28). A low pepsinogen A:C ratio was found in all patients with hypertrophic gastropathy. A pepsinogen A:C ratio above the critical value of 4.7 was found in 14 (70.0%) of the Zollinger-Ellison patients, two (9.5%) of the duodenal ulcer patients, 11 (25.6%) of the patients with chronic renal failure, and in one (7.1%) of the patients receiving longterm omeprazole treatment. In fact, all but three hyperpepsinogenaemia A patients with a pepsinogen A:C ratio greater than 4.7 and normal renal function had the Zollinger-Ellison syndrome. In patients with hyperpepsinogenaemia A, a low pepsinogen A:C ratio may point to hypertrophic gastropathy, while a pepsinogen A:C ratio greater than 4.7 is suggestive for the Zollinger-Ellison syndrome.

Adult↗
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↗