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Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin.

ABSTRACT: The gastric aspartic proteinases (pepsin A, pepsin B, gastricsin and chymosin) are synthesized in the gastric mucosa as inactive precursors, known as zymogens. The gastric zymogens each contain a prosegment (i.e. additional residues at the N-terminus of the active enzyme) that serves to stabilize the inactive form and prevent entry of the substrate to the active site. Upon ingestion of food, each of the zymogens is released into the gastric lumen and undergoes conversion into active enzyme in the acidic gastric juice. This activation reaction is initiated by the disruption of electrostatic interactions between the prosegment and the active enzyme moiety at acidic pH values. The conversion of the zymogen into its active form is a complex process, involving a series of conformational changes and bond cleavage steps that lead to the unveiling of the active site and ultimately the removal and dissociation of the prosegment from the active centre of the enzyme. During this activation reaction, both the prosegment and the active enzyme undergo changes in conformation, and the proteolytic cleavage of the prosegment can occur in one or more steps by either an intra- or inter-molecular reaction. This variability in the mechanism of proteolysis appears to be attributable in part to the structure of the prosegment. Because of the differences in the activation mechanisms among the four types of gastric zymogens and between species of the same zymogen type, no single model of activation can be proposed. The mechanism of activation of the gastric aspartic proteinases and the contribution of the prosegment to this mechanism are discussed, along with future directions for research.

SUBMITTER: Richter C

PROVIDER: S-EPMC1219805 | biostudies-other | 1998 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundPepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the PGC (Progastricsin) gene, is regulated by microRNAs (miRNA), but how PGII levels vary with Helicobacter pylori (H. pylori) infection and miRNAs genotype remains unclear.MethodsSerum levels of PGI and PGII were determined in 80 patients with gastric cancer and persons at risk for gastric cancer (74 first-degree relatives of patients, 62 patients with autoimmune chronic atrophic gastritis, and 2 patients with dysplasia), with and without H. pylori infection. As control from the general population, 52 blood donors were added to the analyses. Associations between PGII levels and genetic variants in PGC and miRNA genes in these groups were explored based on H. pylori seropositivity and the risk for gastric cancer. The two-dimensional difference in gel electrophoresis (2D-DIGE) and the NanoString analysis of messenger RNA (mRNAs) from gastric cancer tissue were used to determine the pathways associated with increased PGII levels.ResultsPGII levels were significantly higher in patients with gastric cancer, and in those with H. pylori infection, than in other patients or controls. A PGI/PGII ratio ? 3 was found better than PGI < 25 ng/mL to identify patients with gastric cancer (15.0% vs. 8.8%). For two genetic variants, namely rs8111742 in miR-Let-7e and rs121224 in miR-365b, there were significant differences in PGII levels between genotype groups among patients with gastric cancer (p = 0.02 and p = 0.01, respectively), but not among other study subjects. Moreover, a strict relation between rs9471643 C-allele with H. pylori infection and gastric cancer was underlined. Fold change in gene expression of mRNA isolated from gastric cancer tissue correlated well with polymorphism, H. pylori infection, increased PGII level, and pathway for bacteria cell entry into the host.ConclusionsSerum PGII levels depend in part on an interaction between H. pylori and host miRNA genotypes, which may interfere with the cut-off of PGI/PGII ratio used to identify persons at risk of gastric cancer. Results reported new findings regarding the relation among H. pylori, PGII-related host polymorphism, and genes involved in this interaction in the gastric cancer setting.

Project description:Carnivorous plants are known to secrete acid proteinases to digest prey, mainly insects, for nitrogen uptake. In the present study, we have purified, for the first time, to homogeneity two acid proteinases (nepenthesins I and II) from the pitcher fluid of Nepenthes distillatoria (a pitcher-plant known locally as badura) and investigated their enzymic and structural characteristics. Both enzymes were optimally active at pH approx. 2.6 towards acid-denatured haemoglobin; the specificity of nepenthesin I towards oxidized insulin B chain appears to be similar, but slightly wider than those of other APs (aspartic proteinases). Among the enzymic properties, however, the most notable is their unusual stability: both enzymes were remarkably stable at or below 50 degrees C, especially nepenthesin I was extremely stable over a wide range of pH from 3 to 10 for over 30 days. This suggests an evolutionary adaptation of the enzymes to their specific habitat. We have also cloned the cDNAs and deduced the complete amino acid sequences of the precursors of nepenthesins I and II (437 and 438 residues respectively) from the pitcher tissue of N. gracilis. Although the corresponding mature enzymes (each 359 residues) are homologous with ordinary pepsin-type APs, both enzymes had a high content of cysteine residues (12 residues/molecule), which are assumed to form six unique disulphide bonds as suggested by computer modelling and are supposed to contribute towards the remarkable stability of nepenthesins. Moreover, the amino acid sequence identity of nepenthesins with ordinary APs, including plant vacuolar APs, is remarkably low (approx. 20%), and phylogenetic comparison shows that nepenthesins are distantly related to them to form a novel subfamily of APs with a high content of cysteine residues and a characteristic insertion, named 'the nepenthesin-type AP-specific insertion', that includes a large number of novel, orthologous plant APs emerging in the gene/protein databases.

Project description:BACKGROUND:Although the high-throughput sequencing technique is useful for evaluating gastric microbiome, it is difficult to use clinically. We aimed to develop a predictive model for gastric microbiome based on serologic testing. METHODS:This study was designed to analyze sequencing data obtained from the Hanyang University Gastric Microbiome Cohort, which was established initially to investigate gastric microbial composition according to the intragastric environment. We evaluated the relationship between the relative abundance of potential gastric cancer-associated bacteria (nitrosating/nitrate-reducing bacteria or type IV secretion system [T4SS] protein gene-contributing bacteria) and serologic markers (IgG anti-Helicobacter pylori [HP] antibody or pepsinogen [PG] levels). RESULTS:We included 57 and 26 participants without and with HP infection, respectively. The relative abundance of nitrosating/nitrate-reducing bacteria was 4.9% and 3.6% in the HP-negative and HP-positive groups, respectively, while that of T4SS protein gene-contributing bacteria was 20.5% and 6.5% in the HP-negative and HP-positive groups, respectively. The relative abundance of both nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria increased exponentially as PG levels decreased. Advanced age (only for nitrosating/nitrate-reducing bacteria), a negative result of IgG anti-HP antibody, low PG levels, and high Charlson comorbidity index were associated with a high relative abundance of nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria. The adjusted coefficient of determination (R2) was 53.7% and 70.0% in the model for nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria, respectively. CONCLUSION:Not only the negative results of IgG anti-HP antibody but also low PG levels were associated with a high abundance of nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria.

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Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin.

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