The pepsinogen is the zymogen of pepsin, a major hydrolytic enzymes responsible for carrying out the digestion of proteins in the mammalian stomach. Zymogens or proenzymes are inactive enzyme precursors, that is, they are incapable of catalyzing the reactions carried out by their active forms.
Its activation depends on changes in the three-dimensional structure of the protein that give rise to the formation of a functional active site. These changes, in most cases, coincide with the proteolytic breakdown of a segment of the protein.
Three-dimensional structure of pepsin, the catalytically active form of pepsinogen. By Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, from Wikimedia Commons
Therefore, pepsinogen must undergo structural changes to acquire the required peptidase activity and favor the digestion of proteins in the stomach, after ingestion of food.
Structure
Pepsinogen is a 371 amino acid protein belonging to the great family of aspartic proteinases, characterized by having aspartic acid residues in its active center.
Its quaternary structure was determined for the first time for the protein expressed in pigs by the X-ray crystallography technique. The result was similar to that exhibited by the mature or active form of the protein, pepsin.
Thus, the only difference found is the presence in the pepsinogen of a peptide of 44 amino acids that folds over the cleft of the active site. In this position, it hinders the interaction of this protease with the proteins to be degraded.
This peptide, which will be cleaved to give rise to the active enzyme, is located at the amino terminal end of the protein.
Since it functions only as a plug, the inability of pepsinogen to degrade proteins is not due to structural deformations of the active center. On the contrary, it remains with the same conformation in both forms of the enzyme.
In this sense, it is worth noting that the crystal structure of pepsinogen constitutes an approximate model of the structure of other zymogens belonging to the large family of aspartic proteinases.
Features
At the beginning of life, pepsin (active form of pepsinogen) is important for the digestion of milk. Subsequently, its function is to break down dietary proteins into their constituents (amino acids) in order to facilitate their easy absorption.
Synthesis and secretion
Pepsinogen is synthesized by the main cells and fundic cells of the gastric mucosa. Subsequently, it is stored in secretory vesicles that remain in the cytoplasm of these cells until such time as their release is required.
Therefore, the secretion of this zymogen is a process that is regulated. Its release from the vesicles, resident in the cytosol through exocytosis, requires hormonal and neural stimuli. Increased levels of the gastric enzymes secretin and gastrin, as well as acetylcholine, cholecystokinin, epidermal growth factor, and nitric oxide stimulate their synthesis and secretion.
Additionally, experiments carried out with AtT20 cells, a cell line commonly used in the study of secretion pathways in mammals, have shown that an increase in cyclic AMP is also capable of inducing said secretion.
In addition to its normal stomach secretion, a relatively low amount of pepsinogen has been detected in both blood and urine, which is why it has been called uropepsinogen.
The origin of uropepsinogen, as well as the role it can play in both locations, remains undetermined. However, its absence in patients whose stomach has been completely removed seems to indicate that its origin is also stomachic.
Types
Two main types of pepsinogen have been described so far: pepsinogen I and pepsinogen II. Both types do not show differences in their catalytic activity and are also activated by hydrochloric acid-dependent proteolytic hydrolysis.
Pepsinogen I is synthesized and secreted both by the main cells and by the fundic cells of the gastric mucosa. Therefore, its secretion decreases in patients with chronic atrophic gastritis, a stomach disease characterized by the total disappearance of the gastric glands.
Unlike the latter, pepsinogen II (PGII) is synthesized by practically all the cells that are part of the gastric mucosa, but more prominently by those of the antral mucosa and those that make up the Brünner glands present in the duodenum..
In patients with chronic atrophic gastritis, this type of pepsinogen compensates for the decrease in pepsinogen I secretion.
The existence of these two types of pepsinogen, which are only differentiated by being secreted by different cells, could seem redundant. However, it may be an evolutionary adaptation to ensure pepsin synthesis whenever necessary.
Activation
Pepsinogen acquires catalytic activity when it is transformed into pepsin, the product of the elimination of the 44 amino acid peptide present in the active site cavity.
Its optimal functioning depends on low pH values in the range of 1.5 to 2. Under physiological conditions, these values are maintained by the secretion of hydrochloric acid in the intracellular channels.
Acid digestion at the stomach level does not take place in all animals, an example of which is insects, which lack pepsinogen. However, vertebrates that have a stomach do have peptic activity.
Pepsinogen, which is stored in the secretory vesicles of the main cells, is released into the gastric duct when necessary. Once it reaches the lumen of the stomach, it is converted to pepsin from the acidic environment and is activated by more pepsinogen molecules.
By action of the intrinsic nerve fibers and the extrinsic vagal stimulation, the production of pepsinogen is stimulated, as well as that of HCl, gastrin and histamine. On the other hand, histamine and gastrin stimulate parietal cells to secrete HCl.
Pepsin, like all endopeptidase, acts on specific bonds between amino acids in proteins to generate smaller peptides.
In other words; hydrolyzes the internal peptide bonds of a protein. Its action is most effective on the peptide bonds close to aromatic amino acids (phenylalanine, tyrosine). Unlike its parent zymogen, adaptive changes in pepsin at pH values greater than 6 produce irreversible decreases in catalytic activity.
References
- Bryksa BC, Tanaka T, Yada RY. N-terminal modification increases the neutral-pH stability of pepsin. Biochemistry. 2003; 42: 13331-13338.
- Foltmann B, Pedreson VB. Comparison of the primary structures of acidic proteases and their zymogens. Adv Exp Med Biol. 1977; 95: 3-22.
- Guyton A, Hall J. (2006). Textbook of Medical Physiology. (11th ed.). USA: Elsevier Saunders.
- Kasper D, Fauci A, Longo D, Braunwald E, Hauser S, Jameson J. (2005). Harrison, Principles of Internal Medicine. (16th ed.). Mexico: McGrawHill.
- Kitahara F, Shimazaki R, Sato T, Kojima Y, Morozumi A, Fujino MA. Severe atrophic gastritis with Helicobacter pylori infection and gastric cancer. Gastric Cancer. 1998; 1: 118-124.
- Lin Y, Fused M, Lin X, Hartsuck JA, Tang J. pH dependence of kinetic parameters of pepsin, Rhizopuspepsin and their active-site hydrogen bonds mutants. J Biol chem. 1992; 267: 18413-18418.
- Mangeat P. Acid secretion and membrane reorganization in single gastric parietal cell in primary culture. Biology cell. 1990; 69: 223-257.
- Prozialeck J, Wershil BK. (2017). Development of gastric secretory function. Fetal and Neonatal Physiology (Fifth Edition). Volume 1, pp. 881-888.
- Schubert ML. Gastric secretion. Current Opin Gastroent 2005; 21: 633-757.
- Sielecki AR, Fedorov AA, Boodhoo A, Andreeva NS, James MNG. The molecular and crystal structures of monoclinic porcine pepsin refined at 1.8 Å resolution. J Mol Biol. 1990; 214: 143-170.
- Webb PM, Hengels KJ, Moller H, Newell DG, Palli D, Elder JB. The epidemiology of low serum pepsinogen A levels and an international association with gastric cancer rates. Gastroenterology. 1994; 107: 1335-1344.
- Wolfe MM, Soll AH. The physiology of gastric acid secretion. N Engl J Med 1998; 319: 1707.