Pepsinogen: Definition, Biological Aspects and Diseases Associated with Excess of This Substance

We are talking about a substance made by the cells of the stomach.

Pepsinogen is a potent and abundant protein digesting enzyme secreted by major gastric cells as a proenzyme and then converted by gastric acid in the gastric lumen to the active enzyme pepsin .

The role of pepsin and its precursor in protein digestion was first described in the 19th century. Pepsinogens consist of a single polypeptide chain with a molecular weight of approximately 42,000 Da.

Pepsinogens are synthesized and secreted primarily by the major gastric cells of the human stomach before being converted into the proteolytic enzyme.

Pepsin, which is crucial for digestive processes in the stomach. Pepsin is secreted from main cells as the inactivated proenzyme pepsinogen.

Pepsinogen secretion parallels gastric acid secretion. Once the pepsinogen reaches the lumen of the stomach, gastric acidity activates the proenzyme.

Pepsins are autocatalytic and can also catalyze increased activation of pepsin. Pepsinogens belong to the endopeptidase family of aspartic proteinases.

Aspartic proteinases are also called acid proteinases because they act between pH 1.5 and 5.0. The mucosal lining of the human gastric mucosa produces four types of pepsinogen: pepsinogen I (PGA or PGI), pepsinogen II (PGC or PGII), cathepsin E, and cathepsin D.

The timing of the first measurable pepsinogen appearance in the fetal stomach has been reported to vary considerably between species. In the human fetus, granules appear in peptic cells at weeks 32 to 36.

Cephalic vagal stimulation strongly stimulates pepsinogen secretion. Acetylcholine, cholecystokinin, gastrin, secretin, VIP, epidermal growth factor, and nitric oxide can stimulate pepsinogen.

Anticholinergics, histamine H receptor antagonists, and vagotomy decrease pepsinogen secretion. Elevated serum levels of type 1 pepsinogen have been associated with duodenal ulcer and gastrinoma, while atrophic gastritis (with or without pernicious anemia) has been associated with low levels of type 1 pepsinogen.

Biological aspects

The human pepsinogen gene contains nine exons. Evidence supports the existence of a multi-gene family for human pepsinogen on the chromosome.

Pepsinogen is synthesized in the main and mucosal cells of the neck of the fundic region of the gastric mucosa and is stored as secretory granules.

The secretion of pepsinogen synthesized from the transfected gene in AtT20 cells responds to cyclic AMP, indicating that pepsinogen is secreted through the regulated secretory pathway.

A small amount of pepsinogen is also found in the bloodstream and is secreted in the urine; the latter is sometimes known as uropepsinogen. The origin of these pepsinogens is apparently stomachic, since they are absent in gastrectomy patients.

No physiological role has been demonstrated for pepsinogen in plasma and urine. The stomach secretes stored pepsinogen in response to hormonal and neural stimuli.

A mass screening program in Japan, using the combination of serum pepsinogen and progastricsin levels and indirect X-ray examination, has dramatically increased early detection of stomach cancer since 1993.

Zymogens and enzymes very similar to pepsinogen and pepsin are not limited to the stomachs of vertebrates. For example, fungi secrete pepsin-like enzymes apparently to digest proteins in the media.

Among these enzymes, rhizopuspepsin and endothiapepsin are well studied. Although zismogens of the native fungal aspartic protease have not been observed, rhizopuspepsinogen has been cloned and recombinant rhizopuspepsinogen is spontaneously activated in acid solutions.

The absence of aspartic protease zymogens in fungal extracts suggests that fungal zymogens are activated in secretory granules.

Diseases caused by excess pepsinogen

The massive secretion of acid and pepsinogen in Zollinger-Ellison syndrome leads to generalized ulceration of the upper gastrointestinal tract. In this disease, ulcers may appear in the esophagus, stomach, and duodenum.

In the duodenum they occur in the same places where they are seen in simple duodenal ulcers, in which the first part of the duodenum is the typical site.

However, they can also occur at more distal sites in the duodenum, due to the very low pH and high pepsin content of the chyme exiting the stomach.