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What Is Pepsin?
Pepsin is an activated digestive enzyme found in gastric juice that cleaves proteins into smaller peptides. It is an endopeptidase that is released in the stomach lining by the gastric chief cells and is one of the crucial digestive enzymes found in humans and other animals.
The enzyme is an aspartic protease that uses a catalytic aspartate in its active site. The two other major endopeptidases found in the human digestive system are trypsin and chymotrypsin. While the endopeptidases cleave the peptide bonds of proteins, there are exopeptidases also found in the digestive system that cleave the terminal amino acids from the proteins.
The endopeptidases and exopeptidases work in conjunction to break down the protein into peptides and amino acids that are easily absorbed by the small intestine.
Pepsin is an activated form of the proenzyme pepsinogen. Pepsinogen is released in the stomach wall by the gastric chief cells; it gets mixed with the hydrochloric acid of the gastric juice to convert into pepsin.
Discovery
The enzyme was first discovered by Theodor Schwann, a German physiologist, in 1836. He coined the word pepsin, which in Greek means digestion. Later in 1929, the chemical structure and crystallisation of pepsin were reported by the American biochemist John Howard Northrop of the Rockefeller Institute. He was also awarded a Nobel Prize for the same.
Activation of Pepsinogen
The precursor of pepsin, pepsinogen, is a zymogen. It contains 44 additional amino acids than its activated form. Pepsinogen is released by the gastric chief cells in the stomach lining. At the same location, the parietal cells release hydrochloric acid, which activates the zymogen.
At the time of food ingestion, the hormone gastrin and vagus nerve set off the release of pepsinogen and HCl. The release of HCl creates an acidic environment, thus allowing pepsinogen to unfold and cleave itself in an autocatalytic manner, removing the additional 44 amino acids to create pepsin.
There are five groups of pepsinogen known based on their primary structure:
- Pepsinogen A
- Pepsinogen B
- Progastriscin
- Prochymosin
- Pepsinogen F
Activity of Pepsin
Acidic environments of pH 1.5 to 2.5 make the pepsin enzyme the most active. The concentration of pepsin in the human stomach is 0.5 – 1 mg/mL. Pepsin is inactivated at the pH of 6.5; however, it does not get irreversibly inactive till it reaches pH 8.0. In a solution of pH 8.0, pepsin can get reactivated by creating acidic conditions.
The stability of pepsin at high pH is directly related to the occurrence of acid reflux. Pepsin has a broad cleavage specificity. The cleavage probability is determined by the position of residues at the P1 and P1’ positions. The presence of leucine, methionine and phenylalanine at the P1 position and tyrosine, tryptophan and phenylalanine at the P1’ position creates a high cleavage possibility.
However, the presence of positively charged amino acids, such as lysine, histidine and arginine, at the P1 position brings down the cleavage probability.
Clinical Significance
At the time of laryngopharyngeal reflux, pepsin becomes one of the major causes of mucosal damage. Pepsin remains in the larynx (pH 6.8) after gastric reflux. The inactivated enzyme remains stable at this pH and can be reactivated by creating acidic conditions. When the laryngeal mucosa gets exposed to the activated form of pepsin, other protective proteins are inhibited, and the mucosal walls are damaged by the highly acidic pepsin enzyme.
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