Pepsin works its best in strong hydrochloric acid. But the similarity with the other enzymes pictured here refers to a second type of acid.
The active site of the acid proteases rely on two acidic aspartate amino acids, which activate a water molecule and use it to cleave protein chains. These aspartates are pictured on the next page. The acid proteases have evolved to fill several functional roles in different organisms. Pepsin, shown at upper left PDB entry 5pep , is optimized for digestion of food in the acidic environment of the stomach. It is very promiscuous, cleaving proteins in many different places.
Chymosin, shown at upper right PDB entry 4cms , is made by young calves to break down milk proteins. A purified form of chymosin, taken from calf stomach, has been used for centuries to curdle milk in the production of cheese.
Cathepsin D, shown at lower left PDB entry 1lyb , digests proteins inside lysozomes, the tiny stomachs inside cells. Other cellular acid proteases, such as renin not shown, PDB entry 1hrn , are designed to make very specific cuts in one particular protein, aiding in the maturation of a hormone or structural protein. Endothiapepsin, shown at lower right PDB entry 4ape , is made by a fungus and excreted into the surrounding environment, breaking up the surrounding proteins and allowing the fungus to feed on the pieces.
Image JSmol Pepsin and Pepstatin. References 1pso: Fujinaga, M. Protein Sci. USA 3psg: Hartsuck, J. Proteins 4cms: Newman, M. Structure and refinement at 2. Its primary structure is composed of 44 amino acids. Compared with pepsin, pepsinogen is stable in neutral and weak alkaline environment, but when exposed to hydrochloric acid in gastric juice, these 44 amino acids are removed in an autocatalytic manner and activated into pepsin.
Parietal cells of the gastric wall release hydrochloric acid HCl , pepsinogen can be activated by hydrochloric acid. Gastrin and vagus nerves trigger the release of pepsinogen and hydrochloric acid from the gastric wall when eating. Hydrochloric acid produces acidic environment, which makes pepsinogen unfold and cleave in an autocatalytic manner, thus producing pepsin.
Pepsin cuts 44 amino acids in pepsinogen into more pepsin. Pepsin is a chain protein monomer composed of two similar folding domains separated by a deep cleft. The catalytic site of pepsin is formed at the junction of the domain, each domain contains two aspartic acid residues, Asp32 and Asp Under the catalysis of pepsin, the water molecule helps the active carboxyl group to bear positive and negative charges with aspartic acid and aspartic acid 32, respectively, which breaks the peptide bond in the protein.
The activity of pepsin was the highest in pH2. Therefore, in the solution below pH8. The stability of pepsin at high pH value is of great significance to the diseases caused by pharynx and larynx reflux. Pepsin is one of the main causes of mucosal injury in pharynx and larynx reflux. Pepsin still stays in the pharynx and larynx after pharyngeal reflux. Although the enzyme is in a neutral environment, it can be reactivated in the subsequent acid reflux event.
After pepsin is activated, laryngeal mucosa is exposed to active pepsin, resulting in a decrease in the expression of protective proteins, thus increasing the susceptibility to laryngeal injury. In addition, pepsin may also cause mucosal damage in weak acid or non-acid reflux events. Pepsin can be internalized in the upper airway by receptor-mediated endocytosis. When cells ingest pepsin, pepsin is stored in intracellular vesicles with a low pH value, at which the enzyme activity of pepsin recovers.
The exposure of pepsin to neutral pH and the internalization of pepsin lead to changes in the expression of genes related to inflammation, which are the basis of signs and symptoms of reflux and tumor progression. Pepsin in airway specimens is considered to be a sensitive and specific marker for pharyngeal reflux.
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