Some proteins rich in disulfide bonds, such as keratins, are resistant to denaturation by low pH, and hence difficult to digest. On the contrary, most of the globular proteins are almost completely hydrolyzed into constituent amino acids. Finally, the low pH of the gastric juice activates pepsinogen, a zymogen, to pepsin , the first enzyme involved in protein digestion.
There are different isoenzymes of pepsinogen, such as type I, synthesized by the cells of the body and fundus of the stomach, and type II that is produced in all the regions of the organ. All the isoenzymes are converted to the active enzyme.
The activation occurs via autocatalysis , at pH values below 5, by an intramolecular process consisting in the hydrolysis of a specific peptide bond and release of a small peptide from the N-terminal end of the proenzyme. This peptide remains bound to the enzyme and continues to act as an inhibitor until the pH drops below 2, or until it is further degraded by pepsin itself. So, once some pepsin is formed, this quickly activates other pepsinogen molecules.
Pepsin, an endopeptidase with an optimum pH of activity at 1. Many digestive enzymes are able to act on a wide range of substrates, and pepsin is no exception, catalyzing the cleavage of peptide bonds adjacent to amino acid residues such as leucine and phenylalanine, tyrosine and tryptophan aromatic amino acids. A mixture of peptides of large size and a few free amino acid are produced. It should be noted that the action of pepsin on collagen, a family of proteins that wrap around and hold together the muscle cells, facilitates the access of the pancreatic protease to meal proteins.
When the gastric content passes into the duodenum, its acidity stimulates S cells, localized in the duodenal mucosa and in the proximal part of the jejunum the next part of the small intestine , to produce and release the hormone secretin into the bloodstream. The hormone causes the secretion of an alkaline pancreatic juice, rich in bicarbonate ions but poor in enzymes, which passes into the duodenum through the pancreatic duct.
In the duodenum, it neutralizes the hydrochloric acid produced by the stomach, raising pH to around 7 neutral levels. Secretin also stimulates bile secretion and reduces gastrin release. The presence of amino acids in the duodenum stimulates, as mentioned above, endocrine cells in the duodenum and jejunum to produce and release cholecystokinin CKK into the bloodstream.
The hormone, among other functions, stimulates exocrine pancreas to secrete a juice rich in enzymes present as zymogens , that is:. Therefore, in the duodenum there is a neutral environment rich in enzymes able to continue, once activated , protein digestion. Moreover, as the proteases have different substrate specificity, each peptide produced by an enzyme can be substrate of another enzyme.
In pancreatic juice, amylase, lipase and nuclease are also present. The first and master step in their activation is the conversion of trypsinogen to trypsin by enteropeptidase also called enterokinase , an endopeptidase produced by cells of the duodenum after cholecystokinin stimulation. Enteropeptidase catalyses the cleavage of a specific peptide bond between a lysine residue and an isoleucine residue of the trypsinogen, with release of a hexapeptide.
This causes a conformational rearrangement of the protein that activates it, that is, trypsin is formed. The enzyme cleaves peptide bonds adjacent to lysine and arginine residues of protein to digest; moreover, it can activate chymotrypsinogen, proelastase and procarboxypeptidase A and B, but also other molecules of trypsinogen, like pepsin autocatalysis. Therefore, the ability of the duodenum to digest proteins increases as the pancreatic zymogens are activated, all triggered by a small amount of enteropeptidase.
Chymotrypsin acts on peptide bonds adjacent to phenylalanine, tryptophan, methionine, tyrosine and leucine residues. Proelastase is activated to elastase by the removal of a small peptide from the N-terminal end. Elastase, which is less specific than the other digestive hydrolases, catalyzes the cleavage of peptide bonds adjacent to amino acids such as glycine, alanine and serine.
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. Pepstatin is a low molecular weight compound, which has a strong inhibitory effect on acid protease.
Statine is a potential transition state analogue of acid protease catalysis. The Styl residue of pepstatin is considered to be related to the inhibition of pepsin. Pepstatin cannot covalently bind to pepsin, so the inhibitory effect of pepstatin on pepsin is reversible.
The hydrochloric acid in the stomach generally provides a pH of about 1. The acid in the stomach causes food proteins to unfold in a process called denaturation. Denaturation exposes the protein's molecular bonds so that pepsin can access them and break the proteins into smaller fragments, called peptides or polypeptides. The small intestine will continue to break down proteins by chopping the peptides into amino acids, which can readily be absorbed into the blood stream.
Pepsin digests proteins for several hours before the partially digested food mix is slowly transferred to the small intestine. Mucus in the stomach protects the lining of the stomach from the potential damage by hydrochloric acid and pepsin. Stomach ulcers are painful sores that can occur when the stomach lining is damaged. A bacteria called Helicobacter pylori is able to live in an acid environment and is thought to prevent the secretion of protective mucus, allowing pepsin to make holes in in the stomach walls.
Antacids work by raising the pH in the stomach and inactivating pepsin, as pepsin works only at low pH. Long-term use of antacids is not advisable because the inhibition of pepsin prevents adequate digestion of proteins.
0コメント