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In biochemistry, serine proteases or serine endopeptidases (newer name) are a class of peptidases (enzymes that cleave peptide bonds in proteins) that are characterised by the presence of a serine residue in the active site of the enzyme. Serine proteases are grouped into clans that share structural homology and then further subgrouped into families that share close sequence homology. The major clans found in humans include the chymotrypsin-like, the subtilisin-like, the alpha/beta hydrolase, and signal peptidase clans. Serine proteases participate in a wide range of functions in the body, including blood clotting, immunity, and inflammation, as well as contributing to digestive enzymes in both prokaryotes and eukaryotes.
Additional recommended knowledge
Digestive serine proteases
The three serine proteases of the chymotrypsin-like clan that have been studied in greatest detail are chymotrypsin, trypsin, and elastase. All three enzymes are synthesized by the pancreatic acinar cells, secreted in the small intestine and are responsible for catalyzing the hydrolysis of peptide bonds. All three of these enzymes are similar in structure, as shown through their X-ray structures. The differing aspect lies in the peptide bond which is being cleaved, which is called the scissile bond. The different enzymes, like most enzymes, are highly specific in the reactions they catalyze. Each of these digestive serine proteases targets different regions of a polypeptide chain, based upon the side chains of the amino acid residues surrounding the site of cleavage:
The combination of these three enzymes make an incredibly effective digestive team, and are primarily responsible for the digestion of proteins.
Subtilisin is a serine protease in prokaryotes. Subtilisin is evolutionary unrelated to the chymotrypsin-clan, but shares the same catalytic mechanism utilising a catalytic triad, to create a nucleophilic serine. This is the classic example used to illustrate convergent evolution, since the same mechanism evolved twice independently during evolution.
The main player in the catalytic mechanism in the chymotrypsin and subtillisin clan enzymes mentioned above is the catalytic triad. The triad is located in the active site of the enzyme, where catalysis occurs, and is preserved in all serine protease enzymes. The triad is a coordinated structure consisting of three essential amino acids: histidine (His 57), serine (Ser 195) (hence the name "serine protease") and aspartic acid (Asp 102). Located very near one another near the heart of the enzyme, these three key amino acids each play an essential role in the cleaving ability of the proteases.
In the event of catalysis, an ordered mechanism occurs in which several intermediates are generated. The catalysis of the peptide cleavage can be seen as a ping-pong catalysis, in which a substrate binds (in this case, the polypeptide being cleaved), a product is released (the N-terminus "half" of the peptide), another substrate binds (in this case, water), and another product is released (the C-terminus "half" of the peptide).
Each amino acid in the triad performs a specific task in this process:
*The serine has an -OH group that is able to act as a nucleophile, attacking the carbonyl carbon of the scissile peptide bond of the substrate.
The whole reaction can be summarized as follows:
Additional stabilizing effects
It was discovered that additional amino acids of the protease, Gly 193 and Ser 195, are involved in creating what is called an oxyanion hole. Both Gly 193 and Ser 195 can donate backbone hydrogens for hydrogen bonding. When the tetrahedral intermediate of step 1 and step 3 are generated, the negative oxygen ion, having accepted the electrons from the carbonyl double bond fits perfectly into the oxyanion hole. In effect, serine proteases preferentially bind the transition state and the overall structure is favored, lowering the activation energy of the reaction. This "preferential binding" is responsible for much of the catalytic efficiency of the enzyme.
There are certain inhibitors which resemble the tetrahedral intermediate, and thus fill up the active site, preventing the enzyme from working properly. Trypsin, a powerful digestive enzyme, is generated in the pancreas. Inhibitors prevent self-digestion of the pancreas itself.
Zymogens are the usually inactive precursors of an enzyme. If the digestive enzymes were active when synthesized, they would immediately start chewing up the synthesizing organs and tissues. Acute pancreatitis is such a condition, in which there is premature activation of the digestive enzymes in the pancreas, resulting in self-digestion (autolysis). It also complicates postmortem investigations, as the pancreas often digests itself before it can be assessed visually.
Zymogens are large, inactive structures, which have the ability to break apart or change into the smaller activated enzymes. The difference between zymogens and the activated enzymes lies in the fact that the active site for catalysis of the zymogens is distorted. As a result, the substrate polypeptide cannot bind effectively, and proteolysis does not occur. Only after activation, during which the conformation and structure of the zymogen change and the active site is opened, can proteolysis occur.
As can be seen, trypsinogen activation to trypsin is essential, because it activates its own reaction, as well as the reaction of both chymotrypsin and elastase. It is therefore essential that this activation doesn't occur prematurely. There are several protective measures taken by the organism to prevent self-digestion:
Serine proteases are inhibited by a diverse group of inhibitors, including synthetic chemical inhibitors for research or therapeutic purposes, and also natural proteinaceous inhibitors. One family of natural inhibitors called "serpins" (abbreviated from serine protease inhibitors) can form a covalent bond with the serine protease, inhibiting its function. The best-studied serpins are antithrombin and alpha 1-antitrypsin, studied for their role in coagulation/thrombosis and emphysema/A1AT respectively. Artificial irreversible small molecule inhibitors include AEBSF and PMSF.
Role in disease
Mutations may lead to decreased or increased activity of enzymes. This may have different consequences, depending on the normal function of the serine protease. For example, mutations in protein C, when leading to insufficient protein levels or activity, predispose to thrombosis.
Determination of serine protease levels may be useful in the context of particular diseases.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Serine_protease". A list of authors is available in Wikipedia.|