| Serine Protease |
Shopping Serine |
Information AboutSerine Protease |
| CATEGORIES ABOUT SERINE PROTEASE | |
| ec 3.4.21 | |
|
DIGESTIVE SERINE PROTEASES Members 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 Bond s. All three of these enzymes are similar in structure, as shown through their X-ray Structure s. The differing aspect lies in the Scissile site. The different Enzymes , like most enzymes, are highly specific in the reactions they catalyze. Each of these digestive serine proteases targets different regions of the Polypeptide chain, based upon the amino acid residues and side chains surrounding the site of cleavage:
A combination of these three make an incredibly effective digestive team, and are primarily responsible for the digestion of Proteins . Catalytic mechanism The main player in the catalytic mechanism in the three digestive serine proteases mentioned above is the '' (His 57), Serine (Ser 195) (hence the name "serine protease") and Aspartic Acid (Asp 102). Located 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 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'' have nitrogen-hydrogen bonds. 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. Zymogens There are certain Inhibitor s which resemble the Tetrahedral Intermediate , and thus fill up the specificity pocket, preventing the enzyme from working properly. Trypsin is generated in the pancrease. As stated above, these are powerful digestive enzymes. In order to prevent them from digesting the pancreas itself, inhibitors often come into play to prevent the organism from self-digestion. '' Zymogen s'' is a term referring to the precursors of an enzyme, usually inactive. So far, we have been discussing digestive enzymes. The reason behind a zymogen should be evident - if the digestive enzymes were active when synthesized, they would immediately start chewing up the organs and tissue that synthesized them. 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 Investigation s, 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 up, can Proteolysis occur. The zymogen for trypsin is trypsino''gen''. When trypsinogen enters the Small Intestine from the pancrease, secretions from the Duodenal Mucosa cleaves the lysine 15 - isoleucine 16 peptide bond of the zymogen. As a result, the zymogen trypsinogen breaks down into trypsin. Recall that trypsin is also responsible for cleaving Lysine peptide bonds, and thus, once a small amount of trypsin is generated, it participates in cleavage of its own zymogen, generating even more trypsin. The process of trypsin activation can thus be called Autocatalytic . ''Chymotrypsinogen'' is the zymogen of ''chymotrypsin''. After the Arg 15 - Ile 16 bond in the chymotrypsinogen zymogen is cleaved by trypsin, the newly generated structure called a pi-chymotrypsin undergoes Autolysis (self digestion), yielding active chymotrypsin. ''Proelastase'' is the zymogen of ''elastase'', and it is activated by cleavage through trypsin. 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:
INHIBITION Serine proteases are inhibited by Serine Protease Inhibitor s ("serpins"), a diverse group of Enzyme s that 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. 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 . DIAGNOSTIC USE Determination of serine protease levels may be useful in the context of particular diseases.
FULL LIST Numbering follows the EC Number s in the ExPasy enzyme list, category 3.4.21 (missing numbers were transferred or deleted):
EXTERNAL LINK
|
|
|