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Highlights Enzyme Control II
1. Another type of covalent modification is that which activates zymogens. Zymogens are enzymes made in an inactive form and then activated by cleavage of one or more peptide bonds in them. Chymotrypsinogen is a zymogen that get activated by peptide cleavage to form chymotrypsin. It is made in the pancreas and normally activated in the digestive system. If it gets activated too soon, pancreatitis results from attack of the enzyme on the proteins in the pancreas.
2. Another important set of zymogens in the body are the proteins involved in the clotting of blood. Like the situation with pancreatitis, activation of these zympogens for the wrong reasons or at the wrong places can have disastrous consequences.
3. Blood clots arise from polymerization of the protein known as fibrin that is in the blood in the zymogen form known as fibrinogen.
4. Chymotrypsin is an enzyme that catalyzes a reaction in two phases - a slow phase and a fast phase. The fast phase occurs first. In this phase, the peptide bond is broken and the first peptide is released. As a result of this action, the other peptide is covalently linked to the enzyme transiently. The release of the second peptide from the enzyme is the slow phase and involves the action of water.
5. Chymotrypsin is a so-called serine protease, meaning that it uses the side chain of serine to catalyze proteolytic cleavage. The side chain of serine (hydroxyl group) is ionized in the reaction as a result of removal of its proton by a nearby histidine. This occurs when the substrate binds the active site, moving the histidine slightly closer to the serine.
6. Serine proteases all act by use of a set of three amino acids known as the catalytic triad. The catalytic triad involves the side chains of serine, histidine, and aspartic acid
7. In the catalytic mechanism of chymotrypsin, serine becomes covalently attached to one peptide when the other peptide is released. This is the fast step of the process. Release of the second peptide from serine requires the action of water. This is the slow step of the process.
8. Serine proteases act by creation of a reactive alkoxide ion. This is made by 1) binding of the proper substrate at the active site; 2) slight changes in shape that bring the catalytic triad (aspartic acid, histidine, and serine) closer together; 3) removal of a proton from the hydroxyl group of serine (creating the alkoxide ion).
9. The alkoxide ion is reactive and attacks the peptide bond in the active site, breaking it. One piece from the break is released and the other piece becomes transiently attached to the oxygen of the serine. This is the fast step of the process. Detachment of the attached peptide requires action of water in the active site. This is the slow step of the reaction. Two regions in serine proteases also play roles in the catalytic process. These are the S1 pocket (place where the substrate binds) and the oxyanion hole (place where reaction intermediate is stabilized).
10. Related proteases include cysteine proteases with activate a sulfur of a sulhydryl group during catalysis instead of activating an oxygen of a hydroxyl.
11. Coenzymes are non-amino acid molecules that help enzymes to catalyze reactions. They are often, but not always covalently attached to the enzymes. Many coenzymes are also vitamins. Examples of coenzymes include biotin (carboxylation reactions), flavins and nicotinamide enzymes (oxidation/reduction reactions), and coenzyme A (oxidation of fatty acids).
12. Reduction/oxidation reactions are known as redox reactions and always involve transfer of electrons. Cells use electron carriers to prevent free electrons from causing undesired reactions in cells.
13. Cellular electron carriers include NAD+/NADH and FAD/FADH2. When an electron carrier is reduced, it accepts electrons. The electrons frcome from from a molecule that gets oxidized. Thus, for every reduction of one molecule, there is oxidation of another. NAD+ is the oxidized form and NADH is the reduced form.