Enzyme Regulation - Irreversible Covalent Modification

Irreversible Covalent ModificationsIrreversible changes in covalent structures are largely restricted to extracellular process. This process involves proteolytic cleavage. This is an important process in digestion, blood clotting, inflammation and fighting infection. It involves amplification cascades. Some digesting enzymes are so potentially damaging to cells that are synthesizing them, they are secreted in an inactive form – called zymogens. Once secreted these are converted to their active form with the activation process being irreversible.

Proteolytic CleavageThe zymogen form is a long polypeptide that must be hydrolysed at a specific location to produce active form of the enzyme. Proteolytic cleave occur at either termini. The sites of cleavage are known as activation sites. Cleavage at the activation sites may release a polypeptide known as a pro-sequence. This results in the activation of the enzyme. This cleavage is a regulatory mechanism of enzyme activity. The proteases are responsible for activation and therefore are regulatory proteases. They are specific for their substrates. One regulatory protease can activate many molecules of zymogen form of another enzyme. If the enzyme being activated is a regulatory enzyme protease responsible for the subsequence activation of another enzyme we get an amplification cascade.

Zymogens Zymogens are inactive precursor enzymes that are regulated by irreversible covalent modification. They work in digestion. Specifically they work in the stomach and pancreas.

Example of ZymogensPepsin Pepsin is an example of an enzyme made by pepsinogen, an inactive zymogen in the stomach. The digestive enzymes are produced in the inactive form to prevent them from digesting cells that produce them. In a zymogen, a peptide blocks the active site of the enzyme. Pepsinogen is activated when chiech cells release HCl which partially activates it. Another partially activated pepsinogen completes the activation by removing the peptide turning the pepsinogen into pepsin. TrypsinTrypsin is an example of an enzyme made by trypsinogen, an inactive zymogen in the pancreas. The pancreas secretes trypsin. Trypsinogen is the precursor form or the zymogen of the pancreatic enzyme trypsin. It is found in pancreatic juice. It is activated by enteropeptidase, which is found in intestinal mucosa, to form trypsin. Once activated, trypsin can activate more trypsinogen into trypsin. Trypsin cleaves the peptide bond at the carboxyl side of amino acids such as arginine and lysine. The activation process becomes autocatalytic.

Irreversible Covalent Modifications