Endopeptidases are enzymes that cleave peptide bonds within proteins. They have various biological activities, including digestion and cell signaling. Medical interest in endopeptidase activity includes prolyl endopeptidase inhibitors as possible antidepressants and neutral endopeptidase inhibitors for pain relief and control of high blood pressure. Endopeptidases are classified into several families based on their active site structure and conditions they prefer. Examples include serine proteases, cysteine proteases, aspartic proteases, and metalloendopeptidases.
An endopeptidase is a type of protease, an enzyme of a large group that degrades proteins. Enzymes are proteins that make reactions happen much faster. Proteins are made up of chains of amino acids, linked by peptide bonds. This bond connects the carboxyl terminus of one amino acid with the amino terminus of the next. Endopeptidases cleave the peptide bonds of amino acids within the protein, in contrast to exopeptidases, which cleave at the ends of the protein.
Endopeptidases are found in all classes of organisms and have a wide range of biological activities. They are involved in the digestion of proteins in food. This includes the enzymes pepsin, trypsin and chymotrypsin. Proteases are also involved in cell signaling by breaking down other proteins, such as antibodies or hormones. They can turn routes on or off.
Proteases are usually first produced as a larger molecule which is inactive. This protects the cell that synthesizes it from damage. Once the protease has been delivered to its target, such as the stomach, a piece of the molecule is removed. This activates the protease.
Because of their myriad roles in cellular function, there is much medical interest in endopeptidase activity. An example of this is prolyl endopeptidase, which specifically cleaves after the amino acid proline. It has been associated with psychological disorders, such as depression, mania and schizophrenia. There is clinical interest in prolyl endopeptidase inhibitors as possible antidepressants.
Another example is neutral endopeptidase, which goes by many other names. It is also known as neprilysin and common acute lymphoblastic leukemia (CALLA) antigen. This protease degrades small secreted peptides, including the peptide that has been implicated as a cause of Alzheimer’s disease and several important signaling peptides. Neutral endopeptidase is sometimes used as a cancer marker, but its role in cancer is unclear. Inhibitors were developed to aid in pain relief and control of high blood pressure.
Endopeptidases are placed into several families, depending on the structure of their active site and the conditions they prefer. There are serine proteases, which have the amino acid serine in their active site. Members of this family include the digestive proteases trypsin and chymotrypsin, along with prolyl endopeptidase. One inhibitor frequently used in biochemical research laboratories is the highly toxic compound phenylmethanesulfonylfluoride (PMSF). It is used during protein isolation and purification to inhibit the activity of serine protease, which can degrade the protein to be purified.
Cysteine proteases have a sulfur group in their active site and are common in fruit. These enzymes are found in meat tenderizers. Papain is an example of such an endopeptidase and is used to treat bee and wasp stings.
The active site of aspartic proteases generally contains two groups of aspartate. Metalloendopeptidases require a metal cofactor for activity. Neutral endopeptidases are part of this family and require zinc for activity.
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