Endopeptidases are enzymes that play an important role in breaking down proteins within biological systems. These enzymes act like molecular scissors, cutting internal bonds of long protein chains. Their widespread activity supports many biological processes.
Understanding Endopeptidases
Endopeptidases are proteases, enzymes that break down proteins and peptides. Unlike exopeptidases, which cleave amino acids from the ends of protein chains, endopeptidases hydrolyze peptide bonds within the molecule. This breaks down large proteins into smaller peptide fragments, not individual amino acids.
Over 500 endopeptidases are known, categorized into four main classes based on their catalytic mechanism: serine, cysteine, aspartic, and metallopeptidases. Each class uses a different residue or metal ion to facilitate peptide bond hydrolysis. This selective cleavage is important for regulating protein function, removing damaged proteins, and recycling amino acids within cells.
Diverse Biological Functions
Endopeptidases are involved in many biological processes, from digestion to immune responses. In the digestive system, enzymes like pepsin, trypsin, and chymotrypsin break down dietary proteins into smaller peptides. Pepsin, found in the stomach, functions best at a low pH, around 2, and initiates protein digestion by cleaving bonds before specific amino acids like leucine or phenylalanine.
Further digestion occurs in the small intestine, where trypsin and chymotrypsin, secreted by the pancreas, continue the breakdown of proteins. Trypsin specifically cleaves peptide bonds after positively charged amino acids like arginine or lysine, while chymotrypsin targets bonds after aromatic amino acids such as phenylalanine, tryptophan, or tyrosine. These enzymes operate optimally at a pH of about 8.
Beyond digestion, endopeptidases participate in hormone processing. Prohormone convertases (PCs), such as PC1/3 and PC2, process inactive prohormones into their active forms. For instance, PC1/3 and PC2 convert proinsulin into active insulin and C-peptide in pancreatic beta cells. They cleave precursors at specific basic amino acid pairs, like lysine-arginine or arginine-arginine sites.
Another example is angiotensin-converting enzyme (ACE), a metallopeptidase that plays a role in blood pressure regulation. ACE converts angiotensin I, an inactive decapeptide, into angiotensin II, a potent vasoconstrictor that causes blood vessels to narrow and increases blood pressure. This enzyme also degrades bradykinin, a vasodilator that helps relax blood vessels.
Endopeptidases also contribute to immune responses and inflammation. They can cleave proteins involved in immune cell signaling, such as antibodies and cytokines. Some proteases activate protease-activated receptors (PARs) on immune cells, modulating immune cell behavior and responses to infections and inflammation.
Endopeptidases and Human Health
The balanced activity of endopeptidases is important for maintaining overall health; their dysregulation can contribute to various diseases. For example, imbalances in digestive endopeptidases can lead to malabsorption and digestive disorders, as proteins may not be broken down efficiently, affecting nutrient absorption.
Dysfunction of endopeptidases is also linked to conditions like hypertension and inflammation. Angiotensin-converting enzyme (ACE) inhibitors, a class of medications, are designed to block the activity of ACE, thereby preventing the formation of angiotensin II and reducing blood pressure. These inhibitors are widely prescribed for high blood pressure, heart failure, and diabetic kidney disease.
Alterations in endopeptidase activity have also been associated with autoimmune diseases and cancer. Researchers are investigating endopeptidases as potential targets for new therapies, including drugs that inhibit their activity to prevent disease progression. For instance, dual inhibitors targeting both ACE and neutral endopeptidase are being explored for cardiovascular disorders, aiming to promote vasodilation and fluid balance.