Serine proteases are a large family of proteoytic enzymes that include digestive enzymes, trypsin and chymotrpsin, components of the complement cascade and of the blood clotting cascade, and enzymes that control the degradation and turnover of macromolecules of the extracellular matrix. They are so named because of the presence of serine residue in the active catalytic site for protein cleavage. They have a wide range of substate specificites and diverse biological functions. However, a common catalytic mechanism is shared among several sub-families through a very similar tertiary structure supported by a highly conserved catalytic triad of serine, histidine and asparate. The active site structure of one serine protease, subtilisn, is among the most studied and best understood (US 2006/0088883).
Serine proteases such as elastase and cathepsin G degrade collagen, proteoglycans and elastin, a protein found in walls of arteries. Additionally, these proteases contribute to activation of matrix metalloproteinases, which cause further destruction of tissue. Serine proteases are associated with numerous other chronic inflammatory disease states. In inflamed joints, serine proteases lead to the destruction of collagen and proteoglycans of articular cartilage associated wtih arthritis. Serine proteases also degrade fibrinogen and fibronectin, proteins involved with homeostasis. Loss of homeostasis can lead to uncontrolled coagulation, fibrinolysis, and inflammation, resulting in sepsis. Serine proteases also aid the spread of HIV because these proteases cleave HIV proteins into active peptides, necessary for proper replication. Serine proteases have a highly reactive serine in their active site. Many proteases are secreted as inactive precursors that can be activated locally when needed. For example, plasminogen is an inactive protease precursor in the blood that is cleaved locally by other proteases called plasminogen activators to yield the active serine proteaseplasmin which helps break up blood clotes. Tissue type plasminogen activator (tPA) is often given to patients who have had thrombotic stroke to help dissolve the arterial.
Examples of Serine Proteases
Plasmin: is a potent serine protease that degrades firbrin into fibrin degradation products. Plasmin is formed from the proteolytic cleavage of the zymogen plasminogen. Plasmin formation is catalyzed by the actions of the two major mammalian activators: tissue-Plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Since t-PA is able to activate plasminogen to plasmin, it is capable of initiating the cascade of events needed to dissolve undesired blood clots. Urokinase type plasminogen activator is a multi domain protein with one domain being a trypin like serine rpotease. This protease domain converts plasminogen to plasmin by cleavage at an arginyl residue. The fibrin clot provides a surface to increase the efficiency of plasmin generation through formation of a ternary complex of fibrin, t-PA and plasminogen. As a result, fibrinolysis almost exclusively occurs on the clot surface and not in the circulation.
PAs are controlled by specific inhibitors such as PA inhibitor type-1 (PAI-1) which inactivates both urokinase-type PA (uPA) and tissue-type PA (tPA). Reduced levels of PAI-1 may result in creased fibrinolysis and an associated bleeding diathesis.
Elastase: also known as human leukocyte elastase (HLE) and human neutrophil elastase (HNE) is a serine protease released from the azurophilic granules of the neutrophile as part of the normal inflammatory response. NE is capable of degrading key structural elements of connective tissue, such as elastin, collagen, and proteoglycan. Under normal hoemeostatic conditions, the protease inhibitor alpha1-antitrypsin serves as an important regulator of proteolysis by HLE, thereby preventing damage of the lung alveolar matrix.
–Neutrophil elastase (NE): is a major proteinase in primary granules in neutrophils that participates in microbicidal activity. NE (Leukocyte elastase, EC 3.4.21.37), a serine endopeptidase, is characterized by serine in the active tripeptide catalytic site: Asp, His, Ser. NE is the most abundant of foru serine proteases present in neutrophils, which also include proteinase 3, cathepsin G,a nd neutrophil serine protease.
NE is a 29.5 kD protein stored in mature form in the azurophilic granules of neutrophils and is present at high concentraitons per azurophilic granule.
Although NE proteinase activity is critical for normal innate immune funciton, rellease of NE into the airway mileiu contributes to lung disease progression. (Shinbashi, “Neutrophil elastase and chronic lung disease” Biomolecules, 2021).
Complement protein B: is a single polypeptide chain serum glycoprotein that carries the catalytic center of the alternative pathway C3-convertase. It is a novel type of serine protease characterized by an unusual structure in the NH2-terminal region of its catalytic fragment Bb, when compared to other serine proteases. Assembly of the biomolecular,C3bBb, C3-convertase proceeds in two well defined steps, First, B binds stoichiometrically to C3b in a reaction requiring Mg2+ or Ni2+ ions. Second, complement protein D catalyzes the cleavage of a single arginyllysyl peptide bond of B resulting in the release of fragment Ba and the formation of the C3bBb protease. For a discussion of the alternative pathway click here.