Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. They are the largest and most diverse family of serine protease inhibitors which are involved in a number of fundamental biological processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and tumor suppression and are expressed in a cell-specific manner. Serpin E1 is a secreted protein which belongs to the Serpin family. Serpin E1 acts as 'bait' for tissue plasminogen activator, urokinase, and protein C. Its rapid interaction with TPA may function as a major control point in the regulation of fibrinolysis. Defects in SERPINE1 are characterized by abnormal bleeding due to Serpin E1 defect in the plasma. High concentrations of Serpin E1 have been associated with thrombophilia which is an autosomal dominant disorder in which affected individuals are prone to develop serious spontaneous thrombosis.
Serpin E2 is a secreted protein that belongs to the serpin family. Serpin E2 is a serine protease inhibitor with activity toward thrombin, trypsin, and urokinase. Serpin E2 expression is weak or absent in all normal pancreas and chronic pancreatitis tissue. In contrast, it was strongly over-expressed in the majority of pancreatic carcinoma as well as gastric and colorectal cancer samples. Serpin E2 promotes neurite extension by inhibiting thrombin. It also can bind heparin. It has been shown that Serpin E2 is a novel target of ERK signaling involved in human colorectal tumorigenesis. It plays an important role in controlling male fertility because its knockout male mice show a marked impairment in fertility from the onset of sexual maturity and its abnormal expression is found in the semen of men with seminal dysfunction.
Serpin F1 is a secreted glycoprotein that belongs to the noninhibitory serpin. It has an alpha/beta core serine-protease inhibitor domain, three major beta-sheets, and ten alpha-helices. As protease inhibitors, serpins have an array of functions including regulating blood clotting, the complement pathway, extracellular matrix remodeling, and cell motility. They are also involved in activities that extend beyond their ability to inhibit proteases. For instance, they may also regulate blood pressure, angiogenesis, or act as storage/transport proteins. Serpin F1 is a new promising approach for the treatment of osteosarcoma and has been described as a natural angiogenesis inhibitor with neurotrophic and immune-modulation properties. The human serpin superfamily consists of at least 35 members that target not only serine proteases, but also selected cysteine proteases and non-protease proteins. Levels of the natural ocular anti-angiogenic factor SentrinF1 (PEDF) is associated with proliferative retinopathy.
SerpinF2, also known as alpha-2 antiplasmin (alpha-2 AP), is a member of the Serpin superfamily. SerpinF2 is the principal physiological inhibitor of serine protease plasmin, and as well as, an efficient inhibitor of trypsin and chymotrypsin. This protease is produced mainly by liver and kidney, and also expressed in muscle, intestine, central nervous system, and placenta also express this protein at a moderate level. It is indicated that Serpin F2 is a key regulator of plasmin-mediated proteolysis in these tissues. Alpha-2 AP is an unusual serpin in that it contains extensive N- and C-terminal sequences flanking the serpin domain. The N-terminal sequence is crosslinked to fibrin by factor XIIIa, whereas the C-terminal region mediates the initial interaction with plasmin. SerpinF2 is one of the inhibitors of fibrinolysis, which acts as the primary inhibitor of plasmin(ogen). It is a specific plasmin inhibitor, and is important in modulating the effectiveness and persistence of fibrin with respect to its susceptibility to digestion and removal by plasmin. Alpha-2 AP plays the dominant role in inhibiting both plasma clot lysis and thrombus lysis, and accordingly, the congenital deficiency of Alpha-2 antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Thus, it may be a useful target for developing more effective treatment of thrombotic diseases.
As protease inhibitors, serpins have an array of functions including regulating blood clotting, the complement pathway, extracellular matrix remodeling, and cell motility. Serpin G1 is a serine protease inhibitor protein. It is the largest member among the serpin class of proteins. Remarkably, Serpin G1 has a 2-domain structure, unlike most family members. The C-terminal serpin domain is similar to other serpins, and this part of Serpin G1 provides the inhibitory activity. The N-terminal domain is not essential for Serpin G1 to inhibit proteinases and has no similarity to other proteins. The main function of Serpin G1 is the inhibition of the complement system to prevent spontaneous activation. Serpin G1 is an acute phase protein and circulates in blood at levels of around 0.25g/L, whose levels rise 2-fold during inflammation. Although named after its complement inhibitory activity, Serpin G1 also inhibits proteinases of the fibrinolytic, clotting, and kinin pathways. Most notably, Serpin G1 play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. It is also the most important physiological inhibitor of fXIIa, chymotrypsin and plasma kallikrein.
Plasma protease C1 inhibitor, also known as C1-inhibiting factor, C1-INH, C1 esterase inhibitor, SERPING1 and C1IN, is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). Owing to its ability to modulate the contact and complement systems and the convincing safety profile, plasma-derived C1 inhibitor is an attractive therapeutic protein to treat inflammatory diseases other than HAE. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass.
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