C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. [5] Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system. [6] [7] C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inhibitor also inhibits proteases of the fibrinolytic, clotting, and kinin pathways. Note that C1-inhibitor is the most important physiological inhibitor of plasma kallikrein, FXIa, and FXIIa.
C1-inhibitor is the largest member among the serpin superfamily of proteins. It can be noted that, unlike most family members, C1-inhibitor has a 2-domain structure. The C-terminal serpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. The N-terminal domain (also some times referred to as the N-terminal tail) is not essential for C1-inhibitor to inhibit proteases. This domain has no similarity to other proteins. C1-inhibitor is highly glycosylated, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated. [7]
The human C1-inhibitor gene (SERPING1) is located on the eleventh chromosome (11q11-q13.1). [8] [9]
Deficiency of this protein is associated with hereditary angioedema ("hereditary angioneurotic edema"), or swelling due to leakage of fluid from blood vessels into connective tissue. [10] Deficiency of C1-inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Also, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. In its most common form, it presents as marked swelling of the face, mouth and/or airway that occurs spontaneously or to minimal triggers (such as mild trauma), but such swelling can occur in any part of the body. In 85% of the cases, the levels of C1-inhibitor are low, while in 15% the protein circulates in normal amounts but it is dysfunctional. In addition to the episodes of facial swelling and/or abdominal pain, it also predisposes to autoimmune diseases, most markedly lupus erythematosus, due to its consumptive effect on complement factors 3 and 4. Mutations in the gene that codes for C1-inhibitor, SERPING1, may also play a role in the development of age-related macular degeneration. [11] At least 97 disease-causing mutations in this gene have been discovered. [12]
Despite uncontrolled auto-activation, it is important to note that levels of key complement components are low during an acute attack because they are being consumed – indeed, low levels of C4 are a key diagnostic test for hereditary angioedema. This situation is analogous to the low levels of clotting factors found in disseminated intravascular coagulation (DIC).
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Trade names | Cinryze, Ruconest, Berinert, others |
Other names | RVG-19303 |
AHFS/Drugs.com | Monograph |
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Routes of administration | Intravenous |
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Blood-derived C1-inhibitor is effective but does carry the risk associated with the use of any human blood product. Cinryze, a pharmaceutical-grade C1-inhibitor, was approved for the use of HAE in 2008 in the US after having been available in Europe for decades. [13] It is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product; it has been approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE. [14]
A recombinant C1-inhibitor obtained from the milk of transgenic rabbits, conestat alfa (trade name Ruconest), is approved for the treatment of acute HAE attacks in adults. [15] [16]
While C1-inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1-inhibitor deficiency, new methods of treating acute attacks have emerged: a plasma kallikrein inhibitor and the bradykinin receptor antagonist icatibant.
Other products also have been introduced including plasma-derived products such as Berinert and Haegarda. [17] [18] [19] [20]
The activation of the complement cascade can cause damage to cells, therefore the inhibition of the complement cascade can work as a medicine in certain conditions. [21] When someone has a heart attack, for instance, the lack of oxygen in heart cells causes necrosis in heart cells: Dying heart cells spill their contents in the extracellular environment, which triggers the complement cascade. Activation of the complement cascade attracts phagocytes that leak peroxide and other reagents, which may increase the damage for the surviving heart cells. Inhibition of the complement cascade can decrease this damage.
C1-inhibitor is contained in the human blood; it can, therefore, be isolated from donated blood. Risks of infectious disease transmission (viruses, prions, etc.) and relative expense of isolation prevented widespread use. It is also possible to produce it by recombinant technology, but Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inhibitor is particularly heavily glycosylated, this sialylated recombinant form would have a short circulatory life (the carbohydrates are not relevant to the inhibitor function). Therefore, C1-inhibitor has also been produced in glycosylated form using transgenic rabbits. [22] This form of recombinant C1-inhibitor also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome. [23]
Alpha-1 antitrypsin or α1-antitrypsin is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases. In older biomedical literature it was sometimes called serum trypsin inhibitor, because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L, but the concentration can rise manyfold upon acute inflammation.
Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.
Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days.
Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.
The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.
Alpha 2-antiplasmin is a serine protease inhibitor (serpin) responsible for inactivating plasmin. Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.
Complement C1r subcomponent is a protein involved in the complement system of the innate immune system. In humans, C1r is encoded by the C1R gene.
Complement component 1s is a protein involved in the complement system. C1s is part of the C1 complex. In humans, it is encoded by the C1S gene.
Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.
Plasminogen activator inhibitor-2, a serine protease inhibitor of the serpin superfamily, is a coagulation factor that inactivates tissue plasminogen activator and urokinase. It is present in most cells, especially monocytes/macrophages. PAI-2 exists in two forms, a 60-kDa extracellular glycosylated form and a 43-kDa intracellular form.
Neutrophil elastase is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Neutrophil elastase is secreted by neutrophils during inflammation, and destroys bacteria and host tissue. It also localizes to neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.
Protein C inhibitor is a serine protease inhibitor (serpin) that limits the activity of protein C.
Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene. Complement factor I is a protein of the complement system, first isolated in 1966 in guinea pig serum, that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b. It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.
Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one of the complement system proteins. Because of redundancies in the immune system, many complement disorders are never diagnosed. Some studies estimate that less than 10% are identified. Hypocomplementemia may be used more generally to refer to decreased complement levels, while secondary complement disorder means decreased complement levels that are not directly due to a genetic cause but secondary to another medical condition.
Pancreatic secretory trypsin inhibitor (PSTI) also known as serine protease inhibitor Kazal-type 1 (SPINK1) or tumor-associated trypsin inhibitor (TATI) is a protein that in humans is encoded by the SPINK1 gene.
Ecallantide is a drug used for the treatment of hereditary angioedema (HAE) and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies inhibiting kallikrein.
Acquired C1 esterase inhibitor deficiency, also referred to as acquired angioedema (AAE), is a rare medical condition that presents as body swelling that can be life-threatening and manifests due to another underlying medical condition. The acquired form of this disease can occur from a deficiency or abnormal function of the enzyme C1 esterase inhibitor (C1-INH). This disease is also abbreviated in medical literature as C1INH-AAE. This form of angioedema is considered acquired due to its association with lymphatic malignancies, immune system disorders, or infections. Typically, acquired angioedema presents later in adulthood, in contrast to hereditary angioedema which usually presents from early childhood and with similar symptoms.
Kunitz domains are the active domains of proteins that inhibit the function of protein degrading enzymes or, more specifically, domains of Kunitz-type are protease inhibitors. They are relatively small with a length of about 50 to 60 amino acids and a molecular weight of 6 kDa. Examples of Kunitz-type protease inhibitors are aprotinin, Alzheimer's amyloid precursor protein (APP), and tissue factor pathway inhibitor (TFPI). Kunitz STI protease inhibitor, the trypsin inhibitor initially studied by Moses Kunitz, was extracted from soybeans.