Human C1 esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein. It belongs to the serine protease inhibitor (serpin) superfamily and plays a role in the regulation of the classical complement pathway, the contact activation system, and the intrinsic coagulation pathway. In addition to its ability to inhibit several proteases, C1INH also exhibits a broad spectrum of non-inhibitory biological activity. Through the study of hereditary angioedema (HAE) caused by plasma functional C1-INH deficiency, C1-INH's role in regulating vascular permeability has been demonstrated. Subsequent research has gradually revealed the structure and biological activity of C1-INH, allowing us to make great progress in understanding its therapeutic potential and research and development based on C1-INH.
Fig.1 Crystal structure of the serpin domain of recombinant non-glycosylated C1-INH. (Karnaukhova, 2013)
C1-INH Structure and Functions
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Structural characterization of C1-INH. C1-INH is a single-chain polypeptide with two domains, of which the C-terminal domain is a typical serine protease inhibitor, and the N-terminal domain is essential for protein integrity and stabilization of the serine protease inhibitory domain. C1-INH is a highly glycosylated protein, and the inherent heterogeneity of the carbohydrate portion greatly promotes the heterogeneity of the entire C1-INH. This may be one of the reasons why the natural glycosylated C1-INH crystal structure is still not available.
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Biosynthesis of C1-INH. Human C1-INH is encoded by the SERPING1 gene on chromosome 11, and is mainly synthesized and secreted by hepatocytes, but is also produced by monocytes, fibroblasts, macrophages, endothelial cells and other cells. C1-INH biosynthesis can be stimulated by cytokines, especially interferon-γ.
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Abundance of C1-INH. Human C1-INH is a forward acute phase plasma glycoprotein, and its concentration is normal in healthy subjects, about 240 µg / mL, but its level may increase 2-2.5 times during inflammation. Low C1-INH plasma levels or dysfunction can lead to activation of complement and exposure to the plasma cascade and may also affect other systems.
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Inhibition of proteases and other activities. C1-INH has the ability to inhibit several proteases and plays a role in the down-regulation of four major plasma cascade systems. It is the sole regulator of classical protease activation (C1s and C1r) early proteases. It is also involved in the regulation of lectin pathway activation through inactivation of mannan-bound lectin-associated serine protease 2 (MASP-2). In the contact system, C1-INH inactivates activated plasma kallikrein and FXIIa. C1-INH inhibited kallikrein much more than α2-macroglobulin. C1-INH is also involved in the regulation of the fibrinolytic pathway through inactivation of plasmin and tissue plasminogen activators, and appears to be involved in the inhibition of thrombin and FXIa of the intrinsic coagulation pathway.
C1-INH Related Diseases
Due to the various biological activities of C1-INH and its important role in many physiological processes, its medical research potential has attracted many people's attention. Early research has been difficult due to the complex regulatory pathways involved in C1-INH; however, in recent years, with the in-depth exploration of the pathological mechanism of HAE, many significant advances have been made in the development of the treatment of C1-INH. Stable, functionally active recombinant human C1-INH has been used in the treatment of HAE in some European countries. In addition, as an effective anti-inflammatory drug, C1-INH is also considered to be used to treat several other serious pathological conditions, including sepsis, acute myocardial infarction, vascular leak syndrome, ischemia-reperfusion injury, and cerebral ischemia. Injuries and other illnesses. Although the application prospect is broad and theoretically safe and reliable, more clinical data are needed to support its efficacy if it is to be put into practical use.
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Reference
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Karnaukhova, E. C1-esterase inhibitor: biological activities and therapeutic applications[J]. J Hematol Thromb Dis, 2013, 1(113): 2.
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