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C1-Esterase Inhibitor & Throm gy b o o l e o t m Journal of Hematology & a b o m Karnaukhova, J Hematol Thromb Dis 2013, 1:3 l e i c H D f DOI: 10.4172/2329-8790.1000113 o i s l e a Thromboembolic Diseases ISSN: 2329-8790 a n s r e u s o J Review Article Open Access C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications Elena Karnaukhova* Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, 20892 USA Abstract Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibi- tor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in hereditary angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma. Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic ap- plication of C1-INH. This manuscript provides an overview of the structure and functions of human C1-INH, its role in HAE, summarizes published data available for recently approved C1-INH therapeutic products, and considers possible use of C1-INH for other applications. Keywords: C1-esterase inhibitor; C1-inhibitor deficiency; Hereditary C1-INH Structure and Functions angioedema Abundance of C1-INH Abbreviations: BK: Bradykinin; B2R: B2-receptor; C1- Human C1-INH is a positive acute-phase plasma glycoprotein with INH: C1-esterase inhibitor; FXIIa: activated factor XII; GAG: normal concentration in healthy subjects ~ 240 µg/mL (~3 µM), but Glycosaminoglycan; HAE: Hereditary Angioedema; HMWK: High its level may increase by 2-2.5 times during inflammation [8,9]. Some Molecular Weight Kininogen; IV: Intravenous; MASP-1 and MASP- characteristics of human C1-INH are summarized in Table 1. Low 2: Mannan-Binding Lectin-Associated Serine Proteases; pd: Plasma- plasma content of C1-INH or its dysfunction result in the activation Derived; RCL: Reactive Center Loop; rhC1-INH: Recombinant Human of both complement and contact plasma cascades, and may affect C1-INH; SC: Subcutaneous other systems as well (vide infra) [10-12]. Decrease in C1-INH plasma Introduction content to levels lower than 55 µg/mL (~25% of normal) was shown to induce spontaneous activation of C1 [13]. Human C1-INH is an important anti-inflammatory plasma protein with a wide range of inhibitory and non-inhibitory biological Biosynthesis and mutations activities. By sequence homology, structure of its C-terminal domain, C1-INH is synthesized and secreted primarily by hepatocytes, but and mechanism of protease inhibition, it belongs to the serpin is also produced by monocytes, fibroblasts, macrophages, microglial superfamily, the largest class of plasma protease inhibitors, which cells, endothelial cells, and some other cells [14-18]. Biosynthesis of C1- also includes antithrombin, α -proteinase inhibitor, plasminogen 1 INH can be stimulated by cytokines, particularly by interferon-γ [19,20]. activator inhibitor, and many other structurally similar proteins that regulate diverse physiological systems [1,2]. Best known for regulating Human C1-INH is encoded by the SERPING1 gene (17 kb) on the complement cascade system, C1-INH also plays a key role in the chromosome 11 (11q12→q13.1) comprised of eight exons and seven regulation of the contact (kallikrein-kinin) amplification cascade, and introns [21-23]. A vast variety of large and small mutations identified participates in the regulation of the coagulation and fibrinolytic systems in C1-INH for patients with HAE results from three types of alterations [3-5]. Since 1963, when Donaldson and Evans linked the symptoms in the gene: (i) deletions or duplications due to high content of Alu of hereditary angioedema (HAE, called hereditary angioneurotic repeat sequences in the introns that causes ~20% of genetic defects edema at that time) to the absence of serum C1-INH, it has been the in HAE [23,24]; (ii) mutations in the codon for Arg444 of the reactive subject of multidisciplinary research [6,7]. Over the past fifty years, our center loop (RCL) which results in dysfunctional C1-INH [25]; and (iii) knowledge about C1-INH structure and its biological functions, the cause(s) of its deficiency, and its role in HAE and other conditions has been significantly advanced. The majority of research still focuses on *Corresponding author: Elena Karnaukhova, PhD, Division of Hematology, the mechanisms and efficient treatments of C1-INH-dependent types Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, National Institutes of Health Building 29, Bethesda, of HAE; however, the physiological and pharmacological activities Maryland 20892, USA, Tel: 301-402-4635; Fax: 301-402-2780; E-mail: of C1-INH are much broader. During the last five years, several C1- [email protected] INH products have been licensed in the US and EU for the treatment Received February 06, 2013; Accepted May 13, 2013; Published May 15, 2013 C1-INH-deficient patients with HAE that dramatically improved the therapeutic options in the battle with this rare disease. Due to C1-INH Citation: Karnaukhova E (2013) C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications. J Hematol Thromb Dis 1: 113. doi: 10.4172/2329- involvement in a variety of physiological processes, its therapeutic 8790.1000113 potential for the treatment of other conditions has also been recognized, yet remains unexplored. This review considers the biochemistry of C1- Copyright: © 2013 Karnaukhova E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted INH, its biological activities, and recent advances in its therapeutic use, distribution, and reproduction in any medium, provided the original author and development. source are credited. J Hematol Thromb Dis ISSN: 2329-8790 JHTD, an open access journal Volume 1 • Issue 3 • 1000113 Citation: Karnaukhova E (2013) C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications. J Hematol Thromb Dis 1: 113. doi: 10.4172/2329-8790.1000113 Page 2 of 7 a large number of single codon mutations over the length of the gene and (2) three N- and at least seven O-linked carbohydrates have been [12,26-28]. All this characterizes C1-INH deficiency as an extremely determined for N-terminal domain [35]. The protein integrity is heterogeneous disease. It is of interest that some mutations in the maintained by connection of the domains with two disulfide bridges SERPING1 gene are associated with the development of age-related formed by Cys101 and Cys108 of the N-terminal domain and Cys406 and macular degeneration [29,30]. Cys183 of C-terminal domain [31]. Although the functional role of the exceptionally long and heavily glycosylated N-terminal domain is still Structural characterization unclear, it may be essential for the protein’s conformational stability, Human C1-INH is a single-chain polypeptide (478 amino acid recognition, affinity to endotoxins and selectins, and clearance. The residues) which forms two domains: (a) C-terminal domain (365 intrinsic heterogeneity of the carbohydrate moiety greatly contributes amino acids), which is a typical serpin; and (b) N-terminal domain to the heterogeneity of the whole C1-INH. This may be one of the (113 amino acids), the role of which is not clearly elucidated, but which reasons why obtaining a crystal structure of native glycosylated C1- seems to be important for protein integrity and stabilization of the INH remains elusive. serpin domain [31] and for interactions with lipopolysaccharides [32]. To date, the only published crystal structure that is available for C1-INH is a heavily glycosylated protein with more than 26% C1-INH has been performed by Beinrohr and co-workers for the (w/w) of carbohydrates. Whereas the calculated molecular weight non-glycosylated serpin domain of recombinant C1-INH, which of the polypeptide part is 52,869 Da [21], the molecular weight of crystallized in its latent form [36]. The crystal structure of the serpin the whole protein is ~76 kDa (by neutron scattering [33]). Using domain features nine α-helices, three β-sheets, and a mobile RCL mass spectrometric analysis we detected it as an ~74 kDa protein exposed for interaction with target serine proteases, features typical (the author’s data); however, it is often referred to as an ~105 kDa for serpins (Figure 1). The alignment of the C1-INH serpin domain glycoprotein as observed by electrophoretic mobility on SDS-PAGE structure with those of antithrombin III and α1-proteinase inhibitor [33,34]. Carbohydrates are very unevenly distributed over the C1-INH illustrates the overall remarkable structural similarity between serpins molecule: (1) three N-attached glycans belong to the serpin domain, [37]. The major difference revealed by Beinrohr et al. for this C1-INH attached to asparagine residues Asn216, Asn231, and Asn330, which is serpin structure is that the C-terminal P’ part of the RCL shows as the new seventh strand of thus-extended β-sheet A, while in other known similar to the glycosylation of archetypal serpin α1-proteinase inhibitor; latent serpin structures it is just a flexible loop [36]. Similar to α1-proteinase inhibitor, C1-INH serpin domain is intrinsically folded into a metastable structure, which is not the most thermodynamically stable form, but is essential for inhibitory function.
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