C1-inhibitor

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.

SERPING1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSERPING1, C1IN, C1INH, C1NH, HAE1, HAE2, serpin family G member 1
External IDsOMIM: 606860 MGI: 894696 HomoloGene: 44 GeneCards: SERPING1
Gene location (Human)
Chr.Chromosome 11 (human)[1]
Band11q12.1Start57,597,387 bp[1]
End57,614,848 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

710

12258

Ensembl

ENSG00000149131

ENSMUSG00000023224

UniProt

P05155

P97290

RefSeq (mRNA)

NM_001032295
NM_000062

NM_009776

RefSeq (protein)

NP_000053
NP_001027466

NP_033906

Location (UCSC)Chr 11: 57.6 – 57.61 MbChr 2: 84.77 – 84.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Proteomics

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]

Genetics

The human C1-inhibitor gene (SERPING1) is located on the eleventh chromosome (11q11-q13.1).[8][9]

Role in disease

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]

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).

Medical use
C1-inhibitor
Clinical data
Trade namesCinryze, Ruconest, Berinert, others
Other namesRVG-19303
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • US: C (Risk not ruled out) [12]
    Routes of
    administration    		Intravenous
    ATC code
    Legal status
    Legal status
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Identifiers
    DrugBank
    UNII

    Hereditary angioedema

    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.[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 autoinjector.[17][18][19][20]

    For other conditions

    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.

    Synthesis

    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]

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    References
    1. GRCh38: Ensembl release 89: ENSG00000149131 - Ensembl, May 2017
    2. GRCm38: Ensembl release 89: ENSMUSG00000023224 - Ensembl, May 2017
    3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
    4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
    5. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, et al. (2006). "An overview of the serpin superfamily". Genome Biology. 7 (5): 216. doi:10.1186/gb-2006-7-5-216. PMC 1779521. PMID 16737556.
    6. Davis AE (September 2004). "Biological effects of C1 inhibitor". Drug News & Perspectives. 17 (7): 439–46. doi:10.1358/dnp.2004.17.7.863703. PMID 15514703.
    7. Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B (November 2005). "C1 inhibitor: molecular and clinical aspects". Springer Seminars in Immunopathology. 27 (3): 286–98. doi:10.1007/s00281-005-0001-4. PMID 16267649.
    8. Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM (April 1990). "Regional assignment of the human C1-inhibitor gene to 11q11-q13.1". Human Genetics. 84 (5): 477–9. doi:10.1007/BF00195824. PMID 2323781.
    9. Carter PE, Duponchel C, Tosi M, Fothergill JE (April 1991). "Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements". European Journal of Biochemistry. 197 (2): 301–8. doi:10.1111/j.1432-1033.1991.tb15911.x. PMID 2026152.
    10. Davis AE (January 2008). "Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema". Annals of Allergy, Asthma & Immunology. 100 (1 Suppl 2): S7-12. doi:10.1016/S1081-1206(10)60580-7. PMID 18220146.
    11. Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A (November 2008). "Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study". Lancet. 372 (9652): 1828–34. doi:10.1016/S0140-6736(08)61348-3. PMC 5983350. PMID 18842294.
    12. "C1 esterase inhibitor (human) Use During Pregnancy". Drugs.com. 26 November 2018. Retrieved 20 April 2020.
    13. "Cinryze". U.S. Food and Drug Administration. 12 July 2017. Archived from the original on 22 July 2017. Retrieved 20 April 2020.CS1 maint: unfit url (link)
    14. "Cinryze Monograph for Professionals". Drugs.com. 23 December 2019. Retrieved 20 April 2020.
    15. Drugs.com: Ruconest 2100 U powder for solution for injection
    16. Summary of product characteristics for Ruconest
    17. Murphy E, Donahue C, Omert L, Persons S, Tyma TJ, Chiao J, Lumry W (January 2019). "Training patients for self-administration of a new subcutaneous C1-inhibitor concentrate for hereditary angioedema". Nursing Open. 6 (1): 126–135. doi:10.1002/nop2.194. PMC 6279717. PMID 30534402.
    18. Li HH (7 September 2016). "Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance". Patient Preference and Adherence. 10: 1727–37. doi:10.2147/PPA.S86379. PMC 5019432. PMID 27660422.
    19. Henry Li H, Riedl M, Kashkin J (April 2019). "Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema". Clinical Reviews in Allergy & Immunology. 56 (2): 207–218. doi:10.1007/s12016-018-8684-1. PMID 29909591.
    20. "Human C1-esterase inhibitor". DrugBank.
    21. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE (March 2000). "C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema". Pharmacological Reviews. 52 (1): 91–112. PMID 10699156.
    22. Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, Kamerling JP (January 2004). "N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits". Glycobiology. 14 (1): 51–64. doi:10.1093/glycob/cwh010. PMID 14514717.
    23. Bernstein JA (January 2008). "Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies". Annals of Allergy, Asthma & Immunology. 100 (1 Suppl 2): S41-6. doi:10.1016/S1081-1206(10)60585-6. PMID 18220151.

    Further reading
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