C1-inhibitor explained

C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily.^[1] Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system.^{[2] [3]} 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.

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.^[3]

Genetics

The human C1-inhibitor gene (SERPING1) is located on the eleventh chromosome (11q11-q13.1).^{[4] [5]}

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.^[6] 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.^[7] At least 97 disease-causing mutations in this gene have been discovered.^[8]

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

Drug Name:	C1 esterase
Tradename:	Cinryze, Ruconest, Berinert, others
Dailymedid:	C1 esterase
Routes Of Administration:	Intravenous
Atc Prefix:	B06
Atc Suffix:	AC01
Legal Ca:	Rx-only
Legal Ca Comment:	^[9] ^[10]
Legal Us:	Rx-only
Legal Status:	Rx-only
Drugbank:	DB06404
Unii:	6KIC4BB60G
Synonyms:	RVG-19303, CSL830

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 in the US after having been available in Europe for decades.^[11] 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.^[12]

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.^{[13] [14]}

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.^{[15] [16] [17] [18]}

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.^[19] 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.^[20] 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.^[21]

Further reading

• Lappin D, Whaley K . Regulation of C1-inhibitor synthesis by interferons and other agents . Behring Institute Mitteilungen . 84 . 180–92 . July 1989 . 2478116 .
• Stein PE, Carrell RW . What do dysfunctional serpins tell us about molecular mobility and disease? . Nature Structural Biology . 2 . 2 . 96–113 . February 1995 . 7749926 . 10.1038/nsb0295-96 . 21223825 .
• Davis AE, Bissler JJ, Cicardi M . Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema . Behring Institute Mitteilungen . 93 . 313–20 . December 1993 . 8172583 .
• Davis AE . The pathophysiology of hereditary angioedema . Clinical Immunology . 114 . 1 . 3–9 . January 2005 . 15596403 . 10.1016/j.clim.2004.05.007 .
• Siddique Z, McPhaden AR, McCluskey D, Whaley K . A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema . Human Heredity . 42 . 4 . 231–4 . 1992 . 1339401 . 10.1159/000154075 .
• Davis AE, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, Kramer J, Strunk RC, Bissler J, Rosen FS . C1 inhibitor hinge region mutations produce dysfunction by different mechanisms . Nature Genetics . 1 . 5 . 354–8 . August 1992 . 1363816 . 10.1038/ng0892-354 . 29076504 .
• Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE . A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu) . FEBS Letters . 301 . 1 . 34–6 . April 1992 . 1451784 . 10.1016/0014-5793(92)80204-T . 28082291 . free .
• Lappin DF, Guc D, Hill A, McShane T, Whaley K . Effect of interferon-gamma on complement gene expression in different cell types . The Biochemical Journal . 281 . Pt 2 . 437–42 . January 1992 . 1531292 . 1130704 . 10.1042/bj2810437 .
• Siddique Z, McPhaden AR, Lappin DF, Whaley K . An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema . Human Genetics . 88 . 2 . 231–2 . December 1991 . 1684567 . 10.1007/bf00206079 . 20492891 .
• Frangi D, Cicardi M, Sica A, Colotta F, Agostoni A, Davis AE . Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema . The Journal of Clinical Investigation . 88 . 3 . 755–9 . September 1991 . 1885769 . 295456 . 10.1172/JCI115373 .
• Carter PE, Duponchel C, Tosi M, Fothergill JE . 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 . April 1991 . 2026152 . 10.1111/j.1432-1033.1991.tb15911.x .
• Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE . Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site . Proceedings of the National Academy of Sciences of the United States of America . 87 . 17 . 6786–90 . September 1990 . 2118657 . 54622 . 10.1073/pnas.87.17.6786 . 1990PNAS...87.6786P . free .
• Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M . Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements . Proceedings of the National Academy of Sciences of the United States of America . 87 . 4 . 1551–5 . February 1990 . 2154751 . 53513 . 10.1073/pnas.87.4.1551 . 1990PNAS...87.1551S . free .
• Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE . Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene . Proceedings of the National Academy of Sciences of the United States of America . 87 . 1 . 265–8 . January 1990 . 2296585 . 53243 . 10.1073/pnas.87.1.265 . 1990PNAS...87..265L . free .
• Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM . Regional assignment of the human C1-inhibitor gene to 11q11-q13.1 . Human Genetics . 84 . 5 . 477–9 . April 1990 . 2323781 . 10.1007/BF00195824 . 21989261 .
• Aulak KS, Cicardi M, Harrison RA . Identification of a new P1 residue mutation (444Arg----Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma . FEBS Letters . 266 . 1–2 . 13–6 . June 1990 . 2365061 . 10.1016/0014-5793(90)81494-9 . 35981265 . free .
• Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC . CpG mutations in the reactive site of human C1 inhibitor . The Journal of Biological Chemistry . 264 . 6 . 3066–71 . February 1989 . 10.1016/S0021-9258(18)94031-7 . 2563376 . free .
• Ariga T, Igarashi T, Ramesh N, Parad R, Cicardi M, Davis AE . Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon . The Journal of Clinical Investigation . 83 . 6 . 1888–93 . June 1989 . 2723063 . 303909 . 10.1172/JCI114095 .
• Tosi M, Duponchel C, Bourgarel P, Colomb M, Meo T . Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily . Gene . 42 . 3 . 265–72 . 1986 . 3089875 . 10.1016/0378-1119(86)90230-1 .

External links

• • The MEROPS online database for peptidases and their inhibitors: I04.024

Notes and References

1. Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC . 6 . An overview of the serpin superfamily . Genome Biology . 7 . 5 . 216 . 2006 . 16737556 . 10.1186/gb-2006-7-5-216 . free . 1779521 .
2. Davis AE . Biological effects of C1 inhibitor . Drug News & Perspectives . 17 . 7 . 439–46 . September 2004 . 15514703 . 10.1358/dnp.2004.17.7.863703 .
3. Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B . C1 inhibitor: molecular and clinical aspects . Springer Seminars in Immunopathology . 27 . 3 . 286–98 . November 2005 . 16267649 . 10.1007/s00281-005-0001-4 . 24583403 .
4. Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM . Regional assignment of the human C1-inhibitor gene to 11q11-q13.1 . Human Genetics . 84 . 5 . 477–9 . April 1990 . 2323781 . 10.1007/BF00195824 . 21989261 .
5. Carter PE, Duponchel C, Tosi M, Fothergill JE . 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 . April 1991 . 2026152 . 10.1111/j.1432-1033.1991.tb15911.x .
6. Davis AE . 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 . January 2008 . 18220146 . 10.1016/S1081-1206(10)60580-7 .
7. Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A . Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study . Lancet . 372 . 9652 . 1828–34 . November 2008 . 18842294 . 10.1016/S0140-6736(08)61348-3 . 5983350 .
8. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
9. Web site: Genetic disorders . . 9 May 2018 . 13 April 2024.
10. Web site: Regulatory Decision Summary for Haegarda . Drug and Health Products Portal . 1 September 2017 . 13 April 2024.
11. Web site: Cinryze . . 12 July 2017 . 22 July 2017 . https://wayback.archive-it.org/7993/20170722071336/https:/www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm150480.htm . dead . 20 April 2020 .
12. Web site: Cinryze Monograph for Professionals . Drugs.com . 23 December 2019 . 20 April 2020.
13. Drugs.com: Ruconest 2100 U powder for solution for injection
14. Web site: Summary of product characteristics for Ruconest . 9 February 2012 . 20 September 2018 . https://web.archive.org/web/20180920030650/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001223/WC500098542.pdf . dead .
15. Murphy E, Donahue C, Omert L, Persons S, Tyma TJ, Chiao J, Lumry W . Training patients for self-administration of a new subcutaneous C1-inhibitor concentrate for hereditary angioedema . Nursing Open . 6 . 1 . 126–135 . January 2019 . 30534402 . 6279717 . 10.1002/nop2.194 .
16. Li HH . Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance . Patient Preference and Adherence . 10 . 1727–37 . 7 September 2016 . 27660422 . 5019432 . 10.2147/PPA.S86379 . free .
17. Henry Li H, Riedl M, Kashkin J . 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 . April 2019 . 29909591 . 10.1007/s12016-018-8684-1 . 49269933 . free .
18. Web site: Human C1-esterase inhibitor . DrugBank.
19. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE . 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 . March 2000 . 10699156 .
20. Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, Kamerling JP . N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits . Glycobiology . 14 . 1 . 51–64 . January 2004 . 14514717 . 10.1093/glycob/cwh010 . free .
21. Bernstein JA . 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 . January 2008 . 18220151 . 10.1016/S1081-1206(10)60585-6 .