C1-inhibitor

{{Short description|Mammalian protein found in humans}} {{More citations needed|date=December 2025}} {{Use dmy dates|date=April 2020}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox_gene}}

'''C1-inhibitor''' ('''C1-inh''', '''C1 esterase inhibitor''') is a protease inhibitor belonging to the serpin superfamily.<ref>{{cite journal | vauthors = Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC | display-authors = 6 | title = An overview of the serpin superfamily | journal = Genome Biology | volume = 7 | issue = 5 | pages = 216 | date = 2006 | pmid = 16737556 | doi = 10.1186/gb-2006-7-5-216 | doi-access = free | pmc = 1779521 }}</ref> Its main function is the inhibition of the complement system (C1r, C1s) to prevent spontaneous activation but also as the major regulator of the contact system (PK, FXIIa, and FXIa).<ref name="pmid15514703">{{cite journal | vauthors = Davis AE | title = Biological effects of C1 inhibitor | journal = Drug News & Perspectives | volume = 17 | issue = 7 | pages = 439–46 | date = September 2004 | pmid = 15514703 | doi = 10.1358/dnp.2004.17.7.863703 }}</ref><ref name="pmid16267649">{{cite journal | vauthors = Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B | title = C1 inhibitor: molecular and clinical aspects | journal = Springer Seminars in Immunopathology | volume = 27 | issue = 3 | pages = 286–98 | date = November 2005 | pmid = 16267649 | doi = 10.1007/s00281-005-0001-4 | s2cid = 24583403 }}</ref><ref name=Long2016>{{cite journal | vauthors = Long AT, Kenne E, Jung R, Fuchs TA, Renné T | title = Contact system revisited: an interface between inflammation, coagulation, and innate immunity | journal = Journal of Thrombosis and Haemostasis | volume = 14 | issue = 3 | pages = 427–437 | date = March 2016 | pmid = 26707513 | doi = 10.1111/jth.13235 | doi-access = free }}</ref>

== 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.<ref name="pmid16267649"/>

== 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.<ref name="pmid18220146">{{cite journal | vauthors = Davis AE | title = Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema | journal = Annals of Allergy, Asthma & Immunology | volume = 100 | issue = 1 Suppl 2 | pages = S7-12 | date = January 2008 | pmid = 18220146 | doi = 10.1016/S1081-1206(10)60580-7 }}</ref> 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.<ref name="pmid18842294">{{cite journal | vauthors = Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A | title = Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study | journal = Lancet | volume = 372 | issue = 9652 | pages = 1828–34 | date = November 2008 | pmid = 18842294 | doi = 10.1016/S0140-6736(08)61348-3 | pmc = 5983350 }}</ref> At least 97 disease-causing mutations in this gene have been discovered.<ref name = "Šimčíková_2019 - supplementary table S7">{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}</ref>

== Medical use ==

{{Infobox drug | drug_name = C1 esterase | image = | width = | alt = | caption =

| pronounce = | tradename = Cinryze, Ruconest, Berinert, others | Drugs.com = {{ubl | {{drugs.com|monograph|c1-esterase-inhibitor-human}} | {{drugs.com|monograph|c1-esterase-inhibitor-recombinant}} | {{drugs.com|mtm|conestat-alfa}} }} | MedlinePlus = | DailyMedID = C1 esterase | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = Intravenous | class = | ATC_prefix = B06 | ATC_suffix = AC01 | ATC_supplemental = {{ATC|B06A|C04}}

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Genetic disorders | website=Health Canada | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/genetic-disorders.html | access-date=13 April 2024}}</ref><ref>{{cite web | title=Regulatory Decision Summary for Haegarda | website=Drug and Health Products Portal | date=1 September 2017 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS00295 | access-date=13 April 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref name="Ruconest 2100 U SmPC">{{cite web | title=Ruconest 2100 U powder and solvent for solution for injection | website=(emc) | date=30 August 2023 | url=https://www.medicines.org.uk/emc/product/8579/smpc | access-date=30 August 2024}}</ref><ref name="Ruconest 2100 U powder for solution SmPC">{{cite web | title=Ruconest 2100 U powder for solution for injection | website=(emc) | date=30 August 2023 | url=https://www.medicines.org.uk/emc/product/8580/smpc | access-date=30 August 2024}}</ref> | legal_US = Rx-only | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | title=Cinryze EPAR | website=European Medicines Agency (EMA) | date=15 June 2011 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cinryze | access-date=27 September 2024}}</ref><ref name="Ruconest EPAR">{{cite web | title=Ruconest EPAR | website=European Medicines Agency (EMA) | date=28 October 2010 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ruconest | access-date=30 August 2024}}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| IUPAC_name = | chemical_formula = | C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I= | K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge= | molecular_weight = | SMILES = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

=== 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.<ref>{{cite web | title=Cinryze | website=U.S. Food and Drug Administration | url=https://www.fda.gov/vaccines-blood-biologics/fractionated-plasma-products/cinryze | date=12 July 2017 | archive-date=22 July 2017 | archive-url=https://wayback.archive-it.org/7993/20170722071336/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm150480.htm | url-status=live | access-date=20 April 2020 }}</ref> 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.<ref>{{cite web | title=Cinryze Monograph for Professionals | website=Drugs.com | date=23 December 2019 | url=https://www.drugs.com/monograph/cinryze.html | access-date=20 April 2020}}</ref>

A recombinant C1-inhibitor obtained from the milk of transgenic rabbits, conestat alfa (brand name Ruconest), is approved for the treatment of acute HAE attacks in adults.<ref name="Ruconest 2100 U SmPC" /><ref name="Ruconest EPAR" /><ref>{{Cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001223/WC500098542.pdf |title=Summary of product characteristics for Ruconest |access-date=9 February 2012 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920030650/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001223/WC500098542.pdf |url-status=dead }}</ref>

Other products also have been introduced including plasma-derived products such as Berinert and Haegarda.<ref>{{cite journal | vauthors = Murphy E, Donahue C, Omert L, Persons S, Tyma TJ, Chiao J, Lumry W | title = Training patients for self-administration of a new subcutaneous C1-inhibitor concentrate for hereditary angioedema | journal = Nursing Open | volume = 6 | issue = 1 | pages = 126–135 | date = January 2019 | pmid = 30534402 | pmc = 6279717 | doi = 10.1002/nop2.194 }}</ref><ref>{{cite journal | vauthors = Li HH | title = Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance | journal = Patient Preference and Adherence | volume = 10 | pages = 1727–37 | date = 7 September 2016 | pmid = 27660422 | pmc = 5019432 | doi = 10.2147/PPA.S86379 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Henry Li H, Riedl M, Kashkin J | title = Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema | journal = Clinical Reviews in Allergy & Immunology | volume = 56 | issue = 2 | pages = 207–218 | date = April 2019 | pmid = 29909591 | doi = 10.1007/s12016-018-8684-1 | s2cid = 49269933 | doi-access = free }}</ref>

=== 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.<ref name="pmid14514717">{{cite journal | vauthors = Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, Kamerling JP | title = N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits | journal = Glycobiology | volume = 14 | issue = 1 | pages = 51–64 | date = January 2004 | pmid = 14514717 | doi = 10.1093/glycob/cwh010 | doi-access = free }}</ref> 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.<ref name="pmid18220151">{{cite journal | vauthors = Bernstein JA | title = Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies | journal = Annals of Allergy, Asthma & Immunology | volume = 100 | issue = 1 Suppl 2 | pages = S41-6 | date = January 2008 | pmid = 18220151 | doi = 10.1016/S1081-1206(10)60585-6 }}</ref>

== Research == 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.<ref name="pmid10699156">{{cite journal | vauthors = Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE | title = C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema | journal = Pharmacological Reviews | volume = 52 | issue = 1 | pages = 91–112 | date = March 2000 | doi = 10.1016/S0031-6997(24)01437-6 | pmid = 10699156 }}</ref>

== References == {{Reflist}}

== Further reading == {{Refbegin}} * {{cite journal | vauthors = Lappin D, Whaley K | title = Regulation of C1-inhibitor synthesis by interferons and other agents | journal = Behring Institute Mitteilungen | issue = 84 | pages = 180–92 | date = July 1989 | pmid = 2478116 }} * {{cite journal | vauthors = Stein PE, Carrell RW | title = What do dysfunctional serpins tell us about molecular mobility and disease? | journal = Nature Structural Biology | volume = 2 | issue = 2 | pages = 96–113 | date = February 1995 | pmid = 7749926 | doi = 10.1038/nsb0295-96 | s2cid = 21223825 }} * {{cite journal | vauthors = Davis AE, Bissler JJ, Cicardi M | title = Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema | journal = Behring Institute Mitteilungen | issue = 93 | pages = 313–20 | date = December 1993 | pmid = 8172583 }} * {{cite journal | vauthors = Davis AE | title = The pathophysiology of hereditary angioedema | journal = Clinical Immunology | volume = 114 | issue = 1 | pages = 3–9 | date = January 2005 | pmid = 15596403 | doi = 10.1016/j.clim.2004.05.007 }} * {{cite journal | vauthors = Siddique Z, McPhaden AR, McCluskey D, Whaley K | title = A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema | journal = Human Heredity | volume = 42 | issue = 4 | pages = 231–4 | year = 1992 | pmid = 1339401 | doi = 10.1159/000154075 }} * {{cite journal | vauthors = Davis AE, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, Kramer J, Strunk RC, Bissler J, Rosen FS | title = C1 inhibitor hinge region mutations produce dysfunction by different mechanisms | journal = Nature Genetics | volume = 1 | issue = 5 | pages = 354–8 | date = August 1992 | pmid = 1363816 | doi = 10.1038/ng0892-354 | s2cid = 29076504 }} * {{cite journal | vauthors = Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE | title = A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu) | journal = FEBS Letters | volume = 301 | issue = 1 | pages = 34–6 | date = April 1992 | pmid = 1451784 | doi = 10.1016/0014-5793(92)80204-T | s2cid = 28082291 | doi-access = free }} * {{cite journal | vauthors = Lappin DF, Guc D, Hill A, McShane T, Whaley K | title = Effect of interferon-gamma on complement gene expression in different cell types | journal = The Biochemical Journal | volume = 281 | issue = Pt 2 | pages = 437–42 | date = January 1992 | pmid = 1531292 | pmc = 1130704 | doi = 10.1042/bj2810437 }} * {{cite journal | vauthors = Siddique Z, McPhaden AR, Lappin DF, Whaley K | title = An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema | journal = Human Genetics | volume = 88 | issue = 2 | pages = 231–2 | date = December 1991 | pmid = 1684567 | doi = 10.1007/bf00206079 | s2cid = 20492891 }} * {{cite journal | vauthors = Frangi D, Cicardi M, Sica A, Colotta F, Agostoni A, Davis AE | title = Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema | journal = The Journal of Clinical Investigation | volume = 88 | issue = 3 | pages = 755–9 | date = September 1991 | pmid = 1885769 | pmc = 295456 | doi = 10.1172/JCI115373 }} * {{cite journal | vauthors = Carter PE, Duponchel C, Tosi M, Fothergill JE | title = Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements | journal = European Journal of Biochemistry | volume = 197 | issue = 2 | pages = 301–8 | date = April 1991 | pmid = 2026152 | doi = 10.1111/j.1432-1033.1991.tb15911.x }} * {{cite journal | vauthors = Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE | title = Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 17 | pages = 6786–90 | date = September 1990 | pmid = 2118657 | pmc = 54622 | doi = 10.1073/pnas.87.17.6786 | bibcode = 1990PNAS...87.6786P | doi-access = free }} * {{cite journal | vauthors = Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M | title = Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 4 | pages = 1551–5 | date = February 1990 | pmid = 2154751 | pmc = 53513 | doi = 10.1073/pnas.87.4.1551 | bibcode = 1990PNAS...87.1551S | doi-access = free }} * {{cite journal | vauthors = Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE | title = Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 1 | pages = 265–8 | date = January 1990 | pmid = 2296585 | pmc = 53243 | doi = 10.1073/pnas.87.1.265 | bibcode = 1990PNAS...87..265L | doi-access = free }} * {{cite journal | vauthors = Theriault A, Whaley K, McPhaden AR, Boyd E, Connor JM | title = Regional assignment of the human C1-inhibitor gene to 11q11-q13.1 | journal = Human Genetics | volume = 84 | issue = 5 | pages = 477–9 | date = April 1990 | pmid = 2323781 | doi = 10.1007/BF00195824 | s2cid = 21989261 }} * {{cite journal | vauthors = Aulak KS, Cicardi M, Harrison RA | title = Identification of a new P1 residue mutation (444Arg----Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma | journal = FEBS Letters | volume = 266 | issue = 1–2 | pages = 13–6 | date = June 1990 | pmid = 2365061 | doi = 10.1016/0014-5793(90)81494-9 | s2cid = 35981265 | doi-access = free }} * {{cite journal | vauthors = Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC | title = CpG mutations in the reactive site of human C1 inhibitor | journal = The Journal of Biological Chemistry | volume = 264 | issue = 6 | pages = 3066–71 | date = February 1989 | doi = 10.1016/S0021-9258(18)94031-7 | pmid = 2563376 | doi-access = free }} * {{cite journal | vauthors = Ariga T, Igarashi T, Ramesh N, Parad R, Cicardi M, Davis AE | title = Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon | journal = The Journal of Clinical Investigation | volume = 83 | issue = 6 | pages = 1888–93 | date = June 1989 | pmid = 2723063 | pmc = 303909 | doi = 10.1172/JCI114095 }} * {{cite journal | vauthors = Tosi M, Duponchel C, Bourgarel P, Colomb M, Meo T | title = Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily | journal = Gene | volume = 42 | issue = 3 | pages = 265–72 | year = 1986 | pmid = 3089875 | doi = 10.1016/0378-1119(86)90230-1 }} {{Refend}}

== External links == * {{UCSC gene info|SERPING1}} * {{ATC|B02|AB03}} * {{PDBe-KB2|P05155|Plasma protease C1 inhibitor}}

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