C1-inhibitor
C1-inhibitor(C1-inh,C1 esterase inhibitor) is aprotease inhibitorbelonging to theserpinsuperfamily.[5]Its main function is the inhibition of thecomplement systemto prevent spontaneous activation but also as the major regulator of the contact system.[6][7]
Proteomics
[edit]C1-inhibitor is the largest member among theserpinsuperfamily of proteins. It can be noted that, unlike most family members, C1-inhibitor has a 2-domainstructure. TheC-terminalserpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. TheN-terminaldomain (also some times referred to as theN-terminal tail) is not essential for C1-inhibitor to inhibit proteases. This domain has no similarity to other proteins. C1-inhibitor is highlyglycosylated,bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated.[7]
Genetics
[edit]The human C1-inhibitorgene(SERPING1) is located on the eleventhchromosome(11q11-q13.1).[8][9]
Role in disease
[edit]Deficiency of this protein is associated withhereditary 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 peptidebradykinin.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 toautoimmune diseases,most markedlylupus 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-relatedmacular degeneration.[11]At least 97 disease-causing mutations in this gene have been discovered.[12]
Medical use
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| Trade names | Cinryze, Ruconest, Berinert, others |
| Other names | RVG-19303, CSL830 |
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| Routes of administration | Intravenous |
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Hereditary angioedema
[edit]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.[19]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.[20]
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.[15][18][21]
Other products also have been introduced including plasma-derived products such as Berinert and Haegarda.[22][23][24]
Synthesis
[edit]C1-inhibitor is contained in the human blood; it can, therefore, be isolated fromdonated blood.Risks of infectious disease transmission (viruses, prions, etc.) and relative expense of isolation prevented widespread use. It is also possible to produce it byrecombinanttechnology, butEscherichia 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.[25]This form of recombinant C1-inhibitor also has been givenorphan drugstatus for delayed graft function following organ transplantation and for capillary leakage syndrome.[26]
Research
[edit]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.[27]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000149131–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000023224–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^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.PMC1779521.PMID16737556.
{{cite journal}}:CS1 maint: overridden setting (link) - ^Davis AE (September 2004). "Biological effects of C1 inhibitor".Drug News & Perspectives.17(7): 439–46.doi:10.1358/dnp.2004.17.7.863703.PMID15514703.
- ^abCicardi 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.PMID16267649.S2CID24583403.
- ^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.PMID2323781.S2CID21989261.
- ^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.PMID2026152.
- ^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.PMID18220146.
- ^Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, et al. (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.PMC5983350.PMID18842294.
- ^Šimčíková D, Heneberg P (December 2019)."Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases".Scientific Reports.9(1): 18577.Bibcode:2019NatSR...918577S.doi:10.1038/s41598-019-54976-4.PMC6901466.PMID31819097.
- ^"Genetic disorders".Health Canada.9 May 2018.Retrieved13 April2024.
- ^"Regulatory Decision Summary for Haegarda".Drug and Health Products Portal.1 September 2017.Retrieved13 April2024.
- ^ab"Ruconest 2100 U powder and solvent for solution for injection".(emc).30 August 2023.Retrieved30 August2024.
- ^"Ruconest 2100 U powder for solution for injection".(emc).30 August 2023.Retrieved30 August2024.
- ^"Cinryze EPAR".European Medicines Agency (EMA).15 June 2011.Retrieved27 September2024.
- ^ab"Ruconest EPAR".European Medicines Agency (EMA).28 October 2010.Retrieved30 August2024.
- ^"Cinryze".U.S.Food and Drug Administration.12 July 2017. Archived fromthe originalon 22 July 2017.Retrieved20 April2020.
- ^"Cinryze Monograph for Professionals".Drugs.com.23 December 2019.Retrieved20 April2020.
- ^"Summary of product characteristics for Ruconest"(PDF).Archived fromthe original(PDF)on 20 September 2018.Retrieved9 February2012.
- ^Murphy E, Donahue C, Omert L, Persons S, Tyma TJ, Chiao J, et al. (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.PMC6279717.PMID30534402.
- ^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.PMC5019432.PMID27660422.
- ^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.PMID29909591.S2CID49269933.
- ^Koles K, van Berkel PH, Pieper FR, Nuijens JH, Mannesse ML, Vliegenthart JF, et al. (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.PMID14514717.
- ^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.PMID18220151.
- ^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.PMID10699156.
Further reading
[edit]- Lappin D, Whaley K (July 1989). "Regulation of C1-inhibitor synthesis by interferons and other agents".Behring Institute Mitteilungen(84): 180–92.PMID2478116.
- Stein PE, Carrell RW (February 1995). "What do dysfunctional serpins tell us about molecular mobility and disease?".Nature Structural Biology.2(2): 96–113.doi:10.1038/nsb0295-96.PMID7749926.S2CID21223825.
- Davis AE, Bissler JJ, Cicardi M (December 1993). "Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema".Behring Institute Mitteilungen(93): 313–20.PMID8172583.
- Davis AE (January 2005). "The pathophysiology of hereditary angioedema".Clinical Immunology.114(1): 3–9.doi:10.1016/j.clim.2004.05.007.PMID15596403.
- Siddique Z, McPhaden AR, McCluskey D, Whaley K (1992). "A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema".Human Heredity.42(4): 231–4.doi:10.1159/000154075.PMID1339401.
- Davis AE, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, et al. (August 1992). "C1 inhibitor hinge region mutations produce dysfunction by different mechanisms".Nature Genetics.1(5): 354–8.doi:10.1038/ng0892-354.PMID1363816.S2CID29076504.
- Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE (April 1992)."A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu)".FEBS Letters.301(1): 34–6.doi:10.1016/0014-5793(92)80204-T.PMID1451784.S2CID28082291.
- Lappin DF, Guc D, Hill A, McShane T, Whaley K (January 1992)."Effect of interferon-gamma on complement gene expression in different cell types".The Biochemical Journal.281(Pt 2): 437–42.doi:10.1042/bj2810437.PMC1130704.PMID1531292.
- Siddique Z, McPhaden AR, Lappin DF, Whaley K (December 1991). "An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema".Human Genetics.88(2): 231–2.doi:10.1007/bf00206079.PMID1684567.S2CID20492891.
- Frangi D, Cicardi M, Sica A, Colotta F, Agostoni A, Davis AE (September 1991)."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.doi:10.1172/JCI115373.PMC295456.PMID1885769.
- 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.PMID2026152.
- Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE (September 1990)."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.Bibcode:1990PNAS...87.6786P.doi:10.1073/pnas.87.17.6786.PMC54622.PMID2118657.
- Stoppa-Lyonnet D, Carter PE, Meo T, Tosi M (February 1990)."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.Bibcode:1990PNAS...87.1551S.doi:10.1073/pnas.87.4.1551.PMC53513.PMID2154751.
- Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE (January 1990)."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.Bibcode:1990PNAS...87..265L.doi:10.1073/pnas.87.1.265.PMC53243.PMID2296585.
- 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.PMID2323781.S2CID21989261.
- Aulak KS, Cicardi M, Harrison RA (June 1990)."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.doi:10.1016/0014-5793(90)81494-9.PMID2365061.S2CID35981265.
- Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC (February 1989)."CpG mutations in the reactive site of human C1 inhibitor".The Journal of Biological Chemistry.264(6): 3066–71.doi:10.1016/S0021-9258(18)94031-7.PMID2563376.
- Ariga T, Igarashi T, Ramesh N, Parad R, Cicardi M, Davis AE (June 1989)."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.doi:10.1172/JCI114095.PMC303909.PMID2723063.
- Tosi M, Duponchel C, Bourgarel P, Colomb M, Meo T (1986). "Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily".Gene.42(3): 265–72.doi:10.1016/0378-1119(86)90230-1.PMID3089875.
External links
[edit]- HumanSERPING1genome location andSERPING1gene details page in theUCSC Genome Browser.
- B02AB03(WHO)
- Overview of all the structural information available in thePDBforUniProt:P05155(Plasma protease C1 inhibitor) at thePDBe-KB.
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