C1-inhibitor

C1インヒビター

WordNet

1. limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
2. control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
3. limit the range or extent of; "Contact between the young was inhibited by strict social customs"
4. the 3rd letter of the Roman alphabet (同)c
5. (music) the keynote of the scale of C major
6. a general-purpose programing language closely associated with the UNIX operating system
7. a substance that retards or stops an activity

PrepTutorEJDIC

1. 〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
2. carbonの化学記号
3. 抑制する人(物) / 化学反応抑制剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/02 19:33:18」(JST)

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SERPING1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2OAY
Identifiers
Aliases	SERPING1, C1IN, C1INH, C1NH, HAE1, HAE2, serpin family G member 1
External IDs	OMIM: 606860 MGI: 894696 HomoloGene: 44 GeneCards: SERPING1
Gene ontology Molecular function • peptidase inhibitor activity • protein binding • serine-type endopeptidase inhibitor activity Cellular component • blood microparticle • extracellular region • extracellular exosome • platelet alpha granule lumen • extracellular space Biological process • hemostasis • blood coagulation, intrinsic pathway • negative regulation of peptidase activity • fibrinolysis • immune system process • aging • platelet degranulation • blood circulation • negative regulation of complement activation, lectin pathway • complement activation, classical pathway • innate immune response • negative regulation of endopeptidase activity • blood coagulation • regulation of complement activation • regulation of blood coagulation • negative regulation of complement activation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
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 Mb	Chr 2: 84.77 – 84.78 Mb
PubMed search
Wikidata
View/Edit Human View/Edit Mouse

C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. 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.

Genetics

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

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. 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.

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).

Therapeutic use

Hereditary angioedema

Blood-derived C1-inhibitor 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. 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.

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.

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.

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. 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 asialylated 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. 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.

Further reading

• Lappin D, Whaley K (July 1989). "Regulation of C1-inhibitor synthesis by interferons and other agents". Behring Institute Mitteilungen (84): 180–92. PMID 2478116. 
• Stein PE, Carrell RW (February 1995). "What do dysfunctional serpins tell us about molecular mobility and disease?". Nature Structural Biology. 2 (2): 96–113. PMID 7749926. doi:10.1038/nsb0295-96. 
• 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. PMID 8172583. 
• Davis AE (January 2005). "The pathophysiology of hereditary angioedema". Clinical Immunology. 114 (1): 3–9. PMID 15596403. doi:10.1016/j.clim.2004.05.007. 
• 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. PMID 1339401. doi:10.1159/000154075. 
• Davis AE, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, Kramer J, Strunk RC, Bissler J, Rosen FS (August 1992). "C1 inhibitor hinge region mutations produce dysfunction by different mechanisms". Nature Genetics. 1 (5): 354–8. PMID 1363816. doi:10.1038/ng0892-354. 
• 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. PMID 1451784. doi:10.1016/0014-5793(92)80204-T. 
• 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) (Pt 2): 437–42. PMC 1130704 . PMID 1531292. doi:10.1042/bj2810437. 
• 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. PMID 1684567. doi:10.1007/bf00206079. 
• 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. PMC 295456 . PMID 1885769. doi:10.1172/JCI115373. 
• 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. PMID 2026152. doi:10.1111/j.1432-1033.1991.tb15911.x. 
• 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. PMC 54622 . PMID 2118657. doi:10.1073/pnas.87.17.6786. 
• 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. PMC 53513 . PMID 2154751. doi:10.1073/pnas.87.4.1551. 
• 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. PMC 53243 . PMID 2296585. doi:10.1073/pnas.87.1.265. 
• 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. PMID 2323781. doi:10.1007/BF00195824. 
• 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. PMID 2365061. doi:10.1016/0014-5793(90)81494-9. 
• 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. PMID 2563376. 
• 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. PMC 303909 . PMID 2723063. doi:10.1172/JCI114095. 
• 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. PMID 3089875. doi:10.1016/0378-1119(86)90230-1. 

External links

• Human SERPING1 genome location and SERPING1 gene details page in the UCSC Genome Browser.
• The MEROPS online database for peptidases and their inhibitors: I04.024
• B02AB03 (WHO)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 後天性C1インヒビター欠損症：臨床症状、疫学、病因、および診断 acquired c1 inhibitor deficiency clinical manifestations epidemiology pathogenesis and diagnosis
• 2. C1インヒビター正常を示す遺伝性血管性浮腫（III型HAE） hereditary angioedema with normal c1 inhibitor type iii hae
• 3. 後天性C1インヒビター欠損症：管理および予後 acquired c1 inhibitor deficiency management and prognosis
• 4. 遺伝性血管浮腫：病因および診断 hereditary angioedema pathogenesis and diagnosis
• 5. 遺伝性血管浮腫：急性発作の治療 hereditary angioedema treatment of acute attacks

English Journal

• An international serum standard for application in assays to detect human complement activation products.

• Bergseth G, Ludviksen JK, Kirschfink M, Giclas PC, Nilsson B, Mollnes TE.SourceResearch Laboratory, Nordland Hospital Bodø, Norway.
• Molecular immunology.Mol Immunol.2013 Dec 15;56(3):232-9. doi: 10.1016/j.molimm.2013.05.221. Epub 2013 Jun 17.
• The importance of the complement system in clinical medicine has become evident during the last decades and complement therapeutics has now reached the clinic. Thus, there is an increased interest in and need for assays to evaluate complement activity and dysfunction. Pathologically increased comple
• PMID 23787367
• PMID 24096073

• Hereditary angioedema with C1 inhibitor deficiency: clinical presentation and quality of life of 193 French patients.

• Bouillet L, Launay D, Fain O, Boccon-Gibod I, Laurent J, Martin L, Montauban V, Finck K, Bouée S, Gompel A, Kanny G; French National Reference Center for Hereditary Angioedema (CREAK).SourceDepartment of Internal Medicine, University Hospital, Grenoble, France. Electronic address: LBouillet@chu-grenoble.fr.
• Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.Ann Allergy Asthma Immunol.2013 Oct;111(4):290-4. doi: 10.1016/j.anai.2013.07.012. Epub 2013 Aug 6.
• BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. New specific treatments are available.OBJECTIVE: To identify patients' features and patients' best therapeutic option.METHODS: A 1-year, multicenter, retrospective study was performed. The primary objective w
• PMID 24054366

Japanese Journal

• 血管性浮腫 (特集 こんなとき困らない 皮膚科救急マニュアル)

• デルマ (249), 124-128, 2016-10
• NAID 40021092116

• 血管性浮腫とC1インヒビター (特集 蕁麻疹の最新知見)

• アレルギー・免疫 23(7), 980-984, 2016-07
• NAID 40020884918

• A Case of Angioedema due to C1 Inhibitor Deficiency Treated Effectively with Lyophilized Human C1-inactivator Concentrate (Berinert^® P) for Airway Stenosis

• 耳鼻咽喉科臨床　補冊 147(0), 56-57, 2016
• NAID 130005284495

Related Links

• C1 esterase inhibitor: MedlinePlus Medical Encyclopedia

C1 esterase inhibitor (C1-INH) is a protein found in the fluid part of your blood. It controls a protein called C1, which is part of the complement system. This system is a group of proteins that move freely through your ...

• C1-inhibitorとは - goo Wikipedia (ウィキペディア)

^Davis AE (September 2004). "Biological effects of C1 inhibitor". Drug News Perspect. 17 (7): 439–46. doi:10.1358/dnp.2004.17.7.863703. PMID 15514703. ^ a b Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B (November ...

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★リンクテーブル★

リンク元	「C1インヒビター」
関連記事	「inhibit」「C」「inhibitor」「C1」「C1 inhibitor」

「C1インヒビター」

　　[★]

英

C1-inhibitor, C1 inhibitor C1INH

同

C1インアクチベータ, C1不活性化因子 C1 inactivator C1INA

関

補体、C1、古典的経路、遺伝性血管神経性浮腫

臨床関連

• 遺伝性血管神経性浮腫

「inhibit」

　　[★]

• v.

• 抑制する、阻害する、阻止する

関

abrogate、block、depress、depression、deter、inhibition、interdict、prevent、prevention、repress、repression、restrain、restraint、suppress、suppression

　 　 　 　

「C」

　　[★]

• 炭素 carbon
• シトシン cytosine
• システイン cysteine
• シチジン
• セルシウス度 摂氏 degrees Celsius degree C
• 産婦人科領域で「子宮外頚 子宮外頚部 exocervix」を表現するための略語

　 　 　 　

「inhibitor」

　　[★]

• n.

• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

関

blocker、depressant、suppressant

　 　

「C1」

　　[★]

• 環椎 atlas、第一頚椎
• 補体第一成分 first component of complement

「C1 inhibitor」

　　[★] C1インヒビター C1 INH欠損症