C1-inhibitor

Mammalian protein found in humans

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; OMA:SERPING1 - orthologs
| Gene location (Human)

Chr.| Chromosome 11 (human)[1]

Band| 11q12.1| Start| 57,597,387 bp[1]
End| 57,619,171 bp[1]
| Gene location (Mouse)

Chr.| Chromosome 2 (mouse)[2]

Band| 2|2 D| Start| 84,595,731 bp[2]
End| 84,605,788 bp[2]
| RNA expression pattern

Bgee| | Human| Mouse (ortholog)

|

| Top expressed in

* right lobe of liver

* right lung

* right coronary artery

* gastric mucosa

* Descending thoracic aorta

* ascending aorta

* popliteal artery

* tibial arteries

* left uterine tube

* right ovary

| Top expressed in

* left lobe of liver

* gastrula

* carotid body

* decidua

* ankle

* right lung

* right lung lobe

* efferent ductule

* white adipose tissue

* uterus

More reference expression data
BioGPS| |

More reference expression data
| 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
* collagen-containing extracellular matrix

Biological process|

* hemostasis
* blood coagulation, intrinsic pathway
* negative regulation of peptidase activity
* fibrinolysis
* immune system process
* ageing
* 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
| 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 – 57.62 Mb| Chr 2: 84.6 – 84.61 Mb
PubMed search| [3]| [4]
Wikidata
| View/Edit Human| View/Edit Mouse

|

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 (C1r, C1s) to prevent spontaneous activation but also as the major regulator of the contact system (PK, FXIIa, and FXIa).[6][7][8]

## Proteomics

[edit]

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]

## Role in disease

[edit]

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.[9] 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.[10] At least 97 disease-causing mutations in this gene have been discovered.[11]

## Medical use

[edit]

Pharmaceutical compound

C1 esteraseClinical data

Trade names| Cinryze, Ruconest, Berinert, others
Other names| RVG-19303, CSL830
AHFS/Drugs.com|

* Monograph
* Monograph
* Multum Consumer Information

License data|

* US DailyMed: C1 esterase

Routes of
administration| Intravenous
ATC code|

* B06AC01 (WHO) B06AC04 (WHO)

Legal status
Legal status|

* CA:  ℞-only[12][13]
* UK: POM (Prescription only)[14][15]
* US: ℞-only
* EU: Rx-only[16][17]
* In general: ℞ (Prescription only)

Identifiers
CAS Number|

* 1018837-94-9
* 80295-38-1

DrugBank|

* DB06404
* DB09228

UNII|

* 6KIC4BB60G
* 5QS67N4551

KEGG|

* D08780
* D10845

### 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.[18] 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.[19]

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.[14][17][20]

Other products also have been introduced including plasma-derived products such as Berinert and Haegarda.[21][22][23]

### Synthesis

[edit]

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.[24] 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.[25]

## 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.[26]

## References

[edit]

1. ^ a b c GRCh38: Ensembl release 89: ENSG00000149131 – Ensembl, May 2017
2. ^ a b c 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.`{{cite journal}}`: CS1 maint: overridden setting (link)
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. ^ a b 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. S2CID 24583403.
8. ^ Long AT, Kenne E, Jung R, Fuchs TA, Renné T (March 2016). "Contact system revisited: an interface between inflammation, coagulation, and innate immunity". Journal of Thrombosis and Haemostasis. 14 (3): 427–437\. doi:10.1111/jth.13235. PMID 26707513.
9. ^ 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.
10. ^ 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. PMC 5983350. PMID 18842294.
11. ^ 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. PMC 6901466. PMID 31819097.
12. ^ "Genetic disorders". Health Canada. 9 May 2018. Retrieved 13 April 2024.
13. ^ "Regulatory Decision Summary for Haegarda". Drug and Health Products Portal. 1 September 2017. Retrieved 13 April 2024.
14. ^ a b "Ruconest 2100 U powder and solvent for solution for injection". (emc). 30 August 2023. Retrieved 30 August 2024.
15. ^ "Ruconest 2100 U powder for solution for injection". (emc). 30 August 2023. Retrieved 30 August 2024.
16. ^ "Cinryze EPAR". European Medicines Agency (EMA). 15 June 2011. Retrieved 27 September 2024.
17. ^ a b "Ruconest EPAR". European Medicines Agency (EMA). 28 October 2010. Retrieved 30 August 2024.
18. ^ "Cinryze". U.S. Food and Drug Administration. 12 July 2017. Archived from the original on 22 July 2017. Retrieved 20 April 2020.
19. ^ "Cinryze Monograph for Professionals". Drugs.com. 23 December 2019. Retrieved 20 April 2020.
20. ^ "Summary of product characteristics for Ruconest" (PDF). Archived from the original (PDF) on 20 September 2018. Retrieved 9 February 2012.
21. ^ 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. PMC 6279717. PMID 30534402.
22. ^ 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.
23. ^ 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. S2CID 49269933.
24. ^ 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. PMID 14514717.
25. ^ 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.
26. ^ 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\. doi:10.1016/S0031-6997(24)01437-6. PMID 10699156.

## 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\. 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\. doi:10.1038/nsb0295-96. PMID 7749926. S2CID 21223825.
* 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\. doi:10.1016/j.clim.2004.05.007. PMID 15596403.
* 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. PMID 1339401.
* 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. PMID 1363816. S2CID 29076504.
* 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. PMID 1451784. S2CID 28082291.
* 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. PMC 1130704. PMID 1531292.
* 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. PMID 1684567. S2CID 20492891.
* 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. PMC 295456. PMID 1885769.
* 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.
* 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. PMC 54622. PMID 2118657.
* 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. PMC 53513. PMID 2154751.
* 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. PMC 53243. PMID 2296585.
* 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. S2CID 21989261.
* 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. PMID 2365061. S2CID 35981265.1–2&rft.pages=13-6&rft.date=1990-06&rft_id=https://api.semanticscholar.org/CorpusID:35981265#id-name=S2CID&rft_id=info:pmid/2365061&rft_id=info:doi/10.1016/0014-5793(90)81494-9&rft.aulast=Aulak&rft.aufirst=KS&rft.au=Cicardi,+M&rft.au=Harrison,+RA&rft_id=https://doi.org/10.1016%2F0014-5793%2890%2981494-9&rfr_id=info:sid/en.wikipedia.org:C1-inhibitor" class="Z3988">
* 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. 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\. doi:10.1172/JCI114095. PMC 303909. PMID 2723063.
* 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. PMID 3089875.

## External links

[edit]

* Human SERPING1 genome location and SERPING1 gene details page in the UCSC Genome Browser.
* B02AB03 (WHO)
* Overview of all the structural information available in the PDB for UniProt: P05155 (Plasma protease C1 inhibitor) at the PDBe-KB.

* v
* t
* e

Other hematological agents (B06)

Enzymes (B06AA)|

* Bromelain
* Chymotrypsin
* Desoxyribonuclease
* Fibrinolysin (+desoxyribonuclease)
* Hyaluronidase
* Streptokinase
* Trypsin

Drugs used in hereditary
angioedema (B06AC)|

* Berotralstat
* C1-inhibitor
* Conestat alfa
* Ecallantide
* Garadacimab
* Icatibant
* Lanadelumab
* Sebetralstat

Drugs used in sickle cell disease
and beta thalassemia (B06AX)|

* Betibeglogene autotemcel
* Crizanlizumab
* Exagamglogene autotemcel
* Lovotibeglogene autotemcel
* Mitapivat
* Voxelotor

Others|

* Hemin

* v
* t
* e

PDB gallery

* 2oay: Crystal structure of latent human C1-inhibitor

* v
* t
* e

Serpins

inhibitory|

* Alpha 1-antichymotrypsin
* Alpha 1-antitrypsin
* Alpha 2-antiplasmin
* Antithrombin
* C1-inhibitor
* CU-2010 and CU-2020
* Heparin cofactor II
* Protein C inhibitor
* Plasminogen activator inhibitor-1
* Plasminogen activator inhibitor-2
* Protein Z-related protease inhibitor

* SERPINA1
* SERPINA2
* SERPINA3
* SERPINA4
* SERPINA5
* SERPINA9
* SERPINA14

* SERPINB1
* SERPINB2
* SERPINB3
* SERPINB4
* SERPINB5
* SERPINB6
* SERPINB7
* SERPINB8
* SERPINB9
* SERPINB10
* SERPINB13

* SERPINC1
* SERPIND1
* SERPINE1
* SERPINE2
* SERPINE2
* SERPINF1
* SERPING1
* SERPINH1
* SERPINI1
* SERPINI2

Cross class inhibitory|

* MENT
* SCCA-1
* CrmA

noninhibitory|

* Heat shock protein 47
* Maspin
* Ovalbumin
* Transcortin
* Thyroxine-binding globulin
* Angiotensinogen
* PEDF

see also disorders of globin and globulin proteins

* v
* t
* e

Complement system

Pathways|

* C
* L
* A

Activators/enzymes|

| Early|

* C: C1
* C1q
* C1r
* C1s
* C4
* C4a
* C4b
* C2

* L: MASP1/MASP2
* MBL

* A: Factor B
* Factor D
* Factor P/Properdin

|

Middle|

* C3
* C3a
* C3b/iC3b
* C5
* C5a
* C5b

* C3-convertase
* C5-convertase

Late|

* MAC
* C5b
* C6
* C7
* C8
* C9

Inhibitors|

* CLA: C1-inhibitor
* Decay-accelerating factor/CD59
* Factor I

* CL: C4BP

* A: Factor H

Complement receptors|

* CR1
* CR2
* CR3
* CR4
* CD11b/CD11c/CD18
* Anaphylatoxin
* C3a
* C5a

Function|

* Cytotoxicity(by MAC)
* immune adherence
* Inducing inflammation
* Opsonization

Portal:

* Medicine

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