C1-inhibitor

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C1-inhibitor
C1-inhibitor
Identifiers
Symbol	SERPING1
HUGO	1228
Entrez	710
OMIM	606860
RefSeq	NM_000062
UniProt	P05155
PDB	1M6Q
Other data
Locus	Chr. 11 q12-q13.1

C1-inhibitor (C1inh) is a serine protease inhibitor (serpin) protein, the main function of which is inhibition of the complement system. It circulates in blood at levels of around 0.25-0.45 g/l.

1 Proteomics
2 Genetics
3 Role in disease
4 Therapeutic use
5 References
6 External links

[edit] Proteomics

C1inh is the largest member of the serpin class of proteins (G1). It is probably the highest glycosylated protein. Remarkably, it has O-glycosylated residues, which is uncommon for proteins that are not membrane-bound (the immunoglobulins IgA1 and IgD are other examples). Especially a certain section of the protein, the 'tail', is highly glycosylated.

[edit] Genetics

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

[edit] Role in disease

Deficiency of this protein is associated with hereditary angioedema (or "angioneurotic edema"), which in layman's terms means swelling of the blood vessels. Most commonly, 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 C1inh 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.

[edit] Therapeutic use

[edit] In hereditary angioedema

Patients with frequent attacks of angioedema may be administered prophylactic C1-inhibitor. It may also shorten the duration or decrease the severity of attacks.

[edit] 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^[1]. 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.

[edit] Production

C1-inhibitor is contained in the human blood; it can therefore be isolated from donated blood. Concentrations in human blood are relativelely low, however, and C1-inhibitor from other species may cause immune reactions. It is also impossible to produce it by recombinant technology, as Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inh is particularly heavily glycosylated, this recombinant form would be ineffective. However, it is possible to produce highly functional glycosylated proteins using a transgenic mammalian system. Pharming Group NV has done this for recombinant human C1 inhibitor and this product is in Phase III clinical trials for acute attacks of hereditary angioedema. [1]. Pharming's recombinant C1 inhibitor also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome [2].

[edit] References

^ 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. Pharmacol Rev 2000;52:91-112. PMID 10699156