C1-inhibitor (C1-inh, C1 esterase inhibitor) is a
protease inhibitor belonging to the
serpin
Serpins are a Protein superfamily, superfamily of proteins with similar structures that were first identified for their Protease inhibitor (biology), protease inhibition activity and are found in all kingdom (biology), kingdoms of life. The acr ...
superfamily. Its main function is the inhibition of the
complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
to prevent spontaneous activation but also as the major regulator of the contact system.
C1-inhibitor is an
acute-phase protein
Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute-p ...
that circulates in
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
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
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...
, 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
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
structure. The
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
serpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. The
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
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
Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...
, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated.
Genetics
The human C1-inhibitor
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
(''SERPING1'') is located on the eleventh
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
(11q11-q13.1).
Role in disease
Deficiency of this protein is associated with
hereditary angioedema
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomitin ...
("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
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and ...
. 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 disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s, most markedly
lupus erythematosus
Lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blo ...
, 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
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
.
At least 97 disease-causing mutations in this gene have been discovered.
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
Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts o ...
(DIC).
Medical use
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. 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
Icatibant, sold under the brand name Firazyr, is a medication for the symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase-inhibitor deficiency. It is not effective in angioedema caused by medication f ...
.
Other products also have been introduced including plasma-derived products such as Berinert and Haegarda.
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
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
, for instance, the lack of oxygen in heart cells causes
necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
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
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' (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.
This form of recombinant C1-inhibitor also has been given
orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
status for delayed graft function following organ transplantation and for capillary leakage syndrome.
References
Further reading
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External links
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* The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...
online database for peptidases and their inhibitors
I04.024*
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{{DEFAULTSORT:C1-Inhibitor
Complement system
Serine protease inhibitors
Takeda Pharmaceutical Company brands