C1-inhibitor
Encyclopedia
C1-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.
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.
(SERPING1) is located on the eleventh chromosome
(11q11-q13.1).
("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 disease
s, 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).
. Blood-derived C1-inhibitor may be more effective and does not carry the side-effects of danazol such as virilization and a risk of liver tumors, 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 was also the first C1-inhibitor approved for use in the United States
. 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. C1 inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1 inhibitor deficiency.
Recently, new methods of treating acute attacks have emerged: a plasma kallikrein inhibitor and a bradykinin receptor antagonist. A cheaper C1-inhibitor alternative - recombinant C1-inhibitor - is also in development.
, 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.
. 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.
Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins....
belonging to the serpin
Serpin
Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...
superfamily. Its main function is the inhibition of the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
at levels of around 0.25 g
Gram
The gram is a metric system unit of mass....
/L
Litér
- External links :*...
. 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
Mannan-binding lectin
Mannose-binding lectin , also named mannose- or mannan-binding protein , is an important factor in innate immunity.-Function:MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune...
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
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
, 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-domainProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
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
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated.
Genetics
The human C1-inhibitor geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(SERPING1) is located on the eleventh chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(11q11-q13.1).
Role in disease
Deficiency of this protein is associated with hereditary angioedemaHereditary angioedema
Hereditary angioedema presents in the second to fourth decade, and is characterized by local swelling in subcutaneous tissues....
("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
Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...
. 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
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s, most markedly lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, 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
Age-related macular degeneration is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults...
.
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
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
(DIC).
Classification
There are three types of C1 inhibitor deficiency:- Type I: Hereditary. Three of the four genes for C1 inhibitor are null genes, leading to low levels of C1 inhibitor.
- Type II: Hereditary. There are high levels of C1 inhibitor, but it is non-functional.
- Type III: Acquired.
In hereditary angioedema
People with frequent attacks of angioedema are often treated using attenuated androgens, such as danazolDanazol
Danazol is a derivative of the synthetic steroid ethisterone, a modified testosterone. Also known as 17alpha-ethinyl testosterone. Before becoming available as a generic drug, Danazol was marketed as Danocrine in the United States. It was approved by the U.S. Food and Drug Administration as the...
. Blood-derived C1-inhibitor may be more effective and does not carry the side-effects of danazol such as virilization and a risk of liver tumors, 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 was also the first C1-inhibitor approved for use in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. 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. C1 inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1 inhibitor deficiency.
Recently, new methods of treating acute attacks have emerged: a plasma kallikrein inhibitor and a bradykinin receptor antagonist. A cheaper C1-inhibitor alternative - recombinant C1-inhibitor - is also in development.
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 attackMyocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, for instance, the lack of oxygen in heart cells causes necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
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 bloodBlood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....
. 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
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
technology, but Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
(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.
External links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: I04.024