Factor XI
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Factor XI or plasma thromboplastin antecedent is the
zymogen In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the activ ...
form of factor XIa, one of the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s of the
coagulation cascade Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
. Like many other coagulation factors, it is a
serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...
. In humans, Factor XI is encoded by the ''F11''
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 b ...
.


Function

Factor XI (FXI) is produced by the
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
and circulates as a homo-dimer in its inactive form. The plasma half-life of FXI is approximately 52 hours. The zymogen factor is activated into ''factor XIa'' by
factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme () of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12'' gene. Struc ...
a (FXIIa),
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
, and FXIa itself; due to its activation by FXIIa, FXI is a member of the "contact pathway" (which includes HMWK,
prekallikrein Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to pr ...
,
factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme () of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12'' gene. Struc ...
, factor XI, and
factor IX Factor IX (or Christmas factor) () is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas ...
). Factor XIa activates factor IX by selectively cleaving arg-
ala Ala, ALA, Alaa or Alae may refer to: Places * Ala, Hiiu County, Estonia, a village * Ala, Valga County, Estonia, a village * Ala, Alappuzha, Kerala, India, a village * Ala, Iran, a village in Semnan Province * Ala, Gotland, Sweden * Alad, S ...
and arg- val peptide bonds. Factor IXa, in turn, forms a complex with Factor VIIIa (FIXa-FVIIIa) and activates
factor X Factor X, also known by the eponym Stuart–Prower factor, is an enzyme () of the coagulation cascade. It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis. Fa ...
. Physiological inhibitors of factor XIa include
protein Z-dependent protease inhibitor Protein Z-dependent protease inhibitor (ZPI) is a protein circulating in the blood which inhibits factors Xa and XIa of the coagulation cascade. It is a member of the class of the serine protease inhibitors (serpins). Its name implies that it re ...
(ZPI, a member of the
serine protease inhibitor Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be i ...
/serpin class of proteins), which is independent of
protein Z Protein Z (PZ or PROZ) is a Protein in humans which is encoded by the ''PROZ'' gene. Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a glycoprotein. Protein Z functi ...
(its action on factor X, however, is protein Z-dependent, hence its name).


Structure

Although synthesized as a single polypeptide chain, FXI circulates as a homodimer. Every chain has a relative molecular mass of approximately 80000. Typical plasma concentrations of FXI are 5 μg/mL, corresponding to a plasma concentration (of FXI dimers) of approximately 30 nM. The FXI gene is 23kb in length, has 15 exons, and is found on chromosome 4q32-35. Factor XI consists of four apple domains, that create a disk-like platform around the base of a fifth, catalytic
serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...
domain. One contains a binding site for
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
, another for high molecular weight kininogen, a third one for
factor IX Factor IX (or Christmas factor) () is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas ...
, heparin and
glycoprotein Ib Glycoprotein Ib (GPIb), also known as CD42, is a component of the GPIb-V-IX complex on platelets. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. It is defici ...
and the fourth is implicated in forming the factor XI homodimer, including a cysteine residue that creates a
disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. In the homodimer, the apple domains create two disk-like platforms connected together at an angle, with the catalytic domains sticking out at each side of the dimer. Activation by thrombin or
factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme () of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12'' gene. Struc ...
a is achieved by cleavage of Arg369-Ile370 peptide bonds on both subunits of the dimer. This results in a partial detachment of the catalytic domain from the disk-like apple domains, still linked to the fourth domain with a disulfide bond, but now farther from the third domain. This is thought that this exposes the factor IX binding site of the third apple domain, allowing factor XI's protease activity on it.


Role in disease

Deficiency of factor XI causes the rare
hemophilia C Haemophilia C (also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome) is a mild form of haemophilia affecting both sexes, due to factor XI deficiency. It predominantly occurs in Ashkenazi Jews. It is the fourth most ...
; this mainly occurs in Ashkenazi
Jew Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""T ...
s and is believed to affect approximately 8% of that population. Less commonly, hemophilia C can be found in Jews of Iraqi ancestry and in Israeli Arabs. The condition has been described in other populations at around 1% of cases. It is an autosomal recessive disorder. There is little spontaneous bleeding, but surgical procedures may cause excessive blood loss, and prophylaxis is required. Low levels of factor XI also occur in many other disease states, including
Noonan syndrome Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...
. High levels of factor XI have been implicated in
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
, although it is uncertain what determines these levels and how serious the procoagulant state is. Pharmacological inhibitors of factor XI that are under clinical development but not yet approved for treatment include the oral factor XIa inhibitors Asundexian (BAY 2433334) and
Milvexian Milvexian is a factor XI Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is enco ...
as well as the monoclonal anti-factor XI antibody Abelacimab (MAA868).


See also

* Contact activation pathway (also known as the ''intrinsic pathway'') *
Tissue factor pathway Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The m ...
(also known as the ''extrinsic pathway'')


References


Further reading

* * * * * * * * * * * * * * * * * * * * * *


External links

* 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 inhibit ...
online database for peptidases and their inhibitors
S01.213
{{DEFAULTSORT:Factor Xi EC 3.4.21 Coagulation system Zymogens