Factor IX
Encyclopedia
Factor IX is one of the serine protease
s of the coagulation
system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B
. It was discovered in 1952 after a young boy named Stephen Christmas
was found to be lacking this exact factor, leading to hemophilia.
Factor IX is produced as a zymogen
, an inactive precursor. It is processed to remove the signal peptide
, glycosylated
and then cleaved by factor XI
a (of the contact pathway) or factor VII
a (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine
-isoleucine
bond in factor X
to form factor Xa.
Factor IX is inhibited by antithrombin
.
Factor IX expression increases with age in humans and mice. In mouse
models mutations within the promoter region of factor IX have an
age-dependent phenotype.
, IX, and X
all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domain
s. These are the Gla domain
, two tandem copies of the EGF domain
and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
The N-terminal EGF domain has been shown to at least in part be responsible for binding Tissue factor
. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the Factor X activating complex.
The structures of all four domains have been solved. A structure of the two EGF domains and trypsin like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR
.
for factor IX is located on the X chromosome
(Xq27.1-q27.2) and is therefore X-linked recessive
: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.
Polly
, a transgenic cloned Poll Dorset
sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut
at the Roslin Institute in 1997.
factor IX is used to treat Christmas disease, and is commercially available as BeneFIX.
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis
.
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid
may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
s of the coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B
Haemophilia B
Haemophilia B is a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX. It is the second most common form of haemophilia, rarer than haemophilia A. It is sometimes called Christmas disease after Stephen Christmas, the first patient described...
. It was discovered in 1952 after a young boy named Stephen Christmas
Stephen Christmas
Stephen Christmas was the first patient described to have Christmas disease in 1952 by a group of British doctors.-Biography:...
was found to be lacking this exact factor, leading to hemophilia.
Physiology
Zymogen
A zymogen is an inactive enzyme precursor. A zymogen requires a biochemical change for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it...
, an inactive precursor. It is processed to remove the signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
, 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...
and then cleaved by factor XI
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 encoded by the F11 gene....
a (of the contact pathway) or factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
a (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
bond in factor X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
to form factor Xa.
Factor IX is inhibited by antithrombin
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...
.
Factor IX expression increases with age in humans and mice. In mouse
models mutations within the promoter region of factor IX have an
age-dependent phenotype.
Domain architecture
Factors VIIFactor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
, IX, and X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domain
Protein 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...
s. These are the Gla domain
Gla domain
Vitamin K-dependent carboxylation/gamma-carboxyglutamic domain is a protein domain that contains post-translational modifications ofmany glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate . The Gla residues are responsible for the high-affinity binding of...
, two tandem copies of the EGF domain
EGF-like domain
EGF-like domain is an evolutionary conserved protein domain, of about thirty to forty amino-acid residues long, which was found in a large number of mostly animal proteins. All these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted...
and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
The N-terminal EGF domain has been shown to at least in part be responsible for binding Tissue factor
Tissue factor
Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin...
. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the Factor X activating complex.
The structures of all four domains have been solved. A structure of the two EGF domains and trypsin like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
.
Genetics
The 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...
for factor IX is located on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
(Xq27.1-q27.2) and is therefore X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.
Polly
Polly and Molly
Polly and Molly , two ewes, were the first mammals to have been successfully cloned from an adult somatic cell and to be transgenic animals at the same time. This is not to be confused with Dolly the Sheep which was the first animal to be successfully cloned from an adult somatic cell where there...
, a transgenic cloned Poll Dorset
Poll Dorset
The Poll Dorset is a short wool, meat producing sheep that was developed in Australia between 1937 and 1954 with the aim of breeding a true Dorset type sheep without horns. The poll gene was introduced into Dorset Horn flocks from two other polled breeds and following a strict back-mating programme...
sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut
Ian Wilmut
Sir Ian Wilmut, OBE FRS FMedSci FRSE is an English embryologist and is currently Director of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. He is best known as the leader of the research group that in 1996 first cloned a mammal from an adult somatic...
at the Roslin Institute in 1997.
Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B). Over 100 mutations of factor IX have been described; some cause no symptoms, but many lead to a significant bleeding disorder. RecombinantRecombinant 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...
factor IX is used to treat Christmas disease, and is commercially available as BeneFIX.
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
.
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid
Tranexamic acid
Tranexamic acid is a drug used to treat or prevent excessive blood loss during surgery and in certain other conditions...
may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.
External links
- GeneReviews/NCBI/NIH/UW entry on Hemophilia B
- 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: S01.214