Factor IX (or Christmas factor) () is one of the

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. ...

s of the

coagulation 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 o ...

system; it belongs to peptidase family S1. Deficiency of this protein causes

haemophilia B Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII defi ...

. It was discovered in 1952 after a young boy named

Stephen Christmas Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII defi ...

was found to be lacking this exact factor, leading to

haemophilia Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...

. Coagulation factor IX is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

Physiology

Factor IX is produced as a

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 active ...

, an inactive precursor. It is processed to remove the

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...

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 ...

and then cleaved by

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 Coagulation factor VII (, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade, and in humans is coded for by the gene ''F7''. It is an enzyme of the serine protease class. Once bound to tis ...

a (of the tissue factor pathway) to produce a two-chain form, where the chains are linked by a

disulfide bridge 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 ...

. When activated into factor IXa, in the presence of Ca²⁺, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the deprot ...

bond in

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. Fac ...

to form factor Xa. Factor IX is inhibited by

antithrombin Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 432-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-An ...

. 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 VII, 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 In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

s: the

Gla domain Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins wi ...

, two tandem copies of the

EGF domain The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostl ...

and a C-terminal

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...

-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, also called platelet tissue factor, factor III, or CD142, is a protein encoded by the ''F3'' gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the ...

. 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 the 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 Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...

. Several structures of 'super active' mutants have been solved, which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics

The

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 ...

for factor IX is located on the

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

(Xq27.1-q27.2) and is therefore

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 always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

: mutations in this gene affect males much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered. The F9 gene was first cloned in 1982 by Kotoku Kurachi and

Earl Davie Earl Warren Davie (October 25, 1927 - June 6, 2020) was an American biochemist. He was a professor emeritus of biochemistry at the University of Washington. Davie studied the blood proteins involved in coagulation and was among the first scientist ...

Polly Polly is a given name, most often feminine, which originated as a variant of Molly (name), Molly (a diminutive of Mary (name), Mary). Polly may also be a short form of names such as Polina (given name), Polina, Polona (given name), Polona, Paula (g ...

, a transgenic cloned

Poll Dorset The Poll Dorset, a short-wool, meat-producing sheep, 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 bre ...

sheep carrying the gene for factor IX, was produced by Dr

Ian Wilmut Sir Ian Wilmut, OBE FRS -- FMedSci FRSE (born 7 July 1944) is an English embryologist and Chair of the Scottish Centre for Regenerative Medicine at the University of Edinburgh. He is best known as the leader of the research group that in 19 ...

at the

Roslin Institute The Roslin Institute is an animal sciences research institute at Easter Bush, Midlothian, Scotland, part of the University of Edinburgh, and is funded by the Biotechnology and Biological Sciences Research Council. It is best known for creati ...

in 1997.

Role in disease

Deficiency of factor IX causes Christmas disease (

hemophilia B Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII defi ...

). Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine. Recombinant factor IX is used to treat Christmas disease. Formulations include: * nonacog alfa (brand name BeneFix) * albutrepenonacog alfa (brand name Idelvion) * eftrenonacog alfa (brand name Alprolix) * nonacog beta pegol (brand name Refixia) 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 (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

. This

gain of function Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host r ...

mutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia. 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 (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken eith ...

may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding. A list of all the mutations in Factor IX is compiled and maintained by EAHAD. Coagulation factor IX is on the

References

External links

* * * * * *
GeneReviews/NCBI/NIH/UW entry on Hemophilia B
* 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 ...