Factor XIII or fibrin stabilizing factor is 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 acti ...

found 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 th ...

of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

of the blood coagulation system that crosslinks

fibrin Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pla ...

. Deficiency of XIII worsens clot stability and increases bleeding tendency. Human XIII is a

heterotetramer A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer c ...

. It consists of 2 enzymatic A peptides and 2 non-enzymatic B peptides. XIIIa is a dimer of activated A peptides.

Function

Within blood, thrombins cleave

fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...

s to fibrins during coagulation and a fibrin-based blood clot forms. Factor XIII is a transglutaminase that circulates in human blood as a

of two A and two B subunits. Factor XIII binds to the clot via their B units. In the presence of fibrins, thrombin efficiently cleaves the R37– G38

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 ( nitrogen number two) of another, along a peptide or protein c ...

of each A unit within a XIII tetramer. A units release their N-terminal activation

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s. Both of the non- covalently bound B units are now able to dissociate from the tetramer with the help of

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...

ions (Ca²⁺) in the blood; these ions also activate the remaining dimer of two A units via a conformational change. Factor XIIIa (dimer of two active A units) crosslinks fibrins within the clot by forming isopeptide bonds between various

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

s and

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated &minu ...

s of the fibrins. These bonds make the clot physically more durable and protect it from premature enzymatic degradation ( fibrinolysis). In humans, plasmin, antithrombin and TFPI are the most relevant proteolytic inhibitors of the active factor XIIIa. α2-macroglobulin is a significant non-proteolytic inhibitor. Factor XIII activation via thrombin.svg, Activation peptides (pink) of A units are removed by thrombin (IIa) in the presence of fibrin. B units (gray) are released with the help of calcium and A unit dimer is activated (XIIIa forms). Stabilisation de la fibrine par le factor XIII.png, XIIIa crosslinks fibrin (simplified picture)

Genetics

Human factor XIII consist of A and B subunits. A subunit

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 ...

is '' F13A1''. It is on the chromosome 6 at the position 6p24–25. It spans over 160 kbp, has 14

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

s and 15

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...

s. Its

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

is 3.9 kbp. It has a 5' UTR of 84 bp and a 3' UTR of 1.6 kbp. ''F13A1'' exon(s) *1 code 5' UTR *2 code activation peptide *2–4 code β-sandwich *4–12 code

catalytic domain In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate ( binding si ...

*12–13 code

β-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...

1 *13–15 code β-barrel 2 B subunit gene is '' F13B''. It is on the

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, whi ...

at the position 1q31–32.1. It spans 28 kpb, has 11 introns and 12 exons. Its mRNA is 2.2 kbp. Exon 1 codes 5' UTR. Exons 2–12 code the 10 different sushi domains.

Structure

Factor XIII of human blood is a

of two A and two B linear polypeptides or "units". A units are potentially catalytic; B units are not. A units form a dimeric center. Non- covalently bound B units form a ring-like structure around the center. B units are removed when XIII is activated to XIIIa. Dimers containing only A units also occur within cells such as

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

s. Large quantities of singular B units (monomers) also occur within blood. These dimers and monomers are not known to participate in coagulation, whereas the tetramers do. A units have a mass of about 83 kDa, 731

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

residues, 5

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 o ...

s (listed from the N-terminal to

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 ...

, residue numbers are in brackets): *activation peptide (1–37) * β-sandwich (38–184) *

(185–515), in which the residues C314, H373, D396 and W279 partake in catalysis *

1 (516–628) *β-barrel 2 (629–731) B units are

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...

s. Each has a mass of about 80 kDa (8.5% of the mass is from

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ...

s), 641 residues and 10 sushi domains. Each domain has about 60 residues and 2 internal disulfide bonds.

Physiology

A subunits of human factor XIII are made primarily by

s and other cells of

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoieti ...

origin. B subunits are secreted into blood by

hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

s. A and B units combine within blood to form heterotetramers of two A units and two B units.

Blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the ...

concentration of the heterotetramers is 14–48 mg/L and

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

is 9–14 days. A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

, while a stabilized clot is resistant to this phenomenon.

Factor XIII deficiency

Deficiency of Factor XIII (FXIIID), while generally rare, does occur, with

Iran Iran, officially the Islamic Republic of Iran, and also called Persia, is a country located in Western Asia. It is bordered by Iraq and Turkey to the west, by Azerbaijan and Armenia to the northwest, by the Caspian Sea and Turkm ...

having the highest global incidence of the disorder with 473 cases. The city of

Khash Khash may refer to: * Khash (dish), South Caucasian dish * Khash Rod District, a district in Nimruz Province, Afghanistan ** Khash, Nimruz, capital of Khash Rod District, Afghanistan *Khash District, a district in Badakhshan Province, Afghanistan ...

, located in

Sistan Sistān ( fa, سیستان), known in ancient times as Sakastān ( fa, سَكاستان, "the land of the Saka"), is a historical and geographical region in present-day Eastern Iran ( Sistan and Baluchestan Province) and Southern Afghanistan ...

and

Balochistan Balochistan ( ; bal, بلۏچستان; also romanised as Baluchistan and Baluchestan) is a historical region in Western and South Asia, located in the Iranian plateau's far southeast and bordering the Indian Plate and the Arabian Sea coastl ...

provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage.

Diagnostic use

Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

s and macrophages, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells.

Discovery

Factor XIII Deficiency is also known as Laki–Lorand factor, after Kalman Laki and

Laszlo Lorand Laszlo Lorand (23 March 1923 – 6 December 2018) was a Hungarian-American biochemist who studied clotting of blood and other bodily fluids. A professor emeritus in cell and molecular biology at the Feinberg School of Medicine, Lorand was a longt ...

, the scientists who first proposed its existence in 1948. A 2005 conference recommended standardization of nomenclature.

References

External links

Factor XIII deficiency at hemophilia.org
* {{Authority control Coagulation system EC 2.3.2 Zymogens