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Antithrombin (AT) is a small protein molecule that inactivates several enzymes of the coagulation system. It 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. a-antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, ß-antithrombin.[1]
Antithrombin is also termed Antithrombin III (AT III). The designations Antithrombin I through to Antithrombin IV originate in early studies carried out in the 1950s by Seegers, Johnson and Fell.[2]
Antithrombin I (AT I) refers to the absorption of thrombin onto fibrin after thrombin has activated fibrinogen. Antithrombin II (AT II) refers to a cofactor in plasma, which together with heparin interferes with the interaction of thrombin and fibrinogen. Antithrombin III (AT III) refers to a substance in plasma which inactivates thrombin, whose activity is independent of heparin. Antithrombin IV (AT IV) refers to an antithrombin which becomes activated during and shortly after blood coagulation.[3] Only AT III and possibly AT I are medically significant. AT III is generally referred to solely as “Antithrombin” and it is Antithrombin III that is discussed in this article.
Antithrombin has a half life in blood plasma of around 3 days.[4] The normal antithrombin concentration in human blood plasma is high at approximately 0.12 mg/ml, which is equivalent to a molar concentration of 2.3 µM.[5] Antithrombin has been isolated from the plasma of a large number of species additional to humans.[6] As deduced from protein and cDNA sequencing, cow, sheep, rabbit and mouse antithrombins are all 433 amino acids in length, which is one amino acid longer than human antithrombin III. The extra amino acid is thought to occur at amino acid position 6. Cow, sheep, rabbit, mouse and human antithrombins share between 84 and 89% amino acid sequence identity.[7] Six of the amino acids form three intramolecular disulfide bonds, Cys8-Cys128, Cys21-Cys95 and Cys248-Cys430. They all have four potential N-glycosylation sites. These occur at asparagine (Asn) amino acid numbers 96, 135, 155 and 192 in humans and at similar amino acid numbers in other species. All these sites are occupied by covalently attached oligosaccharide side chains in the predominant form of human antithrombin, a-antithrombin, resulting in a molecular weight for this form of antithrombin of 58,200.[1] The potential glycosylation site at asparagine 135 is not occupied in a minor form (around 10%) of antithrombin, ß-antithrombin (see Figure 1).[8]
Recombinant antithrombins with properties similar to those of normal human antithrombin have been produced using baculovirus-infected insect cells and mammalian cell lines grown in cell culture.[9][10][11][12] These recombinant antithrombins generally have different glycosylation patterns to normal antithrombin and are typically used in antithrombin structural studies. For this reason many of the antithrombin structures stored in the protein data bank and presented in this article show variable glycosylation patterns.
Antithrombin is a serpin (serine protease inhibitor) and is thus similar in structure to most other plasma protease inhibitors, such as alpha 1-antichymotrypsin, alpha 2-antiplasmin and Heparin cofactor II.
The physiological target proteases of antithrombin are those of the contact activation pathway (formerly known as the intrinsic pathway), namely the activated forms of Factor X (Xa), Factor IX (IXa), Factor XI (XIa), Factor XII (XIIa) and Factor II (thrombin) (IIa) and also the activated form of Factor VII (VIIa) from the tissue factor pathway (formerly known as the extrinsic pathway).[15] The inhibitor also inactivates kallikrein and plasmin, also involved in blood coagulation. However it inactivates certain other serine proteases that are not involved in coagulation such as trypsin and the C1s subunit of the enzyme C1 involved in the classical complement pathway.[7][16]
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