Antithrombin III Property

storage temp. 

-20°C

Safety

HS Code 

3002120090

Hazard and Precautionary Statements (GHS)

Antithrombin III Chemical Properties,Usage,Production

Enzyme inhibitor

This human plasma serpin (MW = 50.2 kDa; CAS 9000-94-6; Abbreviation: AT), also known as human plasma-derived antithrombin, antithrombin III, ATIII, and by its trade name ATryn?, plays a central role in hemostasis, serving as the principal inhibitor of thrombin (Reaction: Fibrinogen + H2O ? Fibrin + Fibrinopeptides a and b) and Factor Xa (Reaction: Prothrombin + H2O ? Thrombin). Given that AT is one of the major naturally occurring inhibitors of coagulation, acquired or hereditary deficiencies of this protein result in excessive thrombin generation. Use of ATryn is indicated for prophylactic treatment of patients with congenital antithrombin deficiency, a disorder that is manifested by dysregulated coagulation, abnormal blood clotting, and deep vein thrombosis. (For a discussion of the likely mechanism of inhibitory action, See Serpins; also a1- Antichymotrypsin) Other Target(s): AT also inhibits Factors IXa, XIa, and XIIab, in addition to kallikrein and plasmin. Primary Mode of Inhibitory Action: Antithrombin is a liver-derived glycoprotein that neutralizes the catalytic activities of thrombin and Factor Xa by forming a complex that is rapidly removed from the circulation. It is essentially unreactive with Factor IXa in the absence of heparin (i.e., kon ≈ 10 M–1 s –1 ) but undergoes a remarkable approximately one million-fold enhancement in reactivity with this proteinase to the physiologically relevant range (i.e., kon ≈ 107 M–1 s –1 ), when activated by heparin in the presence of physiologic levels of calcium. This enhancement results from: (a) allosteric activation of antithrombin by a sequence-specific heparin pentasaccharide (300-500x enhancement), (b) allosteric activation of factor IXa by calcium ions (4-8x enhancement), and (c) heparin bridging of antithrombin and factor IXa, as augmented by calcium ions (130-1000x, depending on heparin chain length. Structural Features: Antithrombin is a 432-residue protein that contains three disulfide bonds and four canonical glycosylation sites. Exosite interactions are responsible for the unusual specificity of antithrombin and heparin for thrombin, Factor IXa, and Factor Xa, each with quite distinct substrate specificities. Antithrombin circulates in blood in two major isoforms, α and β differing in their glycosylation, a property that is linked to differences in their affinities for heparin. Kinetic studies suggest that similar induced-fit mechanisms determine pentasaccharide binding to native and latent antithrombins, and kinetic simulations support a three-step mechanism of allosteric activation of native antithrombin involving successive conformational changes. Equilibrium binding studies of pentasaccharide interactions with native and latent antithrombins and the salt dependence of these interactions suggest that each conformational change is associated with distinct spectroscopic changes and is driven by a progressively better fit of the pentasaccharide in the binding site. Use of Transgenics in Antithrombin Production: Given its complex structure, antithrombin III resisted expression by standard bacterial or yeast protocols. ATryn is thus the first-ever transgenically produced therapeutic protein and the first transgenically produced recombinant antithrombin to be approved in the U.S. ATryn is purified from the milk of a genetically modified goat, after introduction of the antithrombin III gene into the nucleus of its fertilized egg. The glycosylation profile differs from plasma-derived antithrombin, resulting in increased heparin affinity and a higher clearance rate.