K Thrombin

N2. Nakashima, Y., Sueishi, K., and Tanaka, K Thrombin enhances production and release of tissue plasminogen activator from bovine venous endothelial cells. Fibrinolysis 2, 227-234 (1988). 

Olear T, Nouza K. Thrombin and trypsin receptors The same mechanism of signaling on cellular surfaces. Bratisl Lek Listy 1999 100 75-79. 

Huzoor-Akbar and Anwer, K. Thrombin-induced almormal platelet activation in spontaneously... 

Jones-Hertzog D K and W L Jorgensen 1997. Binding Affinities for Sulphonamide Inhibitors witl Human Thrombin Using Monte Carlo Simulations with a Linear Response Method. Journal o Medicinal Chemistry 40 1539-1549. 

Coagulation Factors II, III, VII, IX, X, XI, and Xlla fragments, thrombin, and plasmin are classified as serine proteases because each possesses a serine residue with neighboring histidine and asparagine residues at its enzymatically active site (Table 3). Factors II, VII, IX, and X, Protein C, Protein S, and Protein Z are dependent on the presence of vitamin K [84-80-0] for their formation as biologically functionally active procoagulant glycoproteins. 

Factor II. Prothrombin is a vitamin K-dependent compound synthesized by the Hver. When prothrombin is activated it is cleaved at two sites, resulting in a two-chain molecule linked by a disulfide bond that has a molecular weight of 37,000 daltons. Thrombin is the serine protease that initiates the conversion of soluble fibrinogen into fibrin. 

Protein G. This vitamin K-dependent glycoproteia serine protease zymogen is produced ia the Hver. It is an anticoagulant with species specificity (19—21). Proteia C is activated to Proteia by thrombomodulin, a proteia that resides on the surface of endothefial cells, plus thrombin ia the presence of calcium. In its active form, Proteia selectively iaactivates, by proteolytic degradation. Factors V, Va, VIII, and Villa. In this reaction the efficiency of Proteia is enhanced by complex formation with free Proteia S. la additioa, Proteia activates tissue plasminogen activator, which... 

Protein C is a vitamin K-dependent natural anticoagulant activated by thrombin to form APC in the presence of the endothelial receptor, TM. APC proteolyzes factors Va and Villa, thus downregulating thrombin generation. APC may also have anti-inflammatory... 

Ichinose A, Fujikawa K, Suyama T The activation 80 of pro-urokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986 261 3486-3489. 81... 

Activated partial thromboplastin time aPTT is performed by adding calcium phospholipids and kaolin to citrated blood and measures the time required for a fibrin clot to form. In this manner, aPTT measures the activity of intrinsic and common pathways. Prolongation of aPTT may be due to a deficiency or inhibitor for factors II, V, VIII, IX, X, XI, and XII. It also may be due to heparin, direct thrombin inhibitors, vitamin K deficiency, liver disease, or lupus anticoagulant. 

Synthetic heterocyclic and modified amino acid derivatives have been grouped in a class of thrombin inhibitors called peptidomimetics. An example of such a compound is argatroban, with a molecular mass of 532 Da. It blocks thrombin s active catalytic site by binding to the adjacent apolar binding site. This selective reversible inhibitor of thrombin has a K of 19 nM and blocks thrombin s role in coagulation and fibrinolysis (62). 

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

Von dem Borne P. A. K., Meijers J. C. M., Bouma B. N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995 86, 3035 -42. 

Nesheim M., Blackburn M. N., Lawler C. M., Mann K. G. Dependence of antithrombin III and thrombin binding stoichiometries and catalytic activity on the molecular weight of affinity purified heparin. J Biol Chem 1986 261,3214-21. 

Rydel T. J., Ravichandran K. G., Tulinsky A., et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990 249,277-80. 

Maraganore J. M., Bourdon P Jablonskj J., Ramachandran K. L. Design and characterization of hirulogs A novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990 229, 7095-101. 

Bracht F., Schror K. Isolation and identification of aptamers from defibrotide that act as thrombin antagonists in vitro. Biochem Biophys Res Commun 1994 200,933-7. 

Jones-Hertzog, D.K. Jorgensen, W.L., Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method, J. Med. Chem. 1997, 40, 1539-1549... 

Atha, D.H., Brew, S.A., and Ingham, K.C. (1964) Interactions and thermal stability of fluorescent labeled derivatives of thrombin and antithrombin III. Biochim. Biophys. Acta 785, 1. 

Pmrl Proteinase K Prothrombin fatty acids (378,379) Yeast Golgi Ca2+/Mn2+-ATPase ion pump (380,381) Peptide fragmentation enzyme (382) Thrombin precursor extracellular trigger involved in blood clotting... 

Protein C A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and Villa at the rate-limiting steps of thrombin formation. [NIH]... 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

M. Tanihara, Y. Suzuki, Y. Nishimura, K. Suzuki, Y. Kakimaru, Thrombin-Sensitive Peptide Linkers for Biological Signal-Responsive Drug Release Systems , Peptides 1998, 19, 421 -425 M. Tanihara, Y. Suzuki, Y. Nishimura, K. Suzuki, Y. Kakimaru, Y. Fukunishi, A Novel Microbial Infection-Responsive Drug Release System , J. Pharm. Sci. 1999, 88, 510-514. 

S. D., Lucas, B.J., Gardell, S.J., Lyle, E.A., Appleby, S.D., Cook, J.J., FIolahan, M.A., Stranieri, M.T., Lynch,Y J., Lin, J.H., Chen, I.W., Vastag, K., Naylor-Olsen, A.M., and Vacca, J.P. Discovery and development of the novel potent orally active thrombin inhibitor N-(9-Hydroxy-9-fluorenecarboxy)prolyl tran s -4-amin ocycl ohexylmethyl ami de (L-372,460) coapplication of structure-based design and rapid multiple analog synthesis on solid support. 

Sugano, K., Yoshida, S., Takaku, M., Haramura, M., Saitoh, R., Nabughi, Y., and Ushio, H. Quantitative structure-intestinal permeability relationship of benzamidine analogue thrombin inhibitor. Bioorg. Med. Chem. Lett. 2000, 10, 1939-1942. 

Clasby MC, Chackalamannil S, Czamiecki M, Doller D, Eagen K, Greenlee W, Kao G Lin Y, Tsai H, Xia Y, Ahn HS, Agans-Fantuzzi J, Boykow G Chintala M, Foster C, Smith-Torhan A, Alton K, Bryant M, Hsieh Y, Fan J, Palamanda J. (2007) Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 50 129-138. 

Non-peptide inhibitors of thrombin (obtained by random screening procedures) include compounds based around benzothiophene (e.g. 155) and other ring systems and cyclic and linear oligocarbamate derivatives (e.g. 156). The benzothiophene derivative 155 showed antithrombotic efficacy in a rat model of thrombosis after infusion (ED50 2.3 mg/kg/h). The cyclic oligocarbamate tetramer 156 inhibited thrombin with an apparent K[ of 31 nM. 

Substrates include benzyl (2 g) and cinnamyl (2.7 g) alcohols to acids cyclopentanol (1 g), benzhydrol (3.9 g), benzoin (4 g), pantolactone (2.6 g) to ketones (RuCy TCCA/( Bu N)Br/aq. Kj(C03)/CH3CN) (Fig. 2.14) [25] [[2-[2-hydroxypropyl) amino]-l,2-dioxoethyl]amino]acetic acid ethyl ester (6.21 kg) to [(l,2-dioxo-2-oxopropyl)amino]ethyl)amino] acetic acid ethyl ester, part of the industrial-scale synthesis of thrombin inhibitor (RuCyaq. Na(BrOj)/CH3CN) [166] (H-)-dihydroc-holesterol (8 g) to cholest-3-one (RuO /aq. K(10 )/(BTEAC)/CHCl3) [308] ... 

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