Thrombin protease activated

Ghosal A, Lu X, Penner N, Gao L, Ramanathan R, Chowdhury SK, Kishnani NS, Alton KB (2011) Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos 39 30-38... 

Protease-activated receptors, PAR-1, PAR-2, PAR-3, PAR-4 Thrombin receptors Thrombin-related receptors, Trypsin receptor... 

The protease activated receptors PAR-1 to PARA, of which PAR-1 is the thrombin receptor and PAR-2 conceivably a Factor-VIIa receptor, are particularly interesting cases. The ligands for these receptors are part of the N-terminal extension of the receptor. The enzyme (for example, thrombin) will bind and cleave off most of this extracellular segment and thereby reveal a new,... 

Thrombin, Inflammation, and Protease-Activated Inhibitor Receptors... 

The protease-activated receptors (PARs), a subclass of GPCRs that function in the coagulation cascade, suggest that a comprehensive survey of the GPCR portion of the proteome provides information about the structure and function of this receptor class. The PAR factor II (thrombin) receptor-like 2 (F2RL2) is inactive in the cascade until proteolytic cleavage of its extracellular amino terminus. A Phe240Ser variant that is located in the second intracellular loop, found at a frequency of approx. 8%, disrupts receptor activation by proteolysis. 

Thrombin, a serine protease, cleaves fibrinogen into fibrin to create a fibrous plug and also amplifies its own production through the activation of factor XI and cofactors V and Vlll. Thrombin also plays a crucial role in the activation of platelets through the cleavage of the protease-activated receptors on the platelet surface. Antagonists of G-protein-coupled protease-activated receptor PARi have been synthesised to study the role of thrombin PARi receptor in thrombosis and vascular injury. Thrombosis is the most common cause of death in the industrialised world and, whether through venous thromboembolism, myocardial infarction or stroke, ultimately involves the inappropriate activity of... 

Heparin binds to antithrombin III and induces a conformational change that accelerates the interaction of antithrombin III with the coagulation factors. Heparin also catalyzes the inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent the formation of free thrombin than are needed to inhibit the protease activity of clot-bound thrombin. Inhibition of free thrombin is the basis of low-dose prophylactic therapy. 

Activation of receptors can also be mediated by proteolytic cleavage of the extracellular domain of the receptor by proteases like thrombin. For these protease activated receptors, a proteolytically produced peptide functions as the activating ligand. 

McLaughlin, J. N., Shen, L., Holinstat, M., Brooks, J. D., Dibenedetto, E., and Hamm, H. E. (2005). Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. / Biol. Chem. 280, 25048-25059. 

A THEORETICAL MODEL OF THE HUMAN THROMBIN RECEPTOR (PAR-1), THE FIRST KNOWN PROTEASE-ACTIVATED G-PROTEIN-COUPLED RECEPTOR... 

Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000 407 258-264. 

Thrombin and collagen are the strongest platelet agonists. Thrombin signaling is mediated by a family of G protein-coupled receptors, termed protease-activated receptors (PARs). Four PARs have been identified (PAR-1 through PAR-4) PAR-1, PAR-3, and PAR-4 are thrombin receptors (18). PAR-2 can be activated by trypsin and tryptase, but not by thrombin (19). 

Ishihara H, Connolly AJ, Zeng D, et al, Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997 386 502-506. 

A schematic of the structure of the thrombin molecule is presented in Figure 2. The important binding sites on the surface of the thrombin molecule include the catalytic site and two exosites (anionic and apolar) or substrate recognition sites. Whereas the catalytic site is responsible for the serine protease activity, the separate substrate recognition sites are involved in the binding of heparin, fibrinogen, and thrombomodulin (6). These sites serve as targets for the direct thrombin inhibitors,... 

Dorsam RT Tuluc M, Kunapuli SR Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb FHaemost 2004 2 804-812. 

Trypsin is typically considered an enzyme found in the pancreas and small intestine. However, trypsin, thrombin, and plasmin are also widely expressed in endothelium, including epithelial immune cells as well as neurons. Upregulated expression and release occurs during both acute and chronic inflammation [60], Autocrine release of trypsin and thrombin causes activation of protease-activated receptors (PARs) reaction leading to cellular proliferation and inflammation [4], This response includes release of proteins by all cells during chronic inflammation. Bik prevents PAR activation on cell surfaces. 

Rohatgi T, Sedehizade F, Reymann KG, Reiser G. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection Thrombin as signaling molecule in the brain. Neuroscientist 2004 10 501-512. 

Figure 15. 3- and 4-point multiple pharmacophore overlaps for the thrombin ligand MQPA and the serine protease active-site derived pharmacophores the left-side arrow indicates the incorrect indication of factor Xa selectivity from the 3-point figures, and the right-side arrow the observed activity and the increased resolution of selectivity using the 4-point relative pharmacophores. 

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