Thromboxane A synthase

THROMBOXANE A SYNTHASE THYMIDINE 2 -HYDROXYLASE THYMIDYLATE SYNTHASE TIGHT-BINDING INHIBITOR KINETICS HENDERSON PLOT Tight-binding inhibitors,... 

Golino P, Ambrosio G, Gresde P, Pascucd I, Ragni M, Russolillo E, Leproux GB, Chiaridio M. The in vivo antiplatdet effects of thromboxane A, synthase iidiibitors are potentiated by simultaneous thromboxane A2 ostaglandinH2 receptor blockade. J Pharmacol Exp Ther 1993 266 511-7... 

Yokoyama, C., A. Miyata, H. Ihara, V Ullrich, and T. Tanabe (1991). Molecular cloning of the human platelet thromboxane A synthase. Biochem. Biophys. Res. Commun. 178, 1479-1484. 

YokoyamaC, MiyataA, Ihara H, Ullrich V, Tanabe T (1991) Molecular cloning of human platelet thromboxane A synthase. Biochem Biophys Res Commun 178 1479 1484... 

Park SA, Park BL, Park JH, Lee TK, Sung KB, Lee YK, Chang HS, Park CS, Shin HD (2009) Association of polymorphisms in thromboxane A2 receptor and thromboxane A synthase 1 with cerebral infarction in a Korean population. BMB Rep 42 200-205... 

Thromboxane A synthase (TXAS) catalyses the conversion of PGH to TXAj, a potent mediator of coagulation, vasoconstriction and broncho-constriction. TXA breaks down non-enzymatically into the stable but inactive TXBj (Figure 3). Like PGIS, TXAS is a hemoprotein and member of the cytochrome P450 superfamily. It is expressed in a variety of tissues, including platelets, where its activity is clearly coupled to COX-1 (Miyata et al, 1994 Ullrich et al, 2001). 

FIGURE 21-15 The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes, (a) After arachidonate is released from phospholipids by the action of phospholipase A2/ the cyclooxygenase and peroxidase activities of COX (also called prostaglandin H2 synthase) catalyze the production of PGH2/ the precursor of other... 

In blood platelets and in some other tissues PGG is also transformed to another series of compounds, the thromboxanes,270 which were identified in 1975. Labile hemiacetals, the thromboxanes A (TXA, Fig. 21-7), are derived by rearrangement of PGH (step g). Thromboxane synthase,271-273 which catalyzes the reaction, has characteristics of a cytochrome P450. Cytochromes P450 are known to react with peroxides as well as with 02, and the endoperoxide of PGH may be opened by the synthase prior to rearrangement to TXA.273 Thromboxane A2 is so unstable that its half-life at 37°C in water is 36 s. It is spontaneously converted to TXB2 (Fig. 21-7), which contains an -OH group at C-15. The thromboxanes B are much more stable than TXA but are not very active physiologically. 

Figure 12.11. StractuiES of two thromboxane A receptor blockers (a), and of BM 573, a combined antagonist of both TXA receptor and TXA synthase (b). BM 573 was derived from the diuretic torasemide.

Prostacyclin and thromboxane-A are derived from arachidonic acid which is a constituent of cell walls, both platelet and endothelial. Cyclooxygenase (COX, PGH synthase), an enzyme present in cells at both sites, converts arachidonic acid to cyclic endoperoxides which are further metabolised by prostacyclin synthase to prostacyclin in the endotheliiun and by thromboxane synthase to thromboxane-A in platelets. Thus prostacyclin is principally... 

Cyclooxygenase 1 (COX-1) is the common name used to describe the protein prostaglandin H synthase 1 (PGHS-1), which performs both peroxidase and cyclooxygenase reactions to make PGH, the precursor to prostaglandins E, D, F2 prostacyclin, and thromboxane A, (see Fig. 5.3). Originally described as an... 

Arachidonic acid, which is stored as a cellular membrane phospholipid, is the precursor for series 2 prostaglandins. Aspir in selectively acetylates the hydroxyl group of a single serine residue at position 530 within the polypeptide chain of prostaglandin G/H synthase, the enzyme that converts arachidonate into prostaglandin cyclic endoperoxide. Aspirin thereby reduces the synthesis of the eicosanoids— prostaglandins, prostacyclin, and thromboxane A. 

INHIBITION OF PROSTAGLANDIN BIOSYNTHESIS BY NSAIDS The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as COX. This enzyme converts arachidonic acid (AA) to the unstable intermediates PGGj and PGH and leads to the production of thromboxane A (TXA ) and a variety of prostaglandins (see Chapter 25). 

Ohshima, E., Sato, H., Obase, H., Miki, I., Ishii, A., Kawakage, M., Shirakura, S., Karasawa, A. and Kubo, K. (1993) Dibenzoxepin derivatives Thromboxane A2 synthase inhibition and thromboxane A2 receptor antagonism combined in one molecule. J. Med. Chem. 36 1613-1618. 

Neri Semeri GG, Coccheri S, Marubini E, Violi F (2004) Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease the DAVID study. Eur Heart 125 1845-1852... 

---