Synthases thromboxane

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

TXA2 is produced by activated platelets via the sequential conversion of arachidonic acid by phospholipase A2, cyclooxygenase-1 (COX-1), and thromboxane synthase. Similar to ADP, TXA2 acts as a... 

Figure 23-6. Conversion of arachidonicacid to prostaglandins and thromboxanes of series 2. (PG, prostaglandin TX, thromboxane PGI, prostacyclin HHT, hydroxyheptadecatrienoate.) (Asterisk Both of these starred activities are attributed to one enzyme prostaglandin H synthase. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.)...

Figure 17.1 Injury mosaic. PLA2, phospholipase A2 LKTs, leukotrlenes LTB4, leukotrlene B4 PGs, prostaglandins 5LO, 5-llpoxygenase NO, nitric oxide NOS, nitric oxide synthase TXs, thromboxanes.

Tienilic acid- and dihydralazine-induced hepatitis are associated with antibodies against Cyp 2C9 [53] and Cyp 1A2 [54, 55], respectively. These are also the same cytochrome P450s that are responsible for the formation of reactive metabolites of these two drags. Anticonvulsant hepatotoxicity is associated with antibodies against rodent Cyp 3 A and related human enzymes such as thromboxane synthase [56, 57], It is interesting to note that cytochromes P450 are often the target of autoantibodies in idiopathic autoimmune hepatitis [58],... 

Chevalier D, Lo-Guidice JM, Sergent E, Allorge D, Debuysere H, et al. 2001. Identification of genetic variants in the human thromboxane synthase gene (CYPSAl). Mutat Res 432 61-67. 

Two different pathways lead from arachidonate to prostaglandins, prostacyclins, and thromboxanes, on the one hand, or leuko-trienes on the other. The key enzyme for the first pathway is prostaglandin synthase [2]. Using up O2, it catalyzes in a two-step reaction the cyclization of arachidonate to prostaglandin H2, the parent substance for the prostaglandins, prostacyclins, and thromboxanes. Acetylsalicylic acid (aspirin) irreversibly ace-tylates a serine residue near the active center of prostaglandin synthase, so that access for substrates is blocked (see below). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

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

Prostanoids, which consist of prostaglandins (PCs) and thromboxanes (TXs), are biologically synthesized in the body from arachidonic acid by cyclooxygenase, PG hydroperoxydase, and a family of prostaglandin synthases (Fig. 1). They exert a variety of actions as hormones produced locally in various tissues and cells to maintain homeostasis. 

V. Ulhich, H. Graf (1984). Prostacychn and thromboxane synthase as P-450 enzymes. Trends Pharmacol. Sci. 5 352-355. 

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