Thromboxanes, from arachidonic

NSAIDs are drugs related to acetyls alley lie acid which inhibit cyclooxygenase (COX), the enzyme in the synthesis of PGs and thromboxanes from arachidonic acid. There are two isoforms of cyclooxygenase, COX-1 and COX-2 [121].The former is constitutively expressed in blood vessels, stomach and kidney, while COX-2 is normally not present at these sites. It can,... 

Thiophene, dioxirane oxidation, 1156 Thiourea, dialkyl peroxide synthesis, 706 1,4-Thioxane, oxidation, 805-6 Thiyl radicals, triplet oxygen domino reactions, 221-3, 224, 225, 226 THPO (1,2,3,4-tetrahydronaphthyl hydroperoxide), 331-2 Thromboxanes, from arachidonic hydroperoxides, 612... 

Overview of the biosynthesis and function of some important prostaglandins, leukotrienes, and a thromboxane from arachidonic acid. 

NSAID-Assodated Ulcer. NSAIDs inhibit the production of prostaglandins, prostacyclins, and thromboxanes from arachidonic acid by covalently modifying the enzyme cyclooxygenase (COX) and irreversibly inhibiting the ability of arachidonic acid to bind to the active site on the enzyme. Chronic administration of NSAIDs has been linked to ulcer disease, although there is no evidence that they are the direct cause of ulcer formation. In patients already diagnosed with ulcer disease, chronic administration of NSAIDs was associated with a fourfold increase in the risk of ul-... 

Cyclooxygenases. Figure 1 Pathways for the formation of prostanoids from arachidonic acid. Arachidonic acid is converted by cyclooxygenase to endoperoxides, which are acted upon by various synthesases to form the prostanoids. Prostacyclin and thromboxane are relatively unstable and break down rapidly to form the inactive metabolites 6-oxo-PGF1a and thromboxane B2, respectively. 

Another vasoactive substance produced by the endothelium is thromboxane A2 (TxA2). Normally, small amounts of TxA2 are released continuously however, increased synthesis appears to be associated with some cardiac diseases. Synthesized from arachidonic acid, a plasma membrane phospholipid, TxA2 is a potent vasoconstrictor. Furthermore, this substance stimulates platelet aggregation, suggesting that it plays a role in thrombotic events such as myocardial infarction (heart attack). Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen block formation of TxA2 and reduce formation of blood clots. 

Fatty acid derivatives include a large and diverse group of compounds named eicosanoids, which includes thromboxanes, prostaglandins and leukotrienes, all of which are biochemically derived from arachidonic acid (a long-chain polyunsaturated fatty acid). 

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). 

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. 

Figure 3 Simple schema of the biosynthesis of prostaglandins (PG), thromboxanes (TX), and leukotrienes from arachidonic acid consequent to cell injury (modified after Bonica, 1990).

The thromboxanes have a six-membered ring containing an ether. They are produced by platelets (also called thrombocytes) and act in the formation of blood clots and the reduction of blood flow to the site of a clot. The nonsteroidal antiinflammatory drugs (NSAIDs)— aspirin, ibuprofen, and meclofenamate, for example— were shown by John Vane to inhibit the enzyme prostaglandin H2 synthase (also called cyclooxygenase or COX), which catalyzes an early step in the pathway from arachidonate to prostaglandins and thromboxanes (Fig. 10-18 see also Box 21-2). 

Prostaglandins, thromboxanes, and leukotrienes (the eicosanoids), derived from arachidonate, are extremely potent hormones. 

Thromboxanes, like prostaglandins, contain a ring of five or six atoms the pathway from arachidonate to these two classes of compounds is sometimes called the cyclic pathway, to distinguish it from the linear pathway that leads from arachidonate to the leukotrienes, which are linear compounds (Fig. 21-16). Leukotriene synthesis begins with the action of several lipoxygenases that catalyze the incorporation of molecular oxygen into arachidonate. These enzymes, found in leukocytes and in heart, brain, lung, and spleen, are mixed-function oxidases that use cytochrome P-450 (Box 21-1). The various leukotrienes differ in the position of the peroxide... 

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... 

Unlike the hormones described above, they are not synthesized in advance and stored they are produced, when needed, from arachidonate enzymatically released from membrane phospholipids by phospholipase A2 (see Fig. 10-18). The enzymes of the pathway leading to prostaglandins and thromboxanes (see Fig. 21-15) are very widely distributed in mammalian tissues most cells... 

Prostaglandins Prostaglandins and the other eicosanoids (prostacyclins, thromboxanes and leukotrienes) are derived from arachidonate. These compounds all act as local hormones. Aspirin reduces inflammation by inhibiting prostaglandin synthase, the enzyme that catalyzes the first step in prostaglandin synthesis. 

Figure 16.24 Major prostaglandin and leukotriene products derived from arachidonic acid via the cyclooxygenase and 5-lipooxygenase pathways. Major enzymes 1, cyclooxygenase 2, hydroperoxidase 1 + 2, prostaglandin endoperoxidase synthetase 3, thromboxane synthetase 4, prostacyclin synthetase 5, 5-lipooxygenase 6, 9-ketoisomerase 7, PGH-PGF2a reductase 8, 11-ketoisomerase 9, PGE reductase 10, PGD reductase. (Reproduced by permission from Nelson NA, Kelly RC, Johnson, RA. Prostaglandins and the arachidonic acid cascade. Chem Eng News August 30-44, 1982.)...

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