Arachidonic acid prostanoids from

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. 

Figure 6.2. The biosynthesis of prostanoids from arachidonic acid. Free arachidonic acid is converted to the unstable intermediates PGG, and PGH, by cyclooxygenase (COX) enzymes. PGH, is then converted to the five primary prostanoids by specific synthases.

Synthesis of prostanoids from arachidonic acid. Both activities reside in one enzyme. 

Korbecki, J., I. Baranowska-Bosiacka et al. 2013. The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid. J Physiol Pharmacol 64(4) 409-421. 

Fig. 9.2 Biosynthetic pathways of the synthesis of prostanoids from arachidonic acid by isoenzymes COX-1 and COX-2 catalysis...

Table 1. Physical Properties of Selected Prostanoids Derived from Arachidonic Acid...

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. 

Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin) LT, leukotriene NSAID, nonsteroidal... 

LEUKOTRIENE RECEPTOR AGONISTS act at receptors recognizing leukotrienes and analogues. The lipoxygenase system forms the leukotrienes, which are members of the eicosanoid family of phospholipid mediators. Their name derives from the fact that leukotrienes are found in leucocytes and contain a triene system of double bonds. The other members of the eicosanoid family are the prostanoids (thromboxanes and the prostaglandins), and these are formed by the cyclooxygenase system see cyclooxygenase INHIBITORS. All the eicosanoids are derived mainly from arachidonic acid. These mediators are synthesized on demand, and in some cases their half-lives are short. The... 

While microsomal co-hydroxylation is not believed to represent a major pathway for hepatic fatty acid catabolism under normal physiological conditions, this highly inducible pathway may become important under certain conditions such as fasting or exposure to peroxisome proliferators. In addition to FA catabolism, the cytochrome P450 4As (CYP4As) involved in this pathway catabolize leukotrienes and prostanoids and also generate bioactive molecules from arachidonic acid co-hydroxylation. 

One of the key functional roles of PUFA is as precursors to eicosanoids. Eicosanoids are a family of bioactive mediators that are oxygenated derivatives of the 20-carbon PUFA dihomo-y-linolenic, arachidonic and eicosapentaenoic acids. Eicosanoids include prostaglandins (PG) and thromboxanes (TX), which together are termed prostanoids, and leukotrienes (LT), lipoxins (LX), hydroperoxyeicosatetraenoic acids (HPETE) and hydroxyeicosatetraenoic acids (HETE). In most conditions the principal precursor for these compounds is arachidonic acid, and the eicosanoids produced from arachidonic acid sometimes have more potent biological functions than those released from dihomo-y-linolenic or eicosapentaenoic acids. The precursor PUFA is released from membrane diacylglycerophospholipids by the action of phospholipase A or from membrane phosphatidylinositol-4,5-bisphosphate by the actions of phospholipase C and a diacylglycerol (DAG) lipase (Figure 7). 

Dihomo-y-linolenic acid competes with arachidonic acid for COX and therefore decreases the production of COX products from arachidonic acid, while favouring the production of the 1-series PG and TX for which it is the precursor (e.g. PGEj and TXA there is no PGI analogue formed from dihomo-y-linolenic acid). The prostanoids generated from dihomo-y-linolenic acid have different (less potent) functional properties from those generated from arachidonic acid (see Horrobin, 1990). Dihomo-y-linolenic acid is converted by 15-LOX to form 15-hydroxy-dihomo-y-linolenic acid, which can inhibit 5-LOX activity. 

The number of double bonds in the alkyl chains of all the prostanoids depends on the precursor fatty acid prostanoids of the 1-series (carrying one double bond) derive from dihomo-y-linolenic acid (20 3 -6), the 2-series (carrying two double bonds) from arachidonic acid (20 4 -6), and the 3-series (carrying three double bonds) from eicosapentaenoic acid (20 5n-3). Figure 2 gives the structures of prostaglandins E and F of all three series and their precursor polyunsaturated fatty acids. 

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). 

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoid preclavulone-A via 8-(i )-hydroperoxy-5,l 1,14(Z), 9(A)-cicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

A summary of the processes for producing the eicosanoids from the polyunsaturated fatty acid, arachidonic acid, is presented in Figure 11.27. The two enzymes separate for synthesising the prostanoids or the leucotrienes are cyclooxygenase and lipoxygenase, respectively. Whether prostanoids or leucotrienes are produced in any given tissue will depend on the relative activities of these two enzymes in that tissue. 

Certain polyunsaturated fatty acids are essential in the human diet (see Box 21-B). One of these, arachidonic acid (which may be formed from dietary linoleic acid), serves as a precursor for the formation of the hormones known as prostaglandins and a series of related prostanoids. Lipids of animal origin also... 

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