Arachidonic acid, biosynthesis

Arachidonic acid biosynthesis does not occur in all cell types in the mammals body. Neurons, for instance, can neither elongate nor desaturate linoleic acid and must rely therefore on other cells for their supply of free arachidonate. What type of cells Three complementary sources have been identified hepatocytes, which 

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DEC also possesses action on the neuromuscular system of the parasites. Thus the killing of the microfilariae of O.volvulus by DEC may be a sequel of neuromuscular inhibition and "host reaction" against the parasite [121]. Recently Agrawal et al. [122] have shown that DEC is a potent inhibitor of ATPase of S. cervi in vitro. Liu and Weller [123] believe that the action of DEC may be due to the ability of the drug to inhibit arachidonic acid biosynthesis in the filariids. 

Narce, M., Mimouni, V., and Poisson, J.-P. (1992) Effect of Sodium Loading (3% NaCl) on Arachidonic Acid Biosynthesis in Rat Liver Microsomes, Prostag. Leukote. Ess. 47,193-197. 

This is the biosynthesis of arachidonic acid, biosynthesis of unsaturated fatty acids 18 ... 

Arachidonic acid, biosynthesis, VIII, 63 deficiency, effect on skin, VI, 139 fat deficiency syndrome and, VIII, 59, 61... 

Compounds 57, 58, 60, and the mixture 61/62, tested at a concentration of 3.0pg/mL, were shown to inhibit (33-41%) a-hydroxysteroid-dehydrogenase (3a-HSD), the enzyme involved in the arachidonic acid biosynthesis [264],... 

Fig. 2.1. Biosynthesis of arachidonic acid from linoleic acid in animal tissues. Linoleic acid (short-hand designation, 18 2 derived from the diet, is converted to ylinolenic acid (18 3 by a desaturase activity (D). Two subsequent steps of elongation (E) and desaturation are necessary to complete arachidonic acid biosynthesis.

Prostaglandins arise from unsaturated C20 carboxylic acids such as arachidonic acid (see Table 26 1) Mammals cannot biosynthesize arachidonic acid directly They obtain Imoleic acid (Table 26 1) from vegetable oils m their diet and extend the car bon chain of Imoleic acid from 18 to 20 carbons while introducing two more double bonds Lmoleic acid is said to be an essential fatty acid, forming part of the dietary requirement of mammals Animals fed on diets that are deficient m Imoleic acid grow poorly and suffer a number of other disorders some of which are reversed on feed mg them vegetable oils rich m Imoleic acid and other polyunsaturated fatty acids One function of these substances is to provide the raw materials for prostaglandin biosynthesis... 

Studies of the biosynthesis of PGE2 from arachidonic acid have shown that all three oxygens come from O2 The enzyme involved prostaglandin endoperoxide syn tliase has cyclooxygenase (COX) activity and catalyzes the reaction of arachidonic acids with O2 to give an endoperoxide (PGG2)... 

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. 

The first step in the biosynthesis of eicosanoids from arachidonic acid is generally a lipoxygenation reaction. The resulting hydroperoxides (HPETE s) can undergo reduction to the corresponding alcohols (HETE s). Preparative routes to the 5-, 11-, and 15-HETE s and HPETE s have been developed as oudine below. 

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages. Newer drugs are designed to either inhibit the enzyme 5-lipoxygenase, which acts on arachidonic acid in the first stage of leukotriene biosynthesis, or to block leukotriene receptors. 

All prostaglandins are cyclopentanoic acids derived from arachidonic acid. The biosynthesis of prostaglandins is initiated by an enzyme associated with the endoplasmic reticulum, called prostaglandin endoperoxide synthase, also known as cyclooxygenase. The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic acid. The enzyme is viewed as having two distinct activities, cyclooxygenase and peroxidase, as shown in Figure 25.28. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Figure 7.9 Pathway for the biosynthesis of prostaglandins from arachidonic acid. Steps 2 and 5 are radical addition reactions to 02 steps 3 and 4 are radical additions to carbon-carbon double bonds.

CYP8A1 is the complementary enzyme to CYP5 in that it synthesizes prostacyclin in the arachidonic acid cascade. CYP8B1 catalyzes the steroid 12-alpha hydroxylation in the cholic acid biosynthesis. 

Scheme 5. Proposed biosynthesis of allene oxide 64 from 8i -lipoxygenase initiated metabolism of arachidonic acid and subsequent non-enzymatic transformations to racemic cyclopenteone 30 [86]...

Scheme 6. Proposed biosynthesis of preelavulone A (30) and prostaglandin A2 (41) from arachidonic acid, modified from Corey and coworkers [57]...

Additional hypotheses concerning prostaglandin biosynthesis in P. homomalla resulted from isolation of 11R-HETE (76) from the polar lipid fraction [95]. Apparently, 11R-HETE (76) is also a minor product of incubations of arachidonic acid with acetone powder preparations of P. homomalla [95], In this alternate hypothesis (Scheme 8), an 11-hydroxy or 11-hydroperoxy-8,9-allene oxide intermediate is formed from a sequence of oxidations at C8 and Cll. Opening of the allene oxide to a transient C8 earboeation induces eycli-zation with a consequent addition of water to C15. This proposed pathway leads initially to formation of PGE2 (16 or 38), which following acetylation, elimination of acetic acid from Cl 1-12, and esterification, forms the observed major natural product in the coral, 15-acetoxy methyl PGA2 (36 or 54). Notably, if... 

Hawkins and Brash investigated some aspects of the biosynthesis of 11R-and 12R-HETE in eggs of S. purpuratus [192,194]. Based on experiments using octadeuterio-AA they showed that the 11- or 12-keto intermediate is not involved. Isolation and characterization of both HR- and 12R- hydro-peroxyeicosatetraenoic acids from incubations of desalted ammonium sulfate fractions of the egg homogenate with arachidonic acid support involvement of a lipoxygenase. 

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