Arachidonic acids

The production of ARA by microorganisms (moulds and algae) has been reviewed by Bajpai and Bajpai (1992). Its current commercial source is from animal livers and recoveries are usually only 0.2% (w/w) or even less. Alternative sources would therefore appear attractive. 

The principal research into a possible production organism and process is being conducted by two Japanese groups, one is Lion Corporation Ltd, 

Totani et al, (1992) have used Mort, alpina ATCC 32221 which, when grown in a 4-1 fermenter in a complex medium, yields over 70% ARA in its total fatty acids. The fatty acids were isolated as their methyl esters as evidently the ARA was distributed over a range of lipid types. The biomass, at 46g/l, contained 32% fatty acids. Slightly lower yields were produced in 20 and 3001 fermenters with the need for extended fermentation times of up to 16 days (Tatani et al, 1992). 

In the work sponsored by Suntory Ltd, Yamada et al, (1992) has used both the same organisms as the Lion Corporation group and also a soil isolate, Mort, alpina lS-4. The former mould has been grown to achieve the same yields as given before the latter organism was grown in a 200-1 fermenter yielding 22.5 g dry wt/1 after 10 days at 28°C. If these mycelia are then allowed to stand for a further 6 days at room temperature, the ARA content of the lipid fatty acids increased from 31% to 70%. About 50% of the ARA was in the polar and phospholipid fraction which itself accounted for 23% of the total lipid. The total lipid was about 40% of the biomass. 

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CifiHjjOi. A fatly acid which is easily oxidized in air.-It occurs widely, in the form of glycerides, in vegetable oils and in mammalian lipids. Cholesieryl linoleale is an important constituent of blood. The add also occurs in lecithins. Together with arachidonic acid it is the most important essential fatty acid of human diet. 

Arachidonic acid gets its name from arachidic acid the saturated C20 fatty acid isolated from peanut (Arachts hypogaea) oil... 

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)... 

Transport in the blood is no longer a requisite for a hormonal response. Responses can occur after release of hormones into the interstitial fluid with binding to receptors in nearby ceUs, called paracrine control, or binding to receptors on the ceU that released the hormone, called autocrine control. A class of hormones shown to be synthesized by the tissue in which they act or to act in the local ceUular environment are the prostaglandins (qv). These ubiquitous compounds are derived from arachidonic acid [506-32-1] which is stored in the ceU membranes as part of phosphoHpids. Prostaglandins bind to specific ceUular receptors and act as important modulators of ceU activity in many tissues. 

Leukotrienes and Prostanoids. Arachidonic acid (AA) (213) and its metabohtes are iavolved ia cellular regulatory processes ia all three principal chemical signaling systems endocrine (see Hormones), immune, and neuronal (62). FoUowiag receptor activation or iacreased iatraceUular... 

These steioids aie capable of preventing or suppressing the development of the sweUing, redness, local heat, and tenderness which characterize inflammation. They inhibit not only the acute symptoms of the inflammatory process, such as edema, fibrin deposition, and capillary dilatation, but also the chronic manifestations. There is evidence that glucocorticoids induce the synthesis of a protein that inhibits phosphoHpase A 2 (60), diminishing the release of arachidonic acid from phosphoHpids (Fig. 2), thereby reducing chemotaxis and inflammation. 

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). 

Fig. 2. (a) The basis for prostaglandin nomenclature, where the letters A—F and J define principal families (b) defines the side chains for PG derived from dihomo-y-linolenic acid (c) PG2 derived from arachidonic acid and (d), PG derived from eicosapentaenoic acid. 

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. 

Fig. 3. Putative mechanism of PGH synthase action on arachidonic acid.

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

The prostaglandins (qv) constitute another class of fatty acids with aUcycHc structures. These are of great biological importance and are formed by i vivo oxidation of 20-carbon polyunsaturated fatty acids, particularly arachidonic acid [27400-91-5]. Several prostaglandins, eg, PGE [745-65-3] have different degrees of unsaturation and oxidation when compared to the parent compound, prostanoic acid [25151 -18-9]. 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoidpreclavulone-A via 8-( f )-hydroperoxy-5,ll,14( Z), QfEj-eicosatetraenoic 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. 

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