Prostaglandins, from arachidonic hydroperoxides

Lipid hydroperoxides play an important role in the biosynthesis of prostaglandins from arachidonic acid. The control of the concentration of hydroperoxides, also referred to as peroxide tone, is important for the maintenance of normal cell functions. Hydroperoxides can either stimulate cyclooxygenase activity at low concentrations (0.01 /jM) or inhibit this enzyme at high concentrations (1 M). The enzymes glutathione peroxidase and... 

The arachidonic acid cascade is a biological free radical oxidation of unsaturated fatty acids leading to formation of the prostaglandins (equation 102). Cyclization of a peroxy radical intermediate 66 leading to endoperoxide 67 was proposed as a pathway for this process, and this was demonstrated in chemical model systems, in which the peroxyl radical 66 was generated by hydrogen abstraction from the hydroperoxide corresponding to 66. 

Fig. 6. Three irnportam oxidative pathways for the metabolism of polyunsaturated fatty acids. A. The principal steps in the formation of prostaglandin endoperoxides from arachidonic acid. B. Likely mechanism for the formation of hydroperoxy cis.trans conjugated fatly acids by autooxidalion or by lipoxygena.sc.s. In the latter case, positional as well as stereospecificity arc normally found. The formed hydroperoxides may then be enzymatically transformed into leukotrienes (not shown) or to hydroxy acids. C. The enzymatic sequence in cytochrome P-450 mediated oxygenation. The first electron is donated from NADPH via the f lavoprotein (Fp) NADPH-cytochrome-P-450-reductase. while the second electron comes either from NADPH or NADH. In this way the monooxygenase enzymes inlrrxluce one oxygen from air into the substrate.

The more recently discovered leukotrienes result from arachidonic acid via the 5-hydroperoxide and the 5,6-epoxide (Leukotriene A4, LTA4). The leukotrienes contain a conjugated triene unit within a total of three (from 20 3, n—9), four (from 20 4, n—6), or five (from 20 5, n—3) double bonds. This total unsaturation is indicated by the numerical subscript. While the 8,11,14-triene unit provides the necessary unsaturation for prostaglandins and thromboxanes the 5,8,11-triene unit is required for leukotrienes. The various LTB, LTC, LTD and LTE compounds show a range of pharmacological activities of which the most widely studied is their relation to asthma arising from their bronchoconstricting effect. 

As the first isolable intermediate in the bioconversion of arachidonic acid into prostaglandins and thromboxanes (Eq. 3), PGG2 is a bicyclic peroxide of immense biological importance. It is difficult to obtain pure from natural sources and the presence of the 15-hydroperoxide group adds a further dimension of chemical lability to that associated with the 9,11-peroxide bridge. The chemical synthesis of PGG2 is thus a landmark in prostaglandin chemistry. It also represents a pinnacle of success for the silver-salt route to bicyclic peroxides. 

The essential individual steps are the following First, arachidonic acid bonds ionically to arginine-120 of prostaglandin-H2-synthase. The oxoiron(IV)-por-phyrin complex abstracts a hydrogen radical from tyrosine-385. This then cleaves off, regio- and stereo-selectively, the allylic (13-pro-S)-hydrogen atom of arachidonic acid, and thereby initiates the cycloaddition with oxygen. In the reaction centre of the hydroperoxidase, the hydroperoxide is then reduced to the alcohol in a second step (Fig. 5.97). [216]... 

The most recent findings relating to lipoxygenase pathway in plants concern allene oxides, the primary products of enzymatic transformations of fatty acid hydroperoxides. Spontaneous hydrolysis of allene oxides leads to the formation of a- and y-ketols [1]. It has been also found that hydroperoxide dehydrase from flax seeds converts 8-hydroxy-155-hydroperoxy derivatives of arachidonic and eicosapentaenoic acids into a-ketols and prostaglandin A3 analogues [2]. These data allow us to hypothesize formation of ketols of 9-hydroxy derivative of a-linolenic acid. 

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