Fatty acids endoperoxides

Prostaglandin biosynthesis from C20 polyunsaturated fatty acids occurs by way of the endoperoxides PGG2 and PGH2. 

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. 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

The autoxidation of polyunsaturated fatty acids (cf. Porter et al. 1981) is usually monitored by the formation of malonaldehyde using the 2-thiobarbituric acid essay. This is carried out under rather severe conditions which decomposes its precursor. This malonaldehyde-like product is obviously formed via a cycliza-tion reaction of a peroxyl radical, followed by other processes such as further cyclization and hydroperoxide formation [reactions (21)-(23)]. The resulting hydroperoxides may eliminate malonaldehyde upon a homolytic cleavage of the endoperoxidic intermediate (Pryor and Stanley 1975). 

Pryor WA, Stanley JP (1975) A suggested mechanism for the production of malonaldehyde during the autoxidation of polyunsaturated fatty acids. Nonenzymatic production of prostaglandin endoperoxides during autoxidation. J Org Chem 40 3615-3617... 

Prostaglandins are biosynthesized from arachidonic acid, an unsaturated fatty acid containing four double bonds. The enzyme prostaglandin endoperoxide synthase converts arachidonic acid to PGH2, which serves as the precursor for prostaglandins and related compounds. Aspirin exerts its pharmacological effect by inhibiting this enzyme. 

The benzodioxole ring system is distributed widely in nature and is found in numerous natural products such as safrole and piperonal, as well as a multitude of alkaloids. 1,2-Dioxolanes are intermediates in the arachidonic acid cascade, which is the biochemical pathway from essential fatty acids to prostaglandins and similar hormones. The endoperoxide PGH2 (121) is believed to be formed on initial oxidation of arachidonic acid (120). PGH2 has a half-life of 4-5 minutes and is transformed enzymatically into prostaglandins, prostacyclin and the thromboxanes. These compounds are mediators for the control of platelet aggregation, blood vessel dilation and smooth muscle contraction. 

In polyunsaturated fatty acids with nonconjugated double bonds, O2 reacts with each C=C as if it were isolated, so it yields roughly equivalent amounts of hydroperoxides at both internal and external positions. However, if the double bonds are conjugated (e.g., natural conjugated linoleic acid or oxidized linoleic acid), cyclic endoperoxides are formed. 

CigH3204by HRFABMS, respectively. Extensive analysis of their ID and 2D data led to the gross structures of 20 and 21, which were belong to the same class of endoperoxides derived from fatty acids, Fig. (14). Compound 21 was a dihydo derivative of 20. 

Arachidonic acid released from phospholipids or neutral lipids at sites of inflammation can be converted via the cyclooxygenase system into the biologically active endoperoxide rostaglandin G2 as well as several non-prostanoate hydroxy fatty acids. Alternatively, it may be converted by a lipoxygenase into 2-L-hydroxy-5,8,10-14-eicosatetraneoic a d (HETE). HETE produced by platelet aggregation is chemotactic for PMN (see Chapter 19). 

The endoperoxides decompose into the fatty acid HHT. This transformation is probably a non-enzymatic artifact and no biological activity has been reported for this compound. Another fatty acid, HETE, formed from arachidonic acid by a platelet lipoxygenase , has been found to exhibit chemotactic activity for neutrophils and eosinophils in vitro. The recent suggestion that arachidonic acid is a precursor for SRS-A, while provocative, needs further experimental verification . 

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