Fatty acids hydroperoxy

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). 

Lipoxygenase (EC 1.13.11.12, nonheme iron dioxygenase), the substrate (polyunsaturated fatty acid) is poorly water soluble and the product (hydroperoxy-fatty acid) is hydrophilic. The reaction occurs in the aqueous phase [85,86]. 

FIG. 3 Hydroperoxy-fatty acid S5mthesis from triacylglycerol with successive lipase-catalyzed hydrolysis and lipoxygenation. 

This approach can easily be extended to a large scale to produce hydroperoxy-fatty acids from high concentrations of triacylglycerols with facile extraction. 

The leucotrienes, lipoxins and hydroperoxy fatty acids are also synthesised from arachidoific acid. The initial enzyme... 

The lipoxygenase system also competes for released arachidonic acid in a way that seems to be tissue-selective, giving rise to hydroperoxy fatty acids (HPETE) which can be converted into leukotrienes or reduced to hydroxy fatty acid (HETE) products [115]. The basic scheme for these metabolic conversions involving arachidonic acid is presented in Figure 5.2. Both of the main enzymatic pathways of arachidonic acid metabolism are thought to involve free-radical-mediated reactions [108] and the antioxidant capacity of vitamin E could therefore allow the vitamin to modify the products of these pathways. 

In the course of an investigation into the nature of the biosynthetic intermediate of long chain fatty aldehydes, Hitchcock and James proposed that the (S)-2-hydroxy-fatty acid serves as an intermediate in the a-oxidation of fatty acids (40-41). On the other hand, another mechanism for a-oxidation of fatty acids in peanut cotyledons has been proposed by Shine and Stumpf (34), involving hydroperoxy-fatty acids rather than the hydroxy-fatty acids as a transitory intermediate. However, the hydroperoxy intermediate has not been studied so far in marine algae. 

FIGURE 12.1 Activation of PPARa by dietary oxidized lipids is mediated by binding of hydroxy or hydroperoxy fatty acids, such as 9-HODE, 13-HODE, and 13-HPODE contained in the oxidized lipids to the PPARa protein which subsequently forms a complex with RXR. The PPARa/RXR complex binds to specific DNA sequences, called PPRE, present in and around the promoter of PPAR target genes, and, thereby, stimulates their transcription. PPARa can also negatively regulate transcription of genes, which are under the control of stress-sensitive transcription factors such as NF-kB and encode proteins involved in the stress and inflammation response. This is the molecular basis for the well-documented antiinflammatory effects of PPARa. 

The primary LOX metabolites, the hydroperoxy fatty acids, are further metabolized to an array of secondary products that may be classified into several groups according to their chemical structures (i) leukotrienes containing three conjugated double bonds, (ii) mono- and double-oxygenated polyenoic fatty acids that are not formed via a leukotriene intermediate and (iii) lipoxins and hepoxilins. 

When not transformed into epoxy leukotrienes, hydroperoxy fatty acids formed via the LOX reaction are rapidly reduced to the corresponding alcohols. Alternatively, the hydroperoxy group may undergo homolytic cleavage of the 0-0 bond, leading to the formation of a complex array of secondary lipid peroxidation products which... 

In addition, cyt E-450 may catalyse the rearrangement of hydroperoxy fatty acids to epoxy alcohols (see hepoxilin biosynthesis). The characterization of... 

Since AA is only a minor fatty acid in higher plants, eicosanoids are not of major importance for plant physiology. However, the oxygenation metabolites of linoleic acid and a-linolenic acid, called oxylipins [5,6], do play a role in plant defence reactions, in the formation of phytohormones and in the synthesis of cutin monomers [6,40-43]. Oxylipins constitute a family of lipids that are formed from free fatty acids by a cascade of reactions involving at least one step of dioxygen-dependent oxidation. The biosynthesis of oxylipins proceeds via a large number of metabolic pathways, most of which involve an unsaturated hydroperoxy fatty acid as intermediate (Scheme 10). Conversion of the hydroperoxide via the peroxide lyase pathway, the allene oxide pathway and the recently discovered peroxygenase pathway, leads to a complex pattern of oxidized lipid mediators. 

More than 30 years ago it was reported that flaxseed homogenates convert 13-HpOTrE into a- and -y-ketols, and the enzyme responsible for this reaction was called hydroperoxide isomerase [54]. Later studies indicated that this reaction was actually a two-step process, consisting of an enzyme-catalysed dehydration of the hydroperoxy fatty acid to a rather unstable allene oxide followed by a non-enzymic hydrolysis [55,56]. The enzyme responsible for allene oxide synthesis has been purified and shown to be a cyt E-450 isoform [57]. As an alternative to hydrolysis, the allene oxide may undergo enzymic cyclization forming 12-oxo-phytodienoic acid. This compound is subsequently converted into jasmonic acid, a phytohormone implicated in the reaction of higher plants to a number of stimuli, such as wounding, fungal elicitation, mechanical forces and osmotic stress [54]. 

Scheme 12 Formation of vicinal diols by direct isomerization of hydroperoxy fatty acids...

Fatty acid diols can be formed via enzymic or non-enzymic hydrolysis of epoxy compounds (see above). In addition, vicinal diols may originate from the isomerization of hydroperoxy fatty acids, which may proceed without the intermediate formation of epoxides [59]. An acetone powder of the red alga Gracilariopsis... 

The different lipoxygenase isoenzymes are named according to their prevalent positional specificity for the dioxygenation of ETE. They are named 15-, 12- or 5-lipoxygenase, depending on whether they attach the hydroperoxide function to carbon atom 15, 12 or 5 of ETE respectively. Irrespective of their positional specificity, the majority of the enzymes generate (5)-hydroperoxy fatty acids. Arachidonic acid is converted into (5Z,8Z,112,13 )-(15S)-hydroperoxyeicosa-... 

LOXs catalyse the addition of dioxygen to methyl-interrupted cis double bond [(Z,Z)-pentadiene] in a polyunsaturated fatty acid to produce a hydroperoxy fatty acid containing a Z,E conjugated double bond system. Where multiple pentadienes occur in a single molecule such as arachidonic acid, position-specific oxygenation can take place, resulting in the production of 5-, 12- or 15-hydroperoxyeicosa-tetraenoic acids. These hydroperoxy acids may be subsequently converted into other oxylipins by enzymic or non-enzymic reactions [3]. Table 1 shows some examples of LOX products from fungi. 

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