Lipoxygenases free radical formation

In this chapter the generation of free radicals, mainly superoxide and nitric oxide, catalyzed by prooxidant enzymes will be considered. Enzymes are apparently able to produce some other free radicals (for example, HO and N02), although their formation is not always rigorously proved or verified. The reactions of such enzymes as lipoxygenase and cyclooxygenase also proceed by free radical mechanism, but the free radicals formed are consumed in their catalytic cycles and probably not to be released outside. Therefore, these enzymes are considered separately in Chapter 26 dedicated to enzymatic lipid peroxidation. 

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

Bioactivation to a free radical intermediate has been implicated in the teratological mechanism for a number of xenobiotics, including phenytoin and structurally-related AEDs, benzo[a]pyrene, thalidomide, methamphetamine, valproic acid, and cyclophosphamide (Fantel 1996 Wells et al. 2009 Wells and Winn 1996). Unlike in the case of most CYPs, the embryo-fetus has relatively high activities of PHSs and lipoxygenases (LPOs), which via intrinsic or associated hydroperoxidase activity can oxidize xenobiotics to free radical intermediates (Fig. 10) (Wells et al. 2009). These xenobiotic free radical intermediates can in some cases react with double bonds in cellular macromolecules to form covalent adducts, or more often react directly or indirectly with molecular oxygen to initiate the formation of potentially teratogenic reactive oxygen species (ROS). 

Fig. 10 Bioactivation of xenobiotics via the prostaglandin H synthase (PHS) and lipoxygenase (LPO) pathways-postuiated role in teratogenesis. The hydroperoxidase component of embryonic and fetal PHSs, and hydroperoxidases associated with LPOs, can oxidize xenobiotics to free radical intermediates that initiate the formation of reactive oxygen species causing oxidative stress (modified from Yu and Wells 1995)...

Fig. 11 Biochemical pathways for the formation, detoxification, and cellular effects of xenobiotic free radical intermediates and reactive oxygen species (ROS). Fe iron, G-6-P glucose-6-phos-phate, GSH glutathione, GSSG glutathione disulfide, H2O2 hydrogen peroxide, FIO hydroxyl radical, LPO lipoxygenase, NADP nicotinamide adenine dinucleotide phosphate, O2 superoxide, P450 cytochromes P450, PHS prostaglandin H synthase, SOD superoxide dismutase. (Modified from Wells et al. 1997)...

LOX-catalyzed lipid oxidation differs from the free radical reaction by the formation of hydroperoxides at a certain position of the chain of, most often, a free FA. Lipoxygenases use molecular oxygen to catalyze the stereo- and regiospecific oxygenation of PUFA with -cisA- dY-pentadiene moieties. LOX react enzymat-... 

---