Oxidation hydroperoxidases

Figure 5 Conversion of acetaminophen to its reactive free radical by co-oxidation mediated by the hydroperoxidase activity of prostaglandin H synthase-catalyzed reduction of prostaglandin Ga (PGGa) to prostaglandin Ha (PGHa).

Prostanoids, consisting of prostaglandins (PGs) and thromboxanes (TXs), are members of the lipid mediators derived enzymatically from fatty acids. Arachidonic acid, a C2o essential fatty acid for most mammalians, is freed from the phospholipid molecule by phospholipase A2, which cleaves off the fatty acid precursor. Prostanoids are produced in a wide variety of cells throughout the body from the sequential oxidation of arachidonic acid by cyclooxygenase, PG hydroperoxidase, and a series of prostaglandin synthases (Figure 2.1). 

Radical production from peroxidase-like systems, for example from the peroxide-supported oxidation of amino compounds catalyzed by protohemin and metmyo-globin, has received attention [174]. Both hydrogen peroxide and hydroperoxides (e.g., r-butyl hydroperoxide and cumene hydroperoxide) can be effective sources of oxidizing equivalents for these reactions. Since the enzyme prostaglandin synthase contains both cyclooxygenase and hydroperoxidase activities, either a substrate for the cyclooxygenase or an added hydroperoxide will support the catalyzed oxidation of substrates [175]. 

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)...

The purified enzyme from bovine vesicular gland catalyzes the conversion of PGG to PGH in the presence of tryptophan. If tryptophan is replaced by glutathione, there is essentially no conversion of PGG to PGH. The purified enzyme is free of glutathione peroxidase activity as tested with glutathione and cumene hydroperoxide [38]. Thus, glutathione peroxidase is not involved in the conversion of PGG to PGH so far as it is catalyzed by the PG hydroperoxidase activity of PG endoper-oxide synthetase. 

The oxidation of catecholamines by the hydroperoxidase activity of lipoxygenase (EC 1.13.11.12) is documented by Rosei et al. (1994) and NOnez-Delicado et al. (1996). o-Diphenols are easily studies spectrophotometrically since, when oxidised, they render coloured compounds, quinones, or their corresponding aminochromes. In the case of isoprenaline the maximum of the oxidation product was developed at 490 nm (NOnez-Delicado et al. 1999), which corresponds to that of the aminochrome product (Jim nez et al. 1985, NOnez-Delicado et al. 1996). 

It is convenient to discuss catalase and the peroxidases separately, but the distinction is arbitrary. Peroxidases are enzymes that catalyze oxidations of various substrates by H2O2. Catalase activity may be considered a special case of such an oxidation, in which H2O2 serves as both oxidant and reductant. The discovery that catalase also catalyzes the peroxidation of numerous other molecules, albeit slowly, establishes this enzyme as one of the family of hydroperoxidases. 

All of the reactions of the hydroperoxidases are oxidations, and it is probable that a common mechanism is employed by all enzymes of this group. The chemistry of this mechanism has been investigated by a number of approaches, but remains undetermined, although many speculative schemes have been proposed. 

Other catalysts with firmly bound prosthetic groups, including the iron-porphyrin-bearing cytochromes, have been shown to undergo reversible oxidation. Therefore, it would form a consistent pattern if the hydroperoxidases were also to be oxidized and reduced. To explain the action of these enzymes several schemes have been advanced in which the iron shifts from the ferric to the ferrous state and back. All of these schemes have been criticized when applied to catalase because of the inability to detect a ferrous enzyme by magnetic measurements or by inhibition of the reaction with CO. It does not seem that these objections are overwhelming, as the ferrous state may be very short-lived, and escape detection by physical means, and the reduced enzyme may have less affinity for CO than those enzymes that are inhibited by this compound. 

Mottley C, Mason RP, Chignell CF (1982) The formation of sulfur trioxide radical anion during the prostaglandin hydroperoxidase-catalyzed oxidation of bisulfite (hydrated sulfur dioxide). J Biol Chem 257 5050-5055... 

---