Hydroperoxy-octadecadienoic acid

Natarajan,R.,Reddy,M.A.,MaHk, K.U.,Fatima, S., and Khan, B.V. (2001) Signalling Mechanisms of Nuclear Factor-KB-Me-diated Activation of Inflammatory Genes by 13-Hydroperoxy-octadecadienoic Acid in Cultured Vascular Smooth Muscle Ce ls, Arterioscler. Thromb. Vase. Biol. 21,1408-1413. 

It has been reported that a single methionine residue of rabbit reticulocyte 15-lipoxygenase can be oxidized to its sulphoxide by treatment of the enzyme with 13-hydroperoxy-octadecadienoic acid (a 15-lipoxygenase product from linoleic acid) under anaerobic conditions [59]. Since under this condition the enzyme functioned as lipohydroperoxidase , splitting the hydroperoxide, and resulted in self-inactivation , a central role of the methionine residue was presumed for the catalysis of the enzyme. Recently, this particular methionine has been identified as Met-590 in human 15-lipoxygenase and as Met-591 in rabbit 15-lipoxygenase. When Met-590 in the human enzyme is replaced by leucine by the site-directed mutagenesis, the mutant enzyme is still inactivated by 13-hydroperoxyoctadeca-dienoic acid, 15-HpETE or AA. The result shows that the enzyme inactivation is not attributable to methionine oxidation [60]. 

FIGURE 25.4 Mechanism of conversion of 13-hydroperoxy-9,ll-octadecadienoic acid (13-HPODE) into 4-hydroxynonenal (4-HNE). (Adapted from C Schneider, KA Tallman, NA Porter, AR Brash. J Biol Chem 276 20831-20838, 2001. With permission.)... 

Inhibition and stimulation of LOX activity occurs as a rule by a free radical mechanism. Riendeau et al. [8] showed that hydroperoxide activation of 5-LOX is product-specific and can be stimulated by 5-HPETE and hydrogen peroxide. NADPH, FAD, Fe2+ ions, and Fe3+(EDTA) complex markedly increased the formation of oxidized products while NADH and 5-HETE were inhibitory. Jones et al. [9] also demonstrated that another hydroperoxide 13(5)-hydroperoxy-9,ll( , Z)-octadecadienoic acid (13-HPOD) (formed by the oxidation of linoleic acid by soybean LOX) activated the inactive ferrous form of the enzyme. These authors suggested that 13-HPOD attached to LOX and affected its activation through the formation of a protein radical. Werz et al. [10] showed that reactive oxygen species produced by xanthine oxidase, granulocytes, or mitochondria activated 5-LOX in the Epstein Barr virus-transformed B-lymphocytes. 

I3-hydroperoxy-9-cis, I I-tmrw-octadecadienoic acid 9-hydroperoxy-I0-tmrw,I2 cis octadecadienoic acid 9-hydroxy-I0-fmn, I2,I3 cw-epoxyoctadecadienoic acid 9,10 -cis-epoxy-ll-trans-13 hydroxyoctadecadienoic acid... 

Hamberg found that the corn enzyme generated mainly 9-n-hydro-peroxy-10,12-octadecadienoic acid from linoleic acid. The small amount of 13-hydroperoxy-10,12-octadecadienoic acid which was also formed... 

Lipoxygenase derived from soybean transforms linoleic acid at pH 9.2 nearly exclusively into 13S-hydroperoxy-9Z-l lE-octadecadienoic acid (13S-HPODE, Scheme 4) and linoleinic acid into 16S-9Z 12Z,14E-octadecadienoic acid (13S-HPOTE, Scheme 5) [155]. 

HETE. The 15-lipoxygenase (15-LOX) has been the most extensively characterized pathway in the reticulocytes, leukocytes, and airway epidermal cells (24-27). An outline in Figure 5 shows that 15-LOX can, on the one hand, catalyze the abstraction of a proton from C-13 of 20-carbon AA to produce 155-hydroperoxyeicosatetraenoic acid (155-HPETE), whereas on the other hand, the 18-carbon linoleic acid is converted mainly to 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 9-hydroperoxy-10,12- , Z-octadecadienoic acid (9-HPODE) in the ratio of 10 1 (28). Both the 155-HPETE (intermediate) from AA and 13-HPODE (intermediate) from linoleic acid can be further metabolized by glutathione peroxidase to mainly monohydroxylated 15S-HETE and 13-hydroxy-octadecadienoic acid (HODE), respectively. 

Hamberg, M., Vanadium-Catalyzed Transformation of 13(5)-Hydroperoxy-9(Z), 11 ( )-Octadecadienoic Acid Structural Studies on Epoxy Alcohols and Trihydroxy Acids, Chem. Phys. Lipids 43 55-67 (1987). 

Hamberg, M., Decomposition of Unsaturated Fatty Acid Hydroperoxides by Hemoglobin Structures of Major Products of 13L-Hydroperoxy-9,11-octadecadienoic Acid, Lipids 10 87-92 (1975). 

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