Lipoxygenase reaction specificity

Hatanaka, A., Kajiwara, T, and Matsui, K. Reaction Specificity of Lipoxygenase and Hydroperoxide Lyase. In Progress in Flavour Precursor Studies (Schreier, P. and Winterhalter, P, eds.). Allured Puplishing, pp.151-170 (1993)... 

Major products of the lipoxygenase reaction are 9- and 13-hydroperoxides of IV and V, VI, VII, VIII and IX. Hydroperoxide lyase utilizes the 9- and/or 13-hydroperoxides (VI, VII, VIII and IX). Based on substrate specificity, hydroperoxide lyase is classified into three types. The first type is 9-hydroperoxide-specific. 

The regiospecificity of the lipoxygenase reaction may also be explained by assuming that the substrate is bound in one orientation and the free electron of the enzyme-bound fatty acid radical is localized on either C-1 or C-5 of the (1Z,4Z)-pentadienyl moiety. For the linoleyl radical this would be achieved if rotation around the C-ll-C-12 or C-lO-C-11 blocks delocalization of the free electron over the C-12-C-13 or C-9-C-10 -n-orbital respectively [41]. In yet another model the regiospecificity is achieved by the specific approach of dioxygen through steric interference of the enzyme such that a regio- (and stereo-) selective reaction takes place [62]. 

Feussner, I. and Ktihn, H. (1995) The lipid body lipoxygenase from cucumber seedlings exhibits unusual reaction specificity, FEES Lett. 367, 12-14. 

Applications of peroxide formation are underrepresented in chiral synthetic chemistry, most likely owing to the limited stability of such intermediates. Lipoxygenases, as prototype biocatalysts for such reactions, display rather limited substrate specificity. However, interesting functionalizations at allylic positions of unsaturated fatty acids can be realized in high regio- and stereoselectivity, when the enzymatic oxidation is coupled to a chemical or enzymatic reduction process. While early work focused on derivatives of arachidonic acid chemical modifications to the carboxylate moiety are possible, provided that a sufficiently hydrophilic functionality remained. By means of this strategy, chiral diendiols are accessible after hydroperoxide reduction (Scheme 9.12) [103,104]. 

The biological membranes that surround cells and form the boundaries of intracellular organelles contain polyunsaturated fiitty acids, which are susceptible to oxidation. This reaction is used under controlled conditions by enzymes, such as the lipoxygenases or cyclooxygenases, within cells to produce oxygenated lipids, which can act as mediators of inflammation (Smith and Marnett, 1991 Yamamoto, 1992). Such compounds are characterized by their high potency and specificity in their interaction with cells (Salmon, 1986). While these enzymatic reactions... 

Lipoxygenase [EC 1.13.11.12] catalyzes the reaction of linoleate with dioxygen to produce (9Z,11 )-(135 )-13-hydroperoxyoctadeca-9,ll-dienoate. This iron-depen-dent enzyme can also oxidize other methylene-interrupted polyunsaturated fatty acids. See also specific enzyme... 

Brash, A.R., Ingram, C.D., and Harris, T.M. 1987. Analysis of a specific oxygenation reaction of soybean lipoxygenase-1 with fatty acids esterified in phospholipids. Biochemistry 26 5465-5471. 

The reaction can proceed aerobically or anaerobically, proceed anaerobically only, or not occur. Despite a long-held belief to the contrary, lipoxygenase contains a prosthetic group. Highly purified isoenzymes contain one atom of Fe per molecule. The metal can be removed directly by a Fe -specific chelator or by a F -specific chelator after reduction. The occurrence, role in food, and mechanism of action of lipoxygenase are discussed. 

Besides the design of synthetic molecules, several papers reported the presence of specific enzymatic reactions able to produce also in the cells compounds able to act as reversible FAAH inhibitors (Maccarrone and Finazzi-Agro, 2004a). In particular, it has been found that oxidative metabolites of AEA generated by various lipoxygenases, i.e. the hydroxyanandamides (HAEAs see 12-OH-AEA in Table 4.1), are powerful inhibitors of FAAH (van der Stelt et al., 2002). Instead, derivatives of AEA generated by cyclooxygenase-2, and termed prosta-mides, have been recently shown to be inelfective on FAAH activity (Matias et al., 2004). 

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