Human 122-lipoxygenase

Segraves EN, Shah RR, Segraves NL, Johnson TA, Whitman S, Sui JK, Kenyon VA, Cichewicz RH, Crews P, Holman TR (2004) Probing the Activity Differences of Simple and Complex Brominated Aryl Compounds Against 15-Soybean, 15-Human, and 12-Human Lipoxygenase. J Med Chem 47 4060... 

Kenyon, V., Chorny, L, Carvajal, W.J., Holman, T.R., and Jacobson, M.P. (2006) Novel human lipoxygenase inhibitors discovered using virtual screening with homology models. Journal of Medicinal Chemistry, 49, 1356-1363. 

Skrzypezak-Jankun E, Jankun J, Al-Senaidy A (2012) Human lipoxygenase developments in its structure, function, relevance to diseases and challenges in drug development. Curr Med Chem 19 5122-5127... 

In vitro studies have shown that NDGA induces apoptosis in various human and animal cancer cell linesand cell growth of estrogen-positive human breast cancer cells (MCF-7). Among other activities, it also inhibits platelet aggregation, testosterone release, insulin secretion, " human lipoxygenases, and from topical application, skin tumor formation in rodents. ... 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

Figure 2.2 Oxidation of human LDL by lipoxygenase and exposure to copper. The oxidation of human LDL was monitored by the increase in absorbance at 234 nm after the addition of soybean lipoxygenase (LO) at t = 0 min (— and —) followed by the addition of Cu (10 fiM) at t = 90 min to one LO-treated sample (—) and the control (-). Other conditions were exactly as described in Jessup et af. (1991).

McNally, A.K., Chisholm, G.M., Morel, D.W. and Cathcart, M. (1990). Activated human monocytes oxidise low density lipoprotein by a lipoxygenase dependent pathway. J. Immunol. 145, 254-259. 

Cathcart, M.K., McNally, A.K. and Chisolm, G.M. (1991). Lipoxygenase mediated transformation of human low density lipoprotein to an oxidised and cytotoxic complex. J. Lipid Res. 32, 63-70. 

Hatzelman, A. and Ullrich, V. (1987). Regulation of 5-lipoxygenase activity by the glutathione status in human polymorphonuclear leukocytes. Eur. J. Biochem. 169, 175-184. 

Tornhamre S, Schmidt TJ, Nasman-Glaser B, Ericsson I, Ake L. Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells. Biochem Pharmacol 2001 62 903-911. 

Yeum, K.-J. et al. (1995). Similar metabolites formed from beta-carotene by human gastric mucosal homogenates, lipoxygenase, or linoleic acid hydroperoxyde. Arch. Biochem. Biophys. 321(1) 167-174. 

Yeum, K. J., Y. C. Leekim et al. (1994). In vitro metabolism of beta-carotene by lipoxygenase and human stomach mucosal homogenates. FASEB J. 8(4) A192-A192. 

In KH, Asano K, Beier D et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 1997 99 1130-1137. 

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. 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

Human 15-lipoxygenase and soybean LO-1 H/D-atom transfer from per-H vs. per-D Unoleic acid Cll to Fe-O Soybean lipoxygenase-1, WT and L546A mutant, H-atom transfer from H, D labeled linoleic acid Cll to Fe-O... 

Flynn DL, Rafferty MF, Boctor AM. (1986). Inhibition of human neutrophil 5-lipoxygenase activity by gingerdione, shogaol, capsaicin and related pungent compounds. Prostaglandins Leukot Med. 24(2-3) 195-98. 

Samuelsson B, Hoshiko S, Radmark O. (1991) Characterization of the promoter of the human 5-lipoxygenase gene. Adv Prostaglandin Thromboxane Leukot Res. 21A, 1-8. 

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