The oxygenation of cholesterol esters by the reticulocyte lipoxygenase

Belkner, J; Wiesner, Rainer; Kühn, Hartmut; Ланкин, В. З.

doi:10.1016/0014-5793(91)80263-3

Cited by 71 publications

(38 citation statements)

References 13 publications

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“…The present findings are, in part, inconsistent with the view that exposure to mammalian 15-LO results in direct oxidation LDL's esterified lipids (11)(12)(13)(14). SLO-1 (the isoenzyme used in the experiments described herein) shows similarities to mammalian 15-LO in general properties, enzyme kinetics and the active site (40,41), but requires the presence of bile salts to oxidize esterified lipids such as PL or biomembranes (42).…”

Section: -Lipoxygenase-induced Oxidation Of Ldl Fatty Acids and Esterscontrasting

confidence: 97%

“…In support of this, addition of 18:2 to LDL previously exposed to rhLO for 60 min failed to result in further accumulation of 13-(S)(Z,E)-H(P)ODE. 3 Earlier studies noted that LDL lipid oxidation induced by various 15-LO did not display this characteristic self-inactivation (11)(12)(13)(14). It is well established that FFA peroxyl radicals are released from the active site of 15-LO during enzymic formation of 13-(S)(Z,E)-HPODE (21,38) and that this can lead to the co-oxidation of various compounds, including phenolic antioxidants, PL, cholesterol, and proteins (37,39).…”

Section: -Lipoxygenase-induced Oxidation Of Ldl Fatty Acids and Estersmentioning

confidence: 99%

“…Much of the literature ascribes oxidation of LDL by 15-LO to a direct reaction with esterified fatty acid substrates, including phospholipids (PL) and cholesteryl esters (CE) (11)(12)(13)(14). In LDL exposed to 15-LO, or to cells overexpressing this enzyme (15,16), the major oxidation products found are CE hydroperoxides and hydroxides (collectively referred to as CE-O(O)H).…”

mentioning

confidence: 99%

“…However, the vast majority of CE are normally buried in the core of the lipoprotein particle and hence may be largely inaccessible to 15-LO. In addition, certain aspects of 15-LO catalysis, such as the rapid oxidation and characteristic suicidal inactivation of the enzyme observed with free fatty acid (FFA) substrates, are notably absent from, or distinct to, 15-LO-induced LDL oxidation (11)(12)(13)(14).…”

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confidence: 99%

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Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

Upston

Neužil

Witting

et al. 1997

Journal of Biological Chemistry

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15-Lipoxygenase has been implicated in the in vivo oxidation of low density lipoprotein (LDL) a process thought to be important in the origin and/or progression of human atherogenesis. We have suggested previously that oxidation of LDL's cholesteryl esters (CE) and phospholipids by soybean (SLO) or human recombinant 15-lipoxygenase (rhLO) can be ascribed largely to ␣-tocopherol (␣-TOH)-mediated peroxidation (TMP). In this study we demonstrate that addition to LDL of unesterified linoleate (18:2), other free fatty acid (FFA) substrates, or phospholipase A 2 (PLA 2 ) significantly enhanced the accumulation of CE hydro(pero)xides (CE-O(O)H) induced by rhLO, whereas the corresponding CE and nonsubstrate FFA were without effect. The enhanced CE-O(O)H accumulation showed a dependence on the concentration of free 18:2 in LDL. In contrast, addition of 18:2 had little effect on LDL oxidation induced by aqueous peroxyl radicals or Cu 2؉ ions. Analyses of the regio-and stereoisomers of oxidized 18:2 in SLO-treated native LDL demonstrated that the small amounts of 18:2 associated with the lipoprotein were oxidized enzymically and within minutes, whereas cholesteryl linoleate (Ch18:2) was oxidized nonenzymically and continuously over hours. ␣-Tocopheroxyl radical (␣-TO ⅐ ) formed in LDL exposed to SLO was enhanced by addition of 18:2 or PLA 2 . With rhLO and 18:2-supplemented LDL, oxidation of 18:2 was entirely enzymic, whereas that of Ch18:2 was largely, though not completely, nonenzymic. The small extent of enzymic Ch18:2 oxidation increased with increasing enzyme to LDL ratios. Ascorbate and the reduced form of coenzyme Q, ubiquinol-10, which are both capable of reducing ␣-TO ⅐ and thereby preventing TMP, inhibited nonenzymic Ch18:2 oxidation induced by rhLO. Trolox and ascorbyl palmitate, which also inhibit TMP, ameliorated both enzymic and nonenzymic oxidation of LDL's lipids, whereas probucol, a radical scavenger not capable of preventing TMP, was ineffective. These results demonstrate that rhLO-induced oxidation of CE is largely nonenzymic and increases with LDL's content of FFA substrates. We propose that conditions which increase LDL's FFA content, such as the presence of lipases, increase 15-LO-induced LDL lipid peroxidation and that this process requires only an initial, transient enzymic activity.

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Section: -Lipoxygenase-induced Oxidation Of Ldl Fatty Acids and Esterscontrasting

confidence: 97%

Section: -Lipoxygenase-induced Oxidation Of Ldl Fatty Acids and Estersmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

Upston

Neužil

Witting

et al. 1997

Journal of Biological Chemistry

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“…In contrast, the reticulocyte-type 15-LOXs are capable of oxygenating complex ester lipids (24,25) even if they are bound in biomembranes (26,27) or lipoproteins (28,29). In fact, the oxygenation of membrane lipids was implicated in membrane degradation and/or remodeling during erythropoiesis (30,31) and LOXinduced oxidation of low density lipoprotein was suggested to be involved in the pathogenesis of atherosclerosis (32).…”

mentioning

confidence: 99%

The N-terminal Domain of the Reticulocyte-type 15-Lipoxygenase Is Not Essential for Enzymatic Activity but Contains Determinants for Membrane Binding

Walther¹,

Anton²,

Wiedmann³

et al. 2002

Journal of Biological Chemistry

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The rabbit reticulocyte-type 15-lipoxygenase is capable of oxygenating biomembranes and lipoproteins without the preceding action of ester lipid cleaving enzymes. This reaction requires an efficient membrane binding, and the N-terminal ␤-barrel domain of the enzyme has been implicated in this process. To obtain detailed information on the structural requirements for membrane oxygenation, we expressed the rabbit wildtype 15-lipoxygenase, its ␤-barrel deletion mutant (catalytic domain), and several lipoxygenase point mutations as His-tagged fusion proteins in Escherichia coli and tested their membrane binding characteristics. We found that: (i) the ␤-barrel deletion mutant was catalytically active and its enzymatic properties (K M , V max , pH optimum, substrate specificity) were similar to those of the wild-type enzyme; (ii) when compared with the wildtype lipoxygenase, the membrane binding properties of the N-terminal truncation mutant were impaired but not abolished, suggesting a role of the catalytic domain in membrane binding; and (iii) Phe-70 and Leu-71 (constituents of the ␤-barrel domain) but also Trp-181, which is located in the catalytic domain, were identified as sequence determinants for membrane binding. Mutation of these amino acids to more polar residues (F70H, L71K, W181E) impaired the membrane binding capacity of the recombinant enzyme. These data indicate that the C-terminal catalytic domain of the rabbit 15-lipoxygenase is enzymatically active and that the membrane binding properties of the enzyme are determined by a concerted action of the N-terminal ␤-barrel and the C-terminal catalytic domain.

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Antioxidants: A biological defense mechanism for the prevention of atherosclerosis

Jackson¹,

Ku²,

Thomas³

1993

Medicinal Research Reviews

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The oxygenation of cholesterol esters by the reticulocyte lipoxygenase

Cited by 71 publications

References 13 publications

Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

Oxidation of Free Fatty Acids in Low Density Lipoprotein by 15-Lipoxygenase Stimulates Nonenzymic, α-Tocopherol-mediated Peroxidation of Cholesteryl Esters

The N-terminal Domain of the Reticulocyte-type 15-Lipoxygenase Is Not Essential for Enzymatic Activity but Contains Determinants for Membrane Binding

Antioxidants: A biological defense mechanism for the prevention of atherosclerosis

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