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J Biol Chem, Vol. 273, Issue 36, 23225-23232, September 4, 1998
From the Institute of Biochemistry, University Clinics
Charité, Humboldt University, Hessische Str. 3-4,
D-10115 Berlin, Federal Republic of Germany
The oxidation of low density lipoprotein (LDL) by
mammalian 15-lipoxygenases (15-LOX) was implicated in early
atherogenesis. We investigated the molecular mechanism of 15-LOX/LDL
interaction and found that during short term incubations, LDL
cholesterol esters are oxygenated preferentially by the enzyme. Even
when the LDL particle was loaded with free linoleic acid, cholesteryl linoleate constituted the major LOX substrate. In contrast, only small
amounts of free oxygenated fatty acid isomers were detected, and
re-esterification of oxidized fatty acids into the LDL ester lipid
fraction was ruled out. When LDL was depleted from These data suggest that mammalian 15-LOX preferentially oxidize LDL
cholesterol esters, forming a specific pattern of oxygenation products.
During long term incubations, free radical-mediated secondary
reactions, which lead to a more unspecific product pattern, may become
increasingly important. These secondary reactions appear to be
suppressed when the hydroperoxy lipids formed are immediately reduced,
when 
-tocopherol, specific oxygenation of the cholesterol esters was not prevented, and
the product pattern was not altered. Similar results were obtained at
low (LDL/LOX ratio of 1:1) and high LOX loading (LDL/LOX ratio of 1:10)
of the LDL particle. During long term incubations (up to 24 h), a
less specific product pattern was observed. However, when the
hydroperoxy lipids formed by the 15-LOX were immediately reduced by the
phospholipid hydroperoxide glutathione peroxidase, when the reaction
was carried out with vitamin E-depleted LDL, or when the assay sample
was diluted, the specific pattern of oxygenation products was retained
over a long period of time.
-tocopherol-depleted LDL was used, or when the incubation
sample was diluted. It may be concluded that 15-LOX-initiated LDL
oxidation constitutes a dual-type oxygenase reaction with an initial
enzymatic and a subsequent nonenzymatic phase. The biological relevance
of this dual-type reaction for atherogenesis will be discussed.
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