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Polyunsaturated phospholipids promote the oxidation and fragmentation of gamma-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipids.

ABSTRACT: Low density lipoprotein contains traces of biologically active platelet-activating factor (PAF)-like ether phosphatidylcholines (PCs). These oxidatively truncated alkylacylphosphatidylcholines (OxPAFs) are presumably formed through the oxidative truncation of 1-alkyl-2-polyunsaturated fatty acyl PCs. We now report that a diverse structural variety of OxPAFs are generated in small unilamellar vesicles (SUVs) upon myeloperoxidase (MPO)-promoted autoxidation of ether PCs that incorporate linoleoyl, arachidonyl, or docosahexaenoyl groups at the sn-2 position. Total syntheses are reported that confirm the identities of the new OxPAFs and will facilitate the evaluation of their biologically important chemistry and activities. Especially noteworthy is the formation of OxPAFs containing gamma-hydroxyalkenal functionality. Analogous oxidatively truncated diacylphosphatidylcholines are biologically important because they and their more oxidized derivatives are strong ligands for the scavenger receptor CD36. Furthermore, their covalent adduction with proteins can interfere with protein function or generate biologically active carboxyalkylpyrrole derivatives. We now find a profound influence of membrane composition on the stability of OxPAFs. In the presence of a polyunsaturated diacyl PC, the linoleic acid ester of 2-lysophosphatidylcholine, MPO induces the oxidation of aldehydes to carboxylic acids and the further oxidative truncation of gamma-hydroxyalkenals. Remarkably, these reactions do not occur readily with MPO in SUVs composed entirely of saturated diacyl-PCs. A mechanistic rationale is presented that can account for this dichotomy.

SUBMITTER: Chen X

PROVIDER: S-EPMC2836539 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Polyunsaturated phospholipids promote the oxidation and fragmentation of gamma-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipids.

Chen Xi X Zhang Wujuan W Laird James J Hazen Stanley L SL Salomon Robert G RG

Journal of lipid research 20071229 4

Low density lipoprotein contains traces of biologically active platelet-activating factor (PAF)-like ether phosphatidylcholines (PCs). These oxidatively truncated alkylacylphosphatidylcholines (OxPAFs) are presumably formed through the oxidative truncation of 1-alkyl-2-polyunsaturated fatty acyl PCs. We now report that a diverse structural variety of OxPAFs are generated in small unilamellar vesicles (SUVs) upon myeloperoxidase (MPO)-promoted autoxidation of ether PCs that incorporate linoleoyl, ...[more]

PMID: 18165704

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Project description:The presumptive function for alpha-tocopherol (?toc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % ?toc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state (2)H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on ?toc molecules. This behavior is reflected in the van der Waals energy of interaction between ?toc and acyl chains, and illustrated by density maps of distribution for acyl chains around ?toc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in ?toc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that ?toc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate ?toc can access the chromanol group when it locates at the surface.

Dataset Information

Polyunsaturated phospholipids promote the oxidation and fragmentation of gamma-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipids.

Publications

Polyunsaturated phospholipids promote the oxidation and fragmentation of gamma-hydroxyalkenals: formation and reactions of oxidatively truncated ether phospholipids.

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