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Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease

Journal Article


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Abstract


  • ApoD (apolipoprotein D) is up-regulated in AD (Alzheimer's disease) and upon oxidative stress. ApoD inhibits brain lipid peroxidation in vivo, but the mechanism is unknown. Specific methionine residues may inhibit lipid peroxidation by reducing radical-propagating L-OOHs (lipid hydroperoxides) to non-reactive hydroxides via a reaction that generates MetSO (methionine sulfoxide). Since apoD has three conserved methionine residues (Met49, Met93 and Met157), we generated recombinant proteins with either one or all methionine residues replaced by alanine and assessed their capacity to reduce HpETEs (hydroperoxyeicosatetraenoic acids) to their HETE (hydroxyeicosatetraenoic acid) derivatives. ApoD, apoDM49-A and apoDM157-A all catalysed the reduction of HpETEs to their corresponding HETEs. Amino acid analysis of HpETE-treated apoD revealed a loss of one third of the methionine residues accompanied by the formation of MetSO. Additional studies using apoD(M93-A) indicated that Met93 was required for HpETE reduction. We also assessed the impact that apoD MetSO formation has on protein aggregation by Western blotting of HpETE-treated apoD and human brain samples. ApoD methionine oxidation was associated with formation of apoD aggregates that were also detected in the hippocampus of AD patients. In conclusion, conversion of HpETE into HETE is mediated by apoD Met93, a process that may contribute to apoD antioxidant function.

Publication Date


  • 2012

Citation


  • Bhatia, S., Knoch, B., Wong, J., Kim, W., Else, P., Oakley, A. J. & Garner, B. (2012). Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease. Biochemical Journal, 442 (3), 713-721.

Scopus Eid


  • 2-s2.0-84857818864

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=8072&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4729

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 713

End Page


  • 721

Volume


  • 442

Issue


  • 3

Place Of Publication


  • United Kingdom

Abstract


  • ApoD (apolipoprotein D) is up-regulated in AD (Alzheimer's disease) and upon oxidative stress. ApoD inhibits brain lipid peroxidation in vivo, but the mechanism is unknown. Specific methionine residues may inhibit lipid peroxidation by reducing radical-propagating L-OOHs (lipid hydroperoxides) to non-reactive hydroxides via a reaction that generates MetSO (methionine sulfoxide). Since apoD has three conserved methionine residues (Met49, Met93 and Met157), we generated recombinant proteins with either one or all methionine residues replaced by alanine and assessed their capacity to reduce HpETEs (hydroperoxyeicosatetraenoic acids) to their HETE (hydroxyeicosatetraenoic acid) derivatives. ApoD, apoDM49-A and apoDM157-A all catalysed the reduction of HpETEs to their corresponding HETEs. Amino acid analysis of HpETE-treated apoD revealed a loss of one third of the methionine residues accompanied by the formation of MetSO. Additional studies using apoD(M93-A) indicated that Met93 was required for HpETE reduction. We also assessed the impact that apoD MetSO formation has on protein aggregation by Western blotting of HpETE-treated apoD and human brain samples. ApoD methionine oxidation was associated with formation of apoD aggregates that were also detected in the hippocampus of AD patients. In conclusion, conversion of HpETE into HETE is mediated by apoD Met93, a process that may contribute to apoD antioxidant function.

Publication Date


  • 2012

Citation


  • Bhatia, S., Knoch, B., Wong, J., Kim, W., Else, P., Oakley, A. J. & Garner, B. (2012). Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease. Biochemical Journal, 442 (3), 713-721.

Scopus Eid


  • 2-s2.0-84857818864

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=8072&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4729

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 713

End Page


  • 721

Volume


  • 442

Issue


  • 3

Place Of Publication


  • United Kingdom