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UF CHM 6304 - Cardiolipin

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Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Cardiolipin Xi HuangFeb 3, 2009CardiolipinStructureBiosynthesis and metabolismFunctionCardiolipin in diseaseDiphosphatidylglycerol 1,3-bis(sn-3’-phosphatidyl)-sn-glycerolIt’s usually found in certain membrane of bacteria and of mitochondria.It amounts to about 10% of the phospholipids of bovine heart muscle, and 20% of the phospholipids of the mitochondrial membrane in this organStructure of CardiolipinStructure of Cardiolipin____________________________________________________________________________Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002) 528 35-39Acyl chain - 18:2In heart mitochondria pK1≈3, pK2> 7.5Acid-anion bicyclic resonance structureOne of the protons is trapped____________________________________________________________________________Thomas H. Hainesa", Norbert A. Dencherb. (2002) FEBS Letters 528 35-39N10-N-Nonyl acridineNAOBiosynthesis and metabolismEukaryotic mechanismProkaryotic mechanismBiosynthesis and metabolismPLA2PLA2PLA2PLA2PLA2PLA2PLDPLDBuild quaternary structure 4 Fe 2+ -cytochrome c + 8 H+in + O2 → 4 Fe3+-cytochrome c + 2 H2O + 4 H+out Cytochrome c oxidase (Complex IV)need to form a dimer to catalysis the reaction. Cardiolipin help to connect the subunits with the complexCytochrome bc1(Complex III) also need cardiolipin to maintain its quaternary structureServe as proton trap for oxidative phosphorylation____________________________________________________________________________Thomas H. Hainesa", Norbert A. Dencherb. (2002) FEBS Letters 528 35-39Trigger apoptosis____________________________________________________________________________Natalia A. Belikova, Yury A. Vladimirov, at el. (2006) Biochemistry. 45, 4998-5009Cytochrome c released into cytosol  react with IP3 receptor on ER release calcium  large release of cytochrome cOther Functionscholesterol translocation from outer to the inner membrane of mitochondrial activates mitochondrial cholesterol side-chain cleavageImport protein into mitochondrialanti-coagulant function…..DiseaseBarth syndromemutation in the gene coding for tafazzin  can’t synthesis enough cardiolipin  not enough ATP productionDiabetes  higher heart attack rate diabetes  more active lipid-digesting enzyme  quicker catabolism of cardiolipin  heart attackAlzheimer’s disease and Parkinson’s disease Malfunction of cardiolipin metabolism in brain mitochondriaDifficulties in neutralizing HIV-1 envelopeTwo antibodies directed against MPR, 2F5, 4E10, react with self-antigens, including cardiolipinSuch antibodies would not be easily elicited by vaccination.____________________________________________________________________________Gary J. Nabel. (2005) Science. 308, 1878-1879ReferenceThomas H. Hainesa, Norbert A. Dencherb. (2002) FEBS Lett. 528, 35-39Gary J. Nabel. (2005) Science. 308, 1878-1879Antonio Ortiz, J. Antoinette Killian, et al. (1999) Biophysical Journal. 77, 2003–2014Mei Zhang, Eugenia Mileykovskaya and William Dowhan. (2002) J. Biol. Chem. 277, 43553–43556Natalia A. Belikova, Yury A. Vladimirov, et al. (2006) Biochemistry. 45, 4998-5009Valerian E Kagan, et al. (2005) Nat. Chem. Biol. 1, 223-232Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002) 528


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