Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Cardiolipin Xi HuangFeb 3, 2009CardiolipinStructureBiosynthesis and metabolismFunctionCardiolipin in diseaseDiphosphatidylglycerol 1,3-bis(sn-3’-phosphatidyl)-sn-glycerolIt’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 Functionscholesterol translocation from outer to the inner membrane of mitochondrial activates mitochondrial cholesterol side-chain cleavageImport protein into mitochondrialanti-coagulant function…..DiseaseBarth syndromemutation in the gene coding for tafazzin can’t synthesis enough cardiolipin not enough ATP productionDiabetes higher heart attack rate diabetes more active lipid-digesting enzyme quicker catabolism of cardiolipin heart attackAlzheimer’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, 1878-1879ReferenceThomas H. Hainesa, Norbert A. Dencherb. (2002) FEBS Lett. 528, 35-39Gary J. Nabel. (2005) Science. 308, 1878-1879Antonio Ortiz, J. Antoinette Killian, et al. (1999) Biophysical Journal. 77, 2003–2014Mei Zhang, Eugenia Mileykovskaya and William Dowhan. (2002) J. Biol. Chem. 277, 43553–43556Natalia A. Belikova, Yury A. Vladimirov, et al. (2006) Biochemistry. 45, 4998-5009Valerian E Kagan, et al. (2005) Nat. Chem. Biol. 1, 223-232Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002) 528
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