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Lecture 15

BCH210 2014 Lecture 15.pdf

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Stavroula Andreopoulos

Lecture 15 Fat SynthesisNaturally after this heavy meal insulin rises in the blood and drives fat synthesis in liver o Insulin will be released from pancreas to deal with rise in sugar Liver readily converts glucose into pyruvate via aerobic glycolysiso Forms acetyl CoA CO and NADH 2 Some of acetyl CoA is used for the Krebs cycle for form citrate but acetyl CoA can also be converted into malonyl CoA by acetyl CoA carboxylase o So much fuel doesnt need to mobilize will be making more storage forms of fuels o Krebs does form citrate and going around making small amounts of ATPDoesnt have huge ATP requirements since not doing much exercisingo Excess citrate formed by Krebs can leak out from mitochondria into cytoplasmCan convert back into acetyl CoAo Acetyl CoA in cytoplasm can then be used to make malonyl CoA by putting CO on end of acetyl CoA 2 Carboxylation reactionrequires energyBreaking off CO releases a lot of energy 2 Putting CO on molecule have to supply energy2 Fat synthesis takes place in the cytoplasmFatty acid processing stages 1 Use of mitochondrial acetyl CoA to generate cytoplasmic acetyl CoA 2 Conversion of acetyl CoA to malonyl CoA via carboxylation by acetylCoA carboxylase 3 Use of malonyl CoA to form fatty acid chains 4 steps i Through a carboxylation reaction CitrateMalatePyruvate shuttle o Acetyl CoA cannot cross inner mitochondrial membrane o Citrate synthase converts acetyl CoA and oxaloacetate to citratecrosses inner membrane o ATPcitrate lyase breaks down citrate to reform acetyl CoA and oxaloacetate o OxaloacetateNADHMalatePyruvateNADPH o Aceyl CoA is then used to form fatty acid chains and pyruvate returns to the mitochondriaFatty acid synthesis o Occurs to store excess carbons as triacylgycerides o Acetyl CoA must be exported from the mitochondria to this cytoplasmic pathway o Acetyl CoA is used to produce 2 carbon unit precursors for fatty acid synthesis o Requires ATP and NADPH as reducing power o Also provides NADPH regeneration o Once acetyl CoA is converted into malonyl CoA there is no going back and we must build fatty acidCitrateMalatePyruvate ShuttleacetylCoA cannot cross the inner mitochondrial membranecitrate synthase converts acetylCoA and oxaloacetate to citrate which crosses the inner membraneATPcitrate lyase breaks down citrate to reform acetylCoA and oxaloacetateOxaloacetate NADHmalatepyruvate NADPHacetylCoA is then used to form fatty acid chains and pyruvate returns to the mitochondriaAnabolic Fatty Acid Synthesisfatty acid synthesis occurs to store excess carbons as triacylclyceridesfatty acid synthesis occurs in the cytoplasmacetylCoA must be exported from the mitochondria to this cytoplasmic pathwayacetylCoA is used to produce 2 carbon unit precursors for fatty acid synthesisthis anabolic pathway requires ATP and NADPH as reducing powerin addition to pyruvate regeneration the pentosephosphate pathway also provides NADPHAcetyl CoA Carboxylase ACC Enzyme that carboxylates acetyl CoAmalonyl CoAcytosolic polymeric enzyme that carries 2 reactionscontains biotin cofactors and requires ATPMalonyl CoA inhibits the carnitine shuttle at CPTI or CAT1 enzyme and shuts down fatty acid oxidation o Carnitine shuttleregulates oxidation effects of fatty acids o Already has a ton of sugar doesnt need more sugar o Shut down catabolic processes o Dont want to mobilize fat if insulin is rising since going to anabolic sequence Malonyl CoA is made by acetyl CoA carboxylase ACC in the cytoplasm using ATP as an energy sourceACC has the coenzyme biotin to carry CO for donation to 2acetyl CoA o Biotin first catches CO and bind to enzyme ACC 2o Then take CO on enzyme and add to substrate acetyl CoA to form malonyl ClA 2 Acetyl CoAATPHCO3Malonyl CoAADPPiHMalonyl CoA is the supplier of 2C units in FA synthesisCytosolic polymeric enzyme that carries out two reactionsCarboxylation of biotin o BiotinenzymeATPHCO3CO2biotin enzymeADPPIHBiotin carboxylaseAdds carboxyl group onto biotinTransfer of carboxyl group too acetyl CoA o CO2biotin enzymeacetyl CoAmalonyl CoAbiotin enzyme TranscarboxylaseTransfers CO2 group onto acetyl CoAContains biotin cofactors and requires ATPNeed ATPActivated by citrateInactivated by palmitoylCoAFinal FA product product inhibition Inhibit use of fat for energy o Enzyme needs to bind to CO2 first then take it and transfer it to substrate Insulin also profoundly inhibits hormone sensitive lipase in fat cells and shuts down fat mobilization
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