BMB 462 Lecture 11 Outline of Last Lecture I Overview of Fatty Acid Anabolism II Activation and Regulation by Acetyl CoA Carboxylase ACC III Coordinating Regulation of synthesis and Degradation IV Synthesis Carriers V Synthesis enzymes and cofactors VI Compare and Contrast synthesis vs degradation VII Locations of various processes VIII Sources of electron carriers IX Synthesis transporters and enzymes Outline of Current Lecture I Elongation and Desaturation of fatty acids II Mixed function oxidases III Sources of Glycerol 3 phosphate IV Synthesis of Phosphatidic Acid and Triacylglycerol V Strategy for membrane lipid synthesis VI Phosphatidylethanolamine and Phosphatidylcholine Current Lecture Concepts to remembers from previous courses lectures Mixed function oxidases i e Cytochrome P450 using e from substrate but still need 2nd source of e to get all that is necessary I Elongation and Desaturation of fatty acids a Elongation and desaturation can occur in any order though it s more common to start with elongation b Mostly occurs in the smooth ER some elongation desaturation takes place in the mitochondria c Elongation the cell adds 2 carbons at a time to the carboxyl end of the molecule i It essentially involves the same 4 steps as fatty acid synthesis condensation reduction dehydration and a second reduction These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute d Desaturation double bonds are introduced 3 carbons apart i Desaturase always initially adds a double bond to carbon 9 in humans 1 Animals can only add bonds at positions 4 5 6 and 9 e Essential Fatty Acids because humans can only add double bonds at specific positions in the carbon chain there are fatty acids that can t be synthesized and must be ingested in the diet i i e linoleate Humans can t add double bond to position 12 but plants can so linoleate is an essential fatty acid and must be in diet ii It s important in making arachadonate precursor for eicosanoids signaling molecules iii EPA and DHA omega 3 fatty acids II Mixed function oxidases a i e Fatty acyl CoA Desaturase i It uses molecular oxygen as electron donor need 4 e to reduce oxygen ii e come from 2 from 2 carbons in fatty acid go to oxygen to make water 1 The remaining 2 come from NADPH to make the 2nd water III Sources of Glycerol 3 phosphate a Glycerol 3 phosphate is the backbone for phosphatidic acid b The cell gets glycerol from TAG breakdown i Glycerol is phosphorylated by glycerol kinase for glycerol 3 phosphate c Another route is to reduce the intermediate dihydroxyacetone phosphate i NADH is source of eii Also get glycerol 3 phosphate IV Synthesis of Phosphatidic Acid and Triglycerol a Phosphatidic acid i Phosphatidic acid is common intermediate in synthesis of lipids doesn t exist in any great quantity free in the cell intermediate in synthesis of TAG and phosphoglycerols ii Need to add 2 Fatty Acids to get from glycerol 3 phosphate to phosphatidic acid They re esterified to the carboxylate iii Activated Fatty Acids 1 It is not favourable to just add carboxylate to hydroxyl To aid in the reaction the cell activates them by adding CoAs a CoA added by acyl CoA synthase same enzyme from breakdown 2 CoA acts as an e sink to make the Carbon in the thioester bond more open to reaction This happens twice iv Transfer of Fatty Acids to Hydroxyls 1 Acyl transferases are what actually attach fatty acids to molecule b Triacylglycerols i Dephosphorylate Phosphatidic Acid 1 Need to add a third fatty acid but currently have a phosphate group in the way so need to dephosphorylate via phosphatases 2 Phosphatidic acid phosphatase dephosphorylates to make diacylglycerol and then use acyl transferase again to transfer another activated FA to 3rd hydroxyl ii The fatty acid is then transferred to the OH via acyl transferase V Strategy for membrane lipid synthesis a Both glycerophospholipids and sphingolipids are synthesized by first synthesizing the backbone then adding the fatty acids then the head group and finally altering or exchanging the head group as needed b Attachment of the glycerophospholipid head group i The backbone is made from glycerol 1 To attach the head group the glycerol needs to be activated there is a negative G when breaking down fatty acids and the rearrangement results in a release of free E 2 The cell withdraws e from components to make the backbone more electrophilic and open to attack and make better leaving groups activation does all this ii CTP is often used to activate alcohol head groups i e choline ethanolamine iii UTP is used to activate sugar head groups at least in mammals iv Start with phosphorylated head group and NTP The activated head group will have 2 phosphates attached to it as well as ribose and base CDP or UDP depending on head group CDP UDP linked intermediate is active form v Release pyrophosphate which is converted to 2 phosphates 1 This is a very negative G so it releases a lot of free energy which is needed to make the rest of the reaction move forward vi Strategies for activation you can either activate head group and attach to diacylglycerol or activate the phosphatidic acid and then attach the alcohol to that 1 Strategy 1 Phosphatidate activation Produce CDP diacylglycerol and then the alcohol head group attacks the activated CDP portion CDP leaves and OH head group can bind 2 Strategy 2 Head Group Activation This happens in the opposite way start with CDP head group which gets attacked by OH on diacylglycerol VI Phosphatidylethanolamine and Phosphatidylcholine a Strategy II is used to make phosphatidylethanolamine PE and phosphatidylcholine PC in mammals b To get Phosphatidylserine PS take PE break off ethanolamine and add serine c Getting PC from PE via methylation methyl transferases add the methyl group i AdoMet aka SAM donates methyl group it is an important coenzyme for adding the methyl
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