BMB 462 Lecture 10 Outline of Last Lecture I Continuation of Fatty Acid Catabolism a Beta oxidation of fully saturated fatty acids b ATP yield c Beta oxidation of mono and polyunsaturated fatty acids d Odd chain fatty acids e Peroxisomal beta oxidation f Other types and uses of beta oxidation II Ketone Bodies a Synthesis b Catabolism Outline of Current 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 Current Lecture Concepts to remembers from previous courses lectures Reciprocal regulation i e glycogen synthesis vs glycogen breakdown gluconeogenesis vs glycolysis The Pentose Phosphate Pathway Malate aspartate shuttle I Overview of Fatty Acid Anabolism a The goal is to build a 16 0 fatty acid 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 i Like breakdown synthesis is a repeated 4 step process activation could be considered an additional step ii Has similar steps to breakdown just running in the opposite direction b Activation the cell uses ATP to make Malonyl CoA 1st step requires input of energy to activate the substrate c Condensation activated Acetyl CoA adds 2 carbons to the growing fatty acid i Energy comes from decarboxylation from the starting 3 carbon MalonylCoA 2 carbons are added to the fatty acid and the 3rd leaves as CO2 to provide energy ii A second source of energy is from thioester hydrolysis d Reduction The fatty acid is changed from having a ketone group to a hydroxyl group i The opposite of what happened in beta oxidation ii NADPH donates 2 e1 Catabolism uses NADH and FADH2 NAD and FAD are the eacceptors while anabolism uses NADPH as it s e donor e Dehydration water is removed changing the molecule from a hydroxyl to an enol i Again the opposite of what happened in beta oxidation f Reduction the double bond is removed in the second reduction so that the molecule is fully saturated i NADPH donates 2 eg Repeat begin again by adding the 2 carbons from the activated 3 carbon malonyl precursor i The process repeats until there is a 16 0 fatty acid II Activation and Regulation by Acetyl CoA Carboxylase ACC a Creates malonyl CoA by combining acetyl CoA and CO2 with ATP 2 carbons from acetyl CoA and 1 carbon from CO2 i Carboxylation is similar to the breakdown of branched chain fatty acids ii ACC uses Biotin to add the carbons 1 Both subunits have a site to add carboxyl group to biotin 2 There is a swinging arm that starts at one end ATP is used to add CO2 to biotin and then the arm swings over to other activation site which is substrate specific 3 The substrate gets carboxylated adding C from CO2 4 This common process for carboxylation of substrate though not the only way b Citrate is the precursor for the function of ACC citrate lyase uses citrate to make acetyl CoA c Regulation The body doesn t want to be making fatty acids when glucose levels are low glucose needs to be high i Glucose using the pentose phosphate pathway can generate NADPH for reduction using glycolysis and pyruvate decarboxylase can generate Acetyl CoA that you need as precursor 1 Also generate ATP that you need as energy for biosynthesis ii Allosteric regulation 1 Citrate the precursor for acetyl CoA does feed forward activation a If synthesis is happening in the cytosol and citrate levels start increasing ACC becomes more active i With the precursor coming ACC is more reactive and needs to start making fatty acids 2 There is also feedback inhibition accumulation of product i e palmytoyl CoA stops synthesis iii Phosphorylation Polymerization regulated by glucose insulin and glucagon 1 Their levels tell you about the status of the whole organism Glucagon and epinephrine decrease the activity of ACC while insulin activates it a High blood sugar triggers fatty acid synthesis 2 Insulin dephosphorylates ACC it s quite common for insulin to dephosphorylate the final target enzyme preventing it from functioning a This results in polymerization of ACC which means activation i When dephosphorylated ACC forms long polymers the hormone needed 3 Glucagon and epinephrine signal that you don t want to make fatty acids a ACC becomes phosphorylated which results in depolymerization causing the inactive form III Coordinating Regulation of synthesis and Degradation a Fatty acid synthesis and breakdown are reciprocally regulated b Beta oxidation is controlled by import of fatty acids into the mitochondria i This is facilitated by carnitine acyl transferase which essentially regulates beta oxidation c Citrate in the cytosol is a precursor for malonyl CoA so as citrate increases ACC becomes more active and malonyl CoA levels increase i Citrate becomes a feed forward activator of ACC d As malonyl CoA concentration increases it inhibits the function of Carnitine acyltransferase 1 i This then blocks the import of fatty acids into the mitochondria and stops beta oxidation 1 Carnitine acyl transferase is big in fatty acid breakdown so it s blocked by a synthesis intermediate ii Aka high citrate levels mean fatty acid synthesis will occur and betaoxidation will not don t want to be breaking down fatty acids if you re synthesizing them IV Synthesis Carriers SH groups as carriers a CoA CoA is used in fatty acid breakdown as a fatty acid carrier i It has a reactive SH group that can form thioester bonds with fatty acid groups which activates the fatty acids for beta oxidation ii It requires pantothenic acid for synthesis so in order to make CoA you need pantothenic acid in your diet it s an essential nutrient iii CoA can diffuse between enzyme active sites due to an ADP handle that binds to the enzyme active site 1 Many different enzymes bind to CoA b Acyl Carrier Protein ACP i Analogous to biotin it tethers to the substrate and can swing it so that one reaction occurs at one active site and then it can move the substrate to another active site for another reaction ii Structure 1 Reactive SH group also requires pantothenic acid for synthesis 2 Major difference from CoA there s a prosthetic group that covalently attached to a protein a In animals this means that it is bound to the protein and then the long
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