BMB 462 Lecture 10 Outline of Last Lecture I. Continuation of Fatty Acid Catabolisma. Beta-oxidation of fully saturated fatty acidsb. ATP yieldc. Beta-oxidation of mono- and polyunsaturated fatty acidsd. Odd chain fatty acidse. Peroxisomal beta-oxidationf. Other types and uses of beta-oxidationII. Ketone Bodiesa. Synthesisb. CatabolismOutline of Current Lecture I. Overview of Fatty Acid AnabolismII. Activation and Regulation by Acetyl-CoA Carboxylase (ACC)III. Coordinating Regulation of synthesis and DegradationIV. Synthesis CarriersV. Synthesis enzymes and cofactorsVI. Compare and Contrast synthesis vs. degradationVII. Locations of various processesVIII. Sources of electron carriersIX. Synthesis transporters and enzymesCurrent LectureConcepts to remembers from previous courses/lectures:- Reciprocal regulation (i.e. glycogen synthesis vs. glycogen breakdown; gluconeogenesis vs. glycolysis)- The Pentose Phosphate Pathway- Malate-aspartate shuttleI. Overview of Fatty Acid Anabolisma. The goal is to build a 16:0 fatty acidThese 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 Malonyl-CoA, 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-oxidationii. NADPH donates 2 e-1. Catabolism uses NADH and FADH2 (NAD and FAD are the e- acceptors), while anabolism uses NADPH as it’s e- donore. Dehydration – water is removed, changing the molecule from a hydroxyl to an enol.i. Again, the opposite of what happened in beta-oxidationf. Reduction – the double bond is removed in the second reduction so that the molecule is fully saturated. i. NADPH donates 2 e-g. 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 acidII. 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 carbons1. 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 highi. 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 regulation1. Citrate (the precursor for acetyl-CoA) does feed forward activationa. 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 acids2. There is also feedback inhibition: accumulation of product (i.e. palmytoyl-CoA) stops synthesisiii. Phosphorylation/Polymerization – regulated by glucose, insulin, and glucagon1. 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 synthesis2. 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 activationi. When dephosphorylated ACC forms long polymers, the hormone needed.3. Glucagon and epinephrine signal that you don’t want to make fatty acidsa. ACC becomes phosphorylated, which results in depolymerization, causing the inactive form.III. Coordinating Regulation of synthesis and Degradationa. Fatty acid synthesis and breakdown are reciprocally regulated b. Beta oxidation is controlled by import of fatty acids into the mitochondriai. This is facilitated by carnitine acyl-transferase, which essentially regulates beta-oxidationc. 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 ACCd. As malonyl-CoA concentration increases, it inhibits the function of Carnitine acyl-transferase 1i. This then blocks the import of fatty acids into the mitochondria and stops beta-oxidation1. 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 beta-oxidation will not (don’t want to be breaking down fatty acids if you’re synthesizing them).IV. Synthesis Carriers; –SH groups as carriersa. CoA – CoA is used in fatty acid breakdown as a fatty acid carrieri. 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 CoAb. 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. Structure1. Reactive SH group; also requires pantothenic acid for
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