BMB 462 Exam 2 Study Guide Lectures 10 17 Lecture 10 and 11 Begin Fatty Acid Anabolism Tell the big picture of fatty acid synthesis Goal build a 16 0 fatty acid using repeating 4 step process 1 unofficial step Activation of malonyl CoA using ATP 2 Condensation activated Acetyl CoA adds 2 carbons 3 Reduction the ketone group is reduced to a hydroxyl group a e are donated by NADPH 4 Dehydration water is removed the hydroxyl becomes an enol 5 2nd Reduction NADPH again donates 2 e so that the double bond is fully saturated Metabolic and regulatory roles of acetyl CoA carboxylase ACC uses biotin to add carbons since the biotin acts as a flexible swinging arm to move substrate for different carboxylation reactions Citrate is the precursor for ACC function Regulation ACC doesn t function w low glucose levels allosteric regulation by citrate phosphorylation polymerization regulated by glucagon and insulin depolymerization inhibits activity Reciprocal regulation of Fatty Acid Synthesis and Degradation Beta oxidation is controlled by import of fatty acids into mitochondria inhibition of the carnitine acyl transferase inhibits beta oxidation Citrate is a feed forward activator of ACC which makes malonyl CoA Malonyl CoA blocks carnitine acyl transferase function Compare and contrast sulfur containing compounds in fatty acid metabolism 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 stretchable arm can swing between active sites in big multifunctional enzymes i So rather than have the substrate diffuse through the membrane and have something happen to it it s locked into the enzyme and can t leave iii Function to tether growing fatty acids to the enzyme 1 It attaches growing fatty acids to the fatty acid synthase 2 It also acts as an e sink drawing e away from the active site so that chemistry can occur c Cysteine on Fatty Acid Synthase i Has a reactive SH group because of the cysteine and is tied to an enzyme ii Function to act as a holding slot it temporarily holds intermediates during synthesis Synthesis of Palmitate include intermediates enzymes and cofactors 1 MAT Malonyl Acetyl CoA ACP transferase adds substrates acetyl CoA and malonylCoA 2 KS Beta ketoacyl ACP synthase does a condensation reaction to form betaKetoacyl ACP 3 KR beta ketoacyl ACP reductase reduces the molecule using NADPH as an edonor creates beta hydroxyl 4 Dehydration by HD beta Hydroxyacyl ACP dehydratase to generate a double bond between alpha and beta carbons 5 2nd Reduction by ER Enoyl ACP reductase uses e from NADPH to fully saturate the 4 carbon acyl 6 KS returns to move the saturated fatty acid butyryl back to cysteine Compare and contrast fatty acid synthesis and beta oxidation a Synthesis i Location cytoplasm ii Acyl carrier acyl carrier protein iii Electron Donor NADPH iv D beta hydroxyacyl group v Electron Donor NADPH vi C2 donor malonyl CoA b Degradation i Location Mitochondria ii Acyl Carrier CoA iii Electron Acceptor FAD iv L beta hydroxyacyl group v Electron Acceptor NAD vi C2 product Acetyl CoA Compare and contrast structure of fatty acid synthase i Vertebrates all enzymes on 1 polypeptide 1 Makes it really easy to regulate turn on one protein and the whole thing is functioning 2 But also reduces flexibility in production everything is there so the fatty acid made will only have 16 0 Fas ii Fungi all enzymes on 2 polypeptides iii Plants and Bacteria each enzyme is on a different polypeptide 3 This gives more flexibility part of reason plants can produce a lot more diverse FAs 4 Also means you have to regulate everything carefully so have different promoters to make sure you get the right amount of everything Describe locations of various steps in fatty acid metabolism a Oxidation Mitochondria in animals peroxisomes in plants b Synthesis Occurs in the ER for both plants and animals In plants synthesis also occurs in the chloroplasts In animals it can also occur in the cytosol c Elongation Occurs in the ER for both plants and animals In animals elongation occurs in mitochondria as well iii In this way animal mitochondria and ER are like bacteria the systems probably came from bacteria iv Elongation is the same chemistry as synthesis process but we have a bunch of different enzymes in membrane of ER mito that are doing cyclic process v Elongation is for adding Cs to 16 0 to make it longer d Desaturation Occurs in the ER for both plants and animals Describe substrate energy and reducing power sources and the shuttle system NADPH from the pentose phosphate pathway Malic Enzyme part of shuttle system that moves acetyl CoA out of the mitochondria Citrate transporter moves citrate into cytosol Lecture 12 Describe modification of palmitate to longer and or unsaturated fatty acids Elongation and desaturation typically occurs in the smooth ER Elongation adds 2 carbons at a time to carboxylate end of the fatty acid Essentially uses the same 4 steps described for fatty acid synthesis Desaturation double bonds are added 3 carbons apart starting at position 9 In humans double bonds can only be added to positions 4 5 6 and 9 Explain why some fatty acids are essential to the human diet For fatty acids that require double bonds in positions other than 4 5 6 9 i e linoleate Plants can add a bond to position 12 but humans can t Describe mixed function oxidases oxygeneases relate these to fatty acid desaturation A 2nd source of e is needed 2 e come from the carbons being oxidized but the process needs 4 e total The other 2 e come from donors such as NADPH Begin TAG Glycerophospholipid and sphingolipid anabolism Describe the big picture of lipid
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