LIpid Metabolism

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Biochemistry & Molecular Bio.
David Gross

Chapter 17 Lipid Metabolism • lipoproteins are the primary form of circulating lipid • dietary lipids travel from the intestine to other tissues as chylomicrons • the primary function is to transport dietary triacylglyceros to adipose tissue & cholesterol to liver • liver repackages cholesterol & other lipids into very-low-density lipoproteins (VLDL) • high-density lipoproteins (HDL) is good cholesterol 17-1 FattyAcid Oxidation • oxidation of fatty acids is source of metabolic free nrg • dietary triacylglycerols are primary source of fatty acids used as fuel • triacylglycerols carried by lipoproteins to tissues • hydrolysis releases their fatty acids from glycerol backbone o catalyzed by lipoprotein lipase, happens extracellularly • fatty acids travel through bloodstream bound to albumin • concentration of free fatty acids in body is very low b/c they are detergents • fatty acids are activated before they are degraded o first fatty acid displaces diphosphate group ofATP  has large free nrg, conserves free nrg of cleaved phosphoanhydride bond o then coenzyme Adisplaces AMP group to form acyl-CoA  conserves free nrg in formation of thioester bond o overall rxn has free nrg change near 0  subsequent hydrolysis of PP highly exergonic, makes rxn spontaneous & irreversible o fatty acids activated in cytosol but oxidative pathway occurs in mitochondria • each round of beta oxidation has 4 rxns o beta oxidation pathway degrades acyl-CoAin way that produces acetyl-CoA molecules for further oxidation & nrg production by the CAC o also feeds e- directly into mitochondrial e- transport chain, generatingATP by oxidative phosphorylation o beta oxidation is a spiral pathway, each round consists of 4 enzyme-catalyzed steps that yield 1 molecule of acetyl-CoA& an acyl-CoAshortened by 2 C’s which is the starting point for the next round o the 4 rxns of beta oxidation  oxidation of [email protected] 2,3 position catalyzed by acyl-CoA dehydrogenase, yields 2,3-enoyl-CoA • 2 e- removed from acyl transferred to FAD prosthetic group, eventually transferred to Q  second step catalyzed by hydratase, adds water across double bond produced in first step  hydroxyacyl-CoAoxidized by another dehydrogenase w/ NAD as cofactor  final step, thiolysis, catalyzed by thiolase, releases acetyl-CoA, another round begins o beta oxidation happens @ 2,3 position, not methylated end o each round produces QH2, NADH, & acetyl-CoA  CAC oxidizes acetyl-CoAfor 3 NADH, 1 QH2, 1 GTP  oxidation of reduced cofactors yields approximately 13ATP  in total 14ATP generated from each beta oxidation round o beta oxidation regulated by availability of free CoA& rations of NAD/NADH & Q/QH2 • degradation of unsaturated fatty acids requires isomerization & reduction o enoyl-CoAisomerase converts the cis 3,4 double bond (when encountered) to a trans 2,3 double bond, beta oxidation can then continue o b/c of a double bond @ the 4,5 position (in linoleate) the dienoyl-CoAis not good substrate for enoyl-CoAhydratase  undergoes NADPH-dependent reduction, converts two double bonds to single trans 3,4 double bond  product isomerized again to produce trans 2,3 double bond recognized by enoyl-CoAhydratase • oxidation of odd-chain fatty acids yields propionyl-CoA o the final round of beta oxidation of odd-chain fatty acids leaves 3-C fragment, propionyl-CoAat end rather than acetyl-CoA o complete catabolism of C’s derived from propionyl-CoArequires that succinyl- CoAbe converted to pyruvate and then to acetyl-CoA which enters CAC as substrate o steps of catabolism of propionyl-CoA  propionyl-CoAcarboxylase adds carboxyl group to C2 of propionyl group, forms 4-C methylmalonyl group  racemase interconverts 2 different methylmalonyl-CoA stereoisomers  methylmalonyl-CoAmutase rearranges C skeleton, generates succinyl- CoA  succinyl-CoA(CAC intermediate) converted to malate by rxns 5 – 7 of CAC  malate exported from mitochondria, decarboxylated by malic enzyme, produces pyruvate in cytosol  pyruvate imported into mitochondria, converted to acetyl-CoAby pyruvate dehydrogenase complex • some fatty acid oxidation occurs in peroxisomes o peroxisomes are enclosed by a single membrane and contain a variety of degradative & biosynthetic enzymes o peroxisomal beta oxidation pathway differs from mitochondrial in first step  acyl-CoAoxidase catalyzes rxn instead of acyl-CoAdehydrogenase  product enoyl-CoA identical to mitochondrial product, but e- removed from acyl-CoA transferred to molecular O to produce hydrogen peroxide instead of going to Q o peroxisomal oxidation enzymes specific for very-long-chain fatty acids, serves as chain-shortening system for mitochondria o also responsible for degrading branched-chain fatty acids, not recognized by mitochondrial enzymes 17-2 FattyAcid Synthesis • pathways for fatty a
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