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Metabolism of lipids I. Triacylglycerols Major energy reserve Oxidation: 9 kcal/g (for carbohydrates: 4 kcal/g) 11 kg of 70 kg total body weight Site of accumulation: cytoplasm of ADIPOSE CELLS Specialized for synthesis, storage, mobilization of lipids Lipases Hormone-sensitive lipase - Regulated by hormones: adrenaline, noradrenaline, glucagone, ACTH cAMP stimulation of protein kinase A phosphorylation of lipase LIPOLYSIS Hormone-sensitive lipase Fatty acids • Long hydrocarbon chain and terminal carboxyl group • ( D double bound) . Physiological roles of fatty acids: *Stored as triacylglycerols (triglycerides) *Hormones, intracellular messengers *Fuel molecules *Building blocks of phospholipids, glycolipids The most important fatty acids Number of carbons Number of double bonds Name 16 0 Palmitate 18 0 Stearate 20 0 Arachidate 16 1 Palmitoleate Cis D9 18 1 Oleate Cis D9 18 2 Linoleate Cis D9, D12 18 3 Linolenate Cis D9, D12, D15 20 4 Arachidonate Cis D5, D8, D11, D14 The most important fatty acids • Unbranched, if unsaturated, double bonds always cis • Short chain length and unsaturation – lower melting point - enhanced fluidity Activation of fatty acids Activation of fatty acids: Fatty acid + ATP + CoA <------> Acyl-CoA + PPi + AMP Acyl-CoA synthase O 1. R-COOH + ATP R C AMP + PPi O O R C P O Ribose Adenin O acyl-adenylate O O 2. R C AMP + HS-CoA R C S CoA + AMP acyl-CoA Activation of fatty acids: on the outer mitochondrial membrane Partial reactions are reversible (equilibrium constant ~ 1) Reaction is driven by hydrolysis of pyrophosphatase PPi 2Pi (two high energy bonds are consumed, one is formed) Activation of fatty acids Transport of fatty acids (long chain) in the mitochondrial matrix The mitochondrial Carnitine System CPT I carnitinepalmitoyl transferase I; CT carnitine:acylcarnitine translocase; CPT II carnitinepalmitoyl transferase II; CAT carnitine-acetyl transferase; The Mitochondrial Carnitine System ß-oxydation of fatty acids • One round: – chain is shortened by two carbon atoms • FADH2 • NADH • Acetyl~CoA ß-oxydation of fatty acids • One round: – chain is shortened by two carbon atoms • FADH2 • NADH • Acetyl~CoA Next cycle starts ß-oxydation of fatty acids Energy yield O CH3 CH2 7 CH2 CH2 CH2 1 cycle 1 FADH2 (2) 1 NADH + H+ (3) 1 Ac-CoA (12) CH2 CH2 CH2 C O CH3 C S CoA O CH3 CH2 7 CH2 CH2 CH2 Palmitoyl-CoA + 7 FAD + 7 NAD + 7 CoA + 7 H2O 8 Ac-CoA + 7 FADH2 + 7 NADH + 7 H+ 8 x 12 7x 2 7x 3 131 - 2 (for activation) net: 129 ATP CH2 CH2 CH2 C S O CH3 C S CoA O CH3 CH2 7 CH2 CH2 CH2 C S CoA O CH3 C O CH3 CH2 7 CH2 C S CoA S CoA CoA S CoA For our example using a 16 carbon fatty acid (palmitate) the overall reaction for one round of oxidation is (myristol CoA is palmitoyl CoA minus 2 carbons): Palmitoyl CoA + FAD + NAD + CoA + H2O NADH + H+ + acetyl CoA Myristoyl CoA + FADH2 + Of course to completely degrade palmitoyl CoA would require 7 rounds of beta oxidation: 1) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA 2) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3CO-CoA 3) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA 4) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA 5) CH3-CH2-CH2-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA 6) CH3-CH2-CH2-CH2-CH2-CO-CoA + CH3-CO-CoA 7) CH3-CH2-CH2-CO-CoA + CH3-CO-CoA After the 7th round you are left with an 8th acetyl CoA (CH2-CO-CoA). So the equation for the complete degradation of palmitate is: Palmitoyl CoA + 7FAD + 7NAD + 7CoA + 7H2O 7NADH + 7H+ 8 Acetyl CoA + 7FADH2 + What is the ATP yield from oxidation of palmitate? •8 acetyl CoA enter citric acid cycle and give: •24 NADH = 72 ATP (by oxidative phosphorylation) •8 FADH2 = 16 ATP (by oxidative phosphorylation) •8 GTP = 8 ATP •7 NADH generated by beta oxidation itself = 21 ATP (by oxidative phosphorylation) •7 FADH2 generated by beta oxidation itself = 14 ATP (by oxidative phosphorylation) Total number of ATP from 1 molecule of palmitate = 72 + 16 + 8 + 21 + 14 = 131. But remember we used to high energy phosphate bonds (equivalent of 2 ATP) to activate palmitate to palmitoyl CoA. Therefore, the ATP yield is 129. Oxydation of unsaturated fatty acids • Two additional enzymes are required – Isomerase – Epimerase H H O C1 CH3 CH2 5 C4 C3 CH 2 2 S CoA cis D3 - enoyl-CoA Double bound, cis Wrong position Isomerase • Palmitoleate (C16 D9) – three cycles and in the third round isomerase O H 3 C1 CH3 CH2 5 C4 C CH 2 2 H S CoA trans D2 - enoyl-CoA Oxydation of unsaturated fatty acids CH3 CH2 5 H H CH2 C C O C S CoA cis enoyl-CoA Double bound, cis right position Hydration enoyl CoA hydratase O H CH3 CH2 CH2 C 5 CH2 C S CoA D-hydroxyacyl-CoA CoA L-hydroxyacyl-CoA OH Epimerase OH CH3 CH2 CH2 C 5 H O CH2 C S Conversion of glycerol Glycerol is converted to the Glycolysis intermediate dihydroxyacetone phosphate, by reactions catalyzed by: (1) Glycerol Kinase (2) Glycerol Phosphate Dehydrogenase. Glycolysis Pyruvate Gluconeogenesis Glucose Fatty acids oxidation Sequential removal of two carbon units – 1904 – Franz Knoop Dogs food in the urine COOH CH2 CH2 COOH phenylpropionate CH2 CH2 CH2 COOH phenylbutyrate benzoate CH2 COOH phenylacetate Oxidation of odd chain fatty acids Control of fatty acid oxidation Energy charge (high) Hormones (adrenaline, glucagon) stimulate hormone-sensitive lipase Malonyl-CoA NADH inhibits carnitine acyltransferase I. 3-hydroxiacyl CoA Dehydrogenase & thiolase Free fatty acids Oxidation no entry of fatty acyl CoA into mitochondria ß-oxidation inhibited Oxidation