Lecture 26 FA Catabolism PDF

Lipid metabolism 1. Digestion, mobilisation and oxidation of fats 2. Fatty acid synthesis 3. Cholesterol metabolism About one-third of our energy needs comes from dietary triacylglycerols (TAGs). Oxidation of fatty acids is a major energy source About 80% of energy needs of mammalian heart...

Lipid metabolism 1. Digestion, mobilisation and oxidation of fats 2. Fatty acid synthesis 3. Cholesterol metabolism About one-third of our energy needs comes from dietary triacylglycerols (TAGs). Oxidation of fatty acids is a major energy source About 80% of energy needs of mammalian heart and liver are met by oxidation of fatty acids. Hibernating Animals and Land-locked Polar Bears Get the Majority of Their Energy from Stored Fatty Acids  Fats Provide Efficient Fuel Storage The advantage of fats over polysaccharides: – Fatty acids carry more energy per carbon because they are more reduced. – Fatty acids complex or carry less water because they are nonpolar. Glucose and glycogen are for short-term energy needs and quick delivery. Fats are for long-term (months) energy needs, good storage, and slow delivery.  Mobilisation of fats 1. Dietary fats 2. Storage fats Dietary Fatty Acids Are packaged into chylomicrons FAs released and absorbed in the Small Intestine  Lipids Are Hydrophobic – Must Be ‘Packaged’ to be Transported in the Blood CHYLOMICRONS Released into intestinal lymphatic system before draining into large veins. Bloodstream delivers Chylomicrons throughout body. Application: avoiding hepatic metabolism during drug delivery Small lipophilic drugs associated with a long chain triglycerides can be incorporated into chylomicrons and taken from the intestines to the lymph to the bloodstream, thereby avoiding the liver MCT = medium chain triglycerides GML = glyceryl monolinoleate, a long chain triglyceride SEDDS = a self-emulsifying formula made with GML  Hydrophobic lipids are packaged with apolipoproteins in the blood for transport Chylomicrons: density access to surface of lipid droplet. 7. P-HSL converts DAG to MAG. 8. MAG lipase (MGL), hydrolyzes MAG to fatty acids and glycerol. 9. Fatty acids leave adipocyte, bind serum albumin, and are carried in the blood 10. FAs released from alb., enter myocyte via specific transporter. 11. Myocyte: fatty acids oxidized to CO2 > ATP > muscle contraction and other metabolism. CGI = “comp. gene ID”  In response to cAMP, PKA regulates multiple pathways to achieve glucose homeostasis Glycogen metabolism Activates fatty acid metabolism - glycogen synthase (inhibits, glycogen is - hormone-sensitive lipase (activates) no longer formed from glucose) - the body uses fats as fuel - glycogen phosphorylase kinase (activates, glycogen is broken down into glucose) PKA Inhibits glycolysis - PFK-2 (inhibits)/fructose 2,6-bisphosphatase (activates) - pyruvate kinase (inhibits) - the body stops using glucose as fuel Glycerol from Fat Enters Glycolysis Glycerol kinase phosphorylates glycerol - uses ATP. Subsequent oxidation recovers more than enough ATP to cover this cost. Allows limited anaerobic catabolism of fats Intracellular Transport Requires Conversion to Fatty Acyl-CoA Fatty acid + CoASH + ATP fatty acyl-CoA + AMP + PPi Fatty acyl-CoA synthetase Inorganic pyrophophatase 2 Pi ΔG°’ = -34 kJ/mol  Fatty acids must be transported into mitochondria for oxidation Fats are degraded into fatty acids and glycerol in the cytoplasm of adipocytes. FAs are transported to other tissues via the blood.  oxidation of fatty acids occurs in mitochondria. Small (< 12 carbons) fatty acids diffuse freely across mitochondrial membranes. Larger fatty acids (most free fatty acids) are transported via acyl-carnitine/carnitine transporter. Quaternary ammonium compound  Acyl-Carnitine/Carnitine Transporter - FA into mitochondria Carnitine acyltransferase 2 IMM reattaches fatty acid to Co-A Carnitine Enters matrix - acyltransferase 1 counter-exchange. OMM, attaches FA Acylcarnitine - to carnitine > fatty carnitine transporter acyl carnitine - diffuses across IMS  Fatty Acid Oxidation Occurs in the Mitochondria in Three Stages: Stage 1: oxidative conversion of 2-C units to acetyl-CoA via  oxidation: generates NADH and FADH2. – oxidation of  carbon to thioester of fatty acyl-CoA Stage 2: oxidation of acetyl-CoA into CO2 via citric acid cycle > NADH and FADH2. Stage 3: ATP from NADH and FADH2 via ox. phos.  The -Oxidation Pathway Each “pass” removes one acetyl moiety in the form of acetyl- CoA: Oxidation (FAD) Hydration Oxidation (NAD) Thiolation  Step 1: Acyl-CoA dehydrogenase: Dehydrogenation of Alkane to Alkene Isoforms of acyl-CoA dehydrogenase (AD) on the IMM – very-long-chain AD (12–18 carbons) – medium-chain AD (4–14 carbons) – short-chain AD (4–8 carbons) > trans double bond Analogous to succinate dehydrogenase (TCA cycle) – electrons from bound FAD transferred directly to the electron- transport chain via electron- transferring flavoprotein (ETF)  Step 2: Enoyl-CoA Hydratase Two isoforms – soluble short-chain hydratase (crotonase) – membrane-bound long-chain hydratase Water adds across the double bond yielding alcohol on  carbon. Analogous to fumarase reaction in the citric acid cycle Step 3 - -hydroxyacyl-CoA dehydrogenase Uses NAD as hydride acceptor. Analogous to malate dehydrogenase (CAC) Step 4 - Acyl-CoA acetyltransferase (thiolase) releases acetyl-CoA. CoA-SH picks up the fatty acid chain from the enzyme. Net reaction = thiolysis of the carbon-carbon bond Oxidation of Unsaturated Fatty Acids Results in 1 fewer FADH2 after isomerization, but 1 FADH2 is produced during the first step of the next cycle. NADPH reduces the remaining unsaturated bond, resulting in no further loss of FADH2. NADH and FADH2 serve as sources of ATP TABLE Yield of ATP during Oxidation of One Molecule of 17-1 Palmitoyl-CoA to CO2 and H2O Number of Number of ATP NADH or ultimately Enzyme catalyzing the oxidation step FADH2 formed formeda β Oxidation Acyl-CoA dehydrogenase 7 FADH2 10.5 β-Hydroxyacyl-CoA dehydrogenase 7 NADH 17.5 Citric acid cycle Isocitrate dehydrogenase 8 NADH 20 α-Ketoglutarate dehydrogenase 8 NADH 20 Succinyl-CoA synthetase 8b Succinate dehydrogenase 8 FADH2 12 Malate dehydrogenase 8 NADH 20 Total 108 aThese calculations assume that mitochondrial oxidative phosphorylation produces 1.5 ATP per FADH2 oxidized and 2.5 ATP per NADH oxidized. bGTP produced directly in this step yields ATP in the reaction catalyzed by nucleoside diphosphate kinase (p. 516).