Fatty Acid and Amino Acid Catabolism Figures Essential Biochemistry 3rd Ed Pratt and Cornely Moran Principles of Biochemistry 4th 5th edition Tymoczko Berg Stryer Biochemistry A Short Course Lipoprotein Function Illustrated High density lipoprotein HDL Protein orange Lipid core containing cholesterol triglycerides phospholipids cholesterol esters green Lipoprotein Function refresh We have discussed how fatty acids are transported in the bloodstream primarily as triacylglycerides packaged in lipoproteins Chylomicrons transport fats from intestines to tissues Very low density lipoproteins VLDL transport triacylglycerols and cholesterol from the liver to other tissues Very low density lipoproteins mature to Low density LDL and Intermediate Density Lipoproteins carry to the tissues Both VLDL and LDL are commonly referred to as bad cholesterol High density lipoproteins export cholesterol from the tissues to the liver HDL is commonly referred to as good cholesterol Artherosclerosis Approximately half of all deaths in the US are linked to atherosclerosis A slow progressive disease Characterized by occlusion of the arteries due to lipid deposition and inflammation in blood vessel walls Macrophages come to remove lipid depositions but fail to do so causing inflammation and neointimal hyperplasia proliferation High levels of HDL and low levels of LDL VLDL help to prevent disease progress Physical activity increases levels of HDL and reduces risk of ischemic heart desease Fatty Acid Degradation Energy is stored in adipose tissues as fat triacylglycerols Fat catabolism is activated by hormones Glucagon and Epinephrine via G protein coupled receptor signaling Perilipin P Lipid droplets in adipocytes Perilipin reorganizes a lipid drop to make triglycerides more accessible and activates hormone sensitive lipase Adipocyte Fatty Acid Degradation Liver Glycerol kinase Fat Glycerol glycerol P Glycerol P Dehydrogenase Dihydroxyacetone P Triose phosphate isomerase Glyceraldehyde P Recall the role of Glycerol P Dehydrogenase in delivering electrons from cytoplasmic NADH to mit matrix FAs are transported by Serum albumin Energy demanding tissues Fatty Acid Degradation Glycerol is metabolized in liver to merge with glycolysis gluconeogenesis What enzymes are required for bringing glycerol to glycolysis Fatty acids have to be activated and enter mitochondria in order to be converted to Acetyl CoA and oxidized in TCA cycle Fatty Acid Degradation fate of glycerol Liver Recall the role of Glycerol 3 Phosphate dehydrogenase in delivering electrons from cytoplasmic NADH to mitochondria glycerol3P shuttle Fatty Acid Degradation Activation Fatty acid Acyl CoA 1 Activation via formation of AcylCoA AcylCoA synthetase 1A Formation of Acyl Adenylate and PPi 1B Formation of AcylCoA 1C Hydrolysis of PPi by Pyrophosphatase What is the purpose of the step 1C PPi H2O 2 Pi AcylCoA translocation into mitochondrion 1 Formation of Acyl carnitine from carnitine and Acyl CoA Carnitine Acyltransferase I Acyl CoA 4 Reverse translocation of Carnitine Carnitine Acyltransferase II 2 Translocation of AcylCarnitine across the inner mt membrane 3 Regeneration of AcylCoA from Acyl Carnitine and CoA Classification of metabolic pathways I Anabolic Catabolic Amphibolic II Linear majority Cycles Spiral 11 Acetyl CoA is generated by Fatty Acid Oxidation Oxidation is a Spiral Process Fatty Acids are oxidized two carbon atoms at a time to produce AcetylCoA There are four reactions in each round of oxidation Each round produces acetyl CoA ubiquinol QH2 and NADH Acetyl CoA NADH and FADH2 are generated by Oxidation of Fatty Acids 1 Oxidation 3 Oxidation AcylCoA dehydrogenase Hydroxyacyl CoA dehydrogenase 2 Hydration 4 Thiolysis EnoylCoA hydratase ketothiolase Fatty Acid oxidation proceeds in four recurring steps Why is it called oxidation recall the letter based nomenclature e g omega 3 fatty acids Compare to last 3 reaction of TCA cycle 1 Oxidation 2 Hydration 3 Oxidation A chain of nearly identical reactions generates the same electron carriers FADH2 QH2 and NADH Acetyl CoA NADH and FADH2 are generated by Oxidation 2 Hydration 1 Oxidation AcylCoA dehydrogenase EnoylCoA hydratase Trans 3 Oxidation Hydroxyacyl CoA dehydrogenase 4 Thiolysis ketothiolase Oxidation Generates Significant ATP One round of oxidation produces one molecule of acetyl CoA one ubiquinol QH2 and one NADH A total of 14 ATP molecules can be generated from every two carbons in a fatty acid Acetyl CoA NADH and FADH2 are generated by Fatty Acid Oxidation Cn acyl CoA FAD NAD H2O CoA Cn 2 acyl CoA FADH2 NADH H Acetyl CoA Therefore each 2 carbon atom group of FA generates 1 5 from FADH2 2 5 from NADH 10 from acetyl CoA in TCA cycle 14 molecules of ATP per cycle The last thiolysis reaction generates 2 Acetyl CoA For n 16 Palmitoyl CoA 7FAD 7NAD 7H2O 7CoA 7FADH2 7NADH 7H 8Acetyl CoA Palmitate gives 1 8x10 80 2 7x1 5 10 5 3 7x2 5 17 5 Total 108 But recall that 2 molecules were consumed upon activation Acyl CoA NET 106 molecules of ATP 1 Palmitate Net ATP yield Cn acyl CoA n 2 2 FAD n 2 2 NAD n 2 2H2O n 2 CoA n 2 2 FADH2 n 2 2 NADH n 2 2 H n 2 2 Acetyl CoA Acetyl CoA NET ATP yield for saturated fatty acids is ATP 1 5 2 5 10 n 2 2 10 2 ATP 14 n 2 2 10 2 ATP 7 n 2 8 Degradation of unsaturated fatty acids Palmitoleoyl CoA One less FADH2 molecule is produced for each double bond Same as for saturated Enoyl CoA isomerase converts a cis 3 4 double bond to a trans 2 3 double bond so that oxidation can proceed Same as for saturated How many FADH2 and NADH molecules can be produced from Linolenate Ketone bodies as an alternative fuel source Acetyl CoA can be converted to ketone bodies in the liver Ketone bodies acetoacetate 3 hydroxybutirate acetone Although not as energy efficient as fatty acids ketone bodies are water soluble and can be easily delivered from liver to other tissues Ketone bodies are abundant and particularly important in starvation For example heart can use ketone bodies as a preferable to glucose fuel source Ketone bodies are converted to Acetyl CoA in mitochondria of peripheral tissues Ketone bodies acetoacetate 3 hydroxybutirate acetone TCA cycle Why do we need ketone bodies In contrast to fatty acids they are soluble in water Recall that animals cannot convert Acetyl CoA into Glucose as they are missing the glyoxylate cycle present in fungi plants and bacteria Ketone Body Catabolism Fatty acid synthesis is the reversal of fatty acid decomposition Synthesis 4 steps