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Summary of key points: • for fat synthesis, glucose is converted to pyruvate that in turn produces acetyl CoA in mitochondria; acetyl CoA carbons in the mitochondria are transported to the cytoplasm via citrate formed by condensing oxaloacetate and acetyl CoA; citrate is cleaved in the cytoplasm to liberate acetyl CoA for lipogenesis • NADPH for lipogenesis is derived from malic enzyme and the pentose phosphate pathway • acetyl CoA carboxylase converts acetyl CoA to malonyl CoA in a biotinrequiring reaction • fatty acid synthase progressively adds two carbon units, from malonyl CoA, to a growing acyl chain to form the 16-carbon palmitic acid in a process that requires 2 NADPH for each addition • fatty acid synthase uses acetyl CoA to prime the start of the formation of palmitic acid • in liver fat is stored by esterification of glycerol phosphate from glycerol or dihydroxyacetone phosphate, as carbon backbones, with long chain fatty acids, primarily palmitate while other tissues can only use dihydroxyacetone phosphate Glycerol Fatty Acids Lipolysis Phospholipids A C S Triacylglycerol Phosphatidic Acid Glycerol-P Esterification Fatty Acyl-CoA -Oxidation Glucose Pyruvate Acetyl-CoA Glycolysis L i p o g e n e s i s Steroids Steroidogenesis Cholesterol Cholesterogenesis Ketogenesis 2 CO2 CITRIC ACID CYCLE Ketone Bodies Figure 1. Interactions of lipid metabolic pathways Objectives: 1. Describe the process by which carbons from glucose are used for the synthesis of fatty acids including the intracellular compartments involved in the process of supplying these carbons. Glucose CYTOPLASM Fatty Acids PPP NAD+, CoA Glycolysis CO2 NADPH NADP+ Malate NAD+ MDH NADH Oxaloacetate ADP+Pi CL PDH Pyruvate ATP, CO2 Pyruvate ME FAS Malonyl CoA ADP, Pi ACC CO2, ATP Acetyl CoA MITOCHONDRIAL MATRIX NADH, CO2 Acetyl CoA PC ADP, Pi Oxaloacetate CS ATP, CoA Citrate Citrate Figure 2. Export of acetyl CoA as citrate for fatty acid biosynthesis, generation of NADPH and pathway of lipogenesis. Any compounds that are metabolized to acetyl CoA can be precursors for fat synthesis Acetyl CoA is required for fatty acid synthesis it is produced in the mitochondria from the metabolism of pyruvate via PDH Acetyl CoA is not transported directly across the mitochondria Citrate carries these in from the mitochondria to the cytoplasm Pyruvate transported into mitochondrial matrix and converted to acetyl CoA or Oxaloacetate via PC in = amounts Combine to form citrate in Citric Acid Cylce ↑[ ] in the matrix it is translocated via tricarboxylate translocase In cyctoplasm it is cleaved by citrate lyase(CL) producing acetyl CoA for lipogenesis & oxalacetate as products To recycle carrier carbons oxaloactetate is reduced to malate via a cytoplasmic malate dehydrogenase(MDH) with NADH providing reducing power NADP oxidizes the malate to pyruvate and CO2 in the reaction catalyzed by malic enzyme Oxaloacetate from the citric acid cycle is never consumed in the overall carbon transport 2. Identify the sources of NADPH for lipogenesis. NADPH is derived from malic enzyme & the pentose pathway 3. Describe the acetyl CoA carboxylase and fatty acid synthase reactions, identifying their substrates, products and cofactors as well as the vitamin precursors of the cofactors. Figure 3. Key enzymes in the synthesis of palmitoyl CoA via lipogenesis and acyl CoA synthetase. Acetyl CoA Carboxylase: acetyl CoA + HCO3- + ATP4- malonyl CoA + ADP3- + Pi2Fatty Acid Synthase: acetyl CoA + 7 malonyl CoA + 14 NADPH + 14 H+ palmitate + 7 CO2 + 8 CoA + 14 NADP+ Acyl CoA Synthetase: (also used for fatty acids other than palmitate) palmitate + ATP + CoA palmitoyl CoA + AMP + PPi Acetyl CoA Carboxylase committed step for fat biosynthesis. Highly regulated. Catalyzes a biotin dependant reaction(prosthetic group) Fatty Acid Synthase progressively adds 2 carbon units from malonyl CoA to a growing acyl chain to form the 16-carbon palmitic acid in process that requires 2NADPH for each addition 4. Discuss the general mechanism of the fatty acid synthase reaction. C E A C P ACP = acyl carrier protein CE = condensing enzyme acetyl CoA malonyl CoA SH SH Malonyl CoA CoA 2CoA C E A C P S CO2 COO[2] S C=O C=O C E A C P C E [3] COO- A C P [4] SH S SH S C=O CH3 CH2 C=OC=O COOCH3 CH 3 [5] 2NADP+ 2NADPH CH2 C=O C E A C P C E A C P S SH S S C=O C=O C=O C=O CH2 CH2 CH2 CH2 CH2 CH2 CH2 COO- CH3 CH3 CH3 CH3 Figure 4. General mechanism for FAS. Steps 1 - 4 represent the first cycle that generates a 4-carbon intermediate. Step 5 prepares for further chain growth A C C E P S S C=OC=O CH2 CH2 [9] A C C E P S SH Palmitate C=O [8] A C C E P [7] A C C E P SH S SH S 2NADP+ 2NADPH C=O C=O CH2 CH2 CH2 CH2 CH2 CH2 C=O CH2 CH2 CH2 CH2 CH2 CH3 CH3 CH3 [6] CH2 COOCH3 CO2 Figure 4. General mechanism for FAS. Addition of 2 carbons continues until palmitate is formed and then released for activation Fatty Acid synthase 2 components of the fatty acid complex are the condensing enzyme (CE) and acyl carrier protein (ACP) both contain a free sulfhydryl group (SH) SH group is derived from phosphopanthetheine ACP & CE form a heterodimer therefore the SH groups are in close proximity 1. Attachment of the acetyl group from acetyl CoA to the CE & the malonyl group from malonyl CoA to ACP 2. Acetyl group from CE condenses with the malonyl residue on the ACP causing the release of CO2 & leaving a 4 carbon intermediate covalently bound to ACP 3. 2 molecules of NADPH from niacin a 4 carbon fatty acid is formed 4. That is transferred to the CE site 5. To continue adding 2 carbon units to growing acyl chain a second molecule of malonyl CoA is attached to the vacated site on ACP 6. 6 additional cycles that include condensation of the growing acyl chain from CE with the new malonyl group on ACP 7. Multiple reduction of this product to form a new acyl chain that is 2 carbons longer 8. Transfer of this acyl chain back to the CE site 9. 6 thru 8 continue until palmitate is formed & is released from the ACP site to the CE site Total of 7 cycles are required to form palmitate with oxidation of 14 molecules of NADPH 2 per cycle NOTE → product of lipogenesis is the free fatty acid NOT fatty acyl CoA form Coenzyme A derivative of palmitic acid is formed by a separate enzyme acyl CoA synthetase . 2 high energy bonds are consumed for activation Palmitoyl CoA can undergo elongation & desaturation Elongation → is a microsomal process (ER) requiring malonyl CoA and 2 NADPH in a process similar to that occurring on fatty acid synthase Desaturation → microsomal process reducing power is derived from NADH or NADPH & molecular oxygen is required as well 5. Outline the general process of esterification of glycerol-3-phosphate or dihydroxyacetone phosphate with long chain fatty acids to form triacylglycerols in liver. Glycerol ATP glycerol kinase + (liver/kidney) NAD ADP Glycerol-3-P fatty acyl CoA CoA NADH glycerol-3-phosphate dehydrogenase fatty acyl CoA Lysophosphatidic acid Dihydroxyacetone phosphate (from glycolysis – all tissues) CoA Phosphatidic acid Diacylglycerol Pi fatty acyl CoA CoA Triacylglycerol Figure 6. Formation of phosphatidic acid from glycerol-3-phosphate or dihydroxyacetone phosphate, and its conversion to triacylglycerol Palmitoyl CoA is incorporated into acylglycerols via esterfication Adipose tissue cells lack glycerol kinase so that DHAP is the only source of carbon backbones in this tissue Phospholipids are formed by addition of polar head groups to the phosphate moiety