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Fatty Acid Synthesis

Fatty Acid Synthesis. Fatty Acid Synthase Acetyl-CoA serves as a primer Addition of two-carbon units from malonyl-CoA Each two-carbon unit added must be reduced by 2 NADPH + 2 H + Reaction for the synthesis of Palmitic acid (C:16): Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14H +

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Fatty Acid Synthesis

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  1. Fatty Acid Synthesis • Fatty Acid Synthase • Acetyl-CoA serves as a primer • Addition of two-carbon units from malonyl-CoA • Each two-carbon unit added must be reduced by 2 NADPH + 2 H+ • Reaction for the synthesis of Palmitic acid (C:16): Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14H+ Palmitic acid + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O

  2. Cytosolic Acetyl-CoA & NADPH Generation (presented as in most text books, this scheme ignores the specificities of mitochondrial transporters; a more accurate description is in the handout) Glycolysis Mitochondrion Acetyl-CoA Pyruvate Citrate Pyruvate Oxaloacetate TCA cycle Malate Citrate Cytosol ATP + CoA Citrate lyase Malate dehydrogenase ADP + Pi Malic enzyme Pyruvate Malate Oxaloacetate + Acetyl-CoA NADPH + H+ + CO2 NADP+ NAD+ NADH+H+ ATP + CO2 Acetyl-CoA carboxylase ADP + Pi Malonyl-CoA Fatty acid synthesis

  3. Fatty Acid Synthesis • Malonyl-CoA is produced by Acetyl-CoA carboxylase Acetyl-CoA (cytoplasmic) + HCO3-Malonyl-CoA O || CH3-C-S-CoA O O || || - O-C-CH2-C-S-CoA ATP ADP + Pi Acetyl-CoA Carboxylase Requires Biotin

  4. Fatty Acid Synthesis • Acetyl-CoA Carboxylase • Rate limiting reaction for fatty acid synthesis • ACC1 is a liver isozyme • Small amounts of ACC2 are present in muscle where malonyl-CoA has a regulatory function (Fatty acid oxidation)

  5. Fatty Acid Synthesis • Acetyl-CoA Carboxylase 1 • Highly regulated • Allosteric activation by citrate; inhibition by palmitoyl-CoA. • Inhibited by phosphorylation in the fasting state. • (low blood glucose inhibits; phosphorylation state is determined by both glucagon activation of a kinase and insulin activation of a phosphatase). • Transcriptional up regulation by ChREBP (high carbohydrate diet increases amount of ACC1 and most other enzymes of fatty acid synthetic pathway)

  6. P P Transcriptional control Fatty Acid Synthesis Acetyl-CoA Carboxylase 1 Xylulose-5-phosphate Acetyl-CoA + Insulin Transcription Citrate Palmitoyl-CoA H2O Pi + ─ + CO2 ATP ADP + Pi Protein phosphatase Phosphorylated Acetyl CoA carboxylase PKA AMPK Acetyl CoA carboxylase Acetyl CoA carboxylase + + (Inactive) (Active) ADP + Pi ATP (Inactive) Glucagon AMP Malonyl-CoA Allosteric regulation Covalent modification

  7. Triacylglycerol Synthesis • Long-term transcriptional regulation by ChREBP (Carbohydrate Regulatory Element Binding Protein). • In addition to short term regulation of Acetyl-CoA carboxylase • Many enzymes of fatty acid & triacylglycerol synthetic pathway are coordinately regulated by ChREBP. • ChREBP is inhibited by Protein Kinase A dependent phosphorylation. • ChREBP is activated by Protein Phosphatase 2A dependent dephophorylation (PP2A is stimulated by Xyulose-5-P). Low Glucose: Glucagon cAMP Protein kinase A Inactive ChREPB-P Fatty acid synthesis High Glucose: Xyulose-5-P Protein Phosphatase A2 Active ChREPB-OH Fatty acid synthesis

  8. Fatty Acid Synthesis • The main product of fatty acid synthase is palmitic acid (16:0). • Fatty acids can be elongated by other enzymes that add two carbon units from malonyl-CoA. Elongation is particularly important in brain. • Still other enzymes can add double bonds (usually at 9 ). Omega-3 and omega-6 fatty acids can not be synthesized by humans.

  9. Triacylglycerol Synthesis • Fatty acids must be activated to Acyl-CoA Fatty acid + CoA + ATP Acyl-CoA + AMP + PPi PPi + H2O 2 Pi Acyl-CoA synthetase Pyrophosphatase

  10. Triacylglycerol Synthesis • Glycerol-3-phosphate is required for triacylglycerol synthesis. H2C-OH | HOCH O | | H2C-O-P-O - || O - H2C-OH | O=C O | | H2C-O-P-O - || O - Glycerol-3-phosphate dehydrogenase Dihydroxyacetone Phosphate Glycerol-3-phosphate NADH + H+ NAD+ Glycerol-3-phosphate dehydrogenase

  11. Triacylglycerol Synthesis • Addition of 3 Acyl groups from Acyl-CoA to Glycerol-3-phosphate Glycerol-3-phosphate Phosphatidate Triacylglycerol 2 Acyl-CoA CoA Acyl-CoA CoA + Pi

  12. VLDL formation Apolipoprotien B-100 has a repeating -helix/-sheet structure: Lipids are packaged as apolipoprotein B-100 is being synthesized: From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157

  13. VLDL formation • VLDL stands for Very Low Density Lipoprotein • As it is synthesized, VLDL contains: • One molecule of apoliprotein B-100 • Triacylglycerol • Phospholipid • Cholesterol ester • Microsomal Triacylglycerol Transfer Protein(MTP) assists in the formation of the VLDL • Other components are added to the VLDL in the blood.

  14. VLDL formation • Apolipoprotein B-100 synthesis is required for the transport of lipid out of the liver • If protein synthesis is reduced (e.g. by malnutrition) fat droplets accumulate in the liver. • If the rate of lipid synthesis is greatly elevated with respect to protein synthesis (e.g. in type I diabetes or glucose 6-phosphatase deficiency) fat droplets accumulate in the liver.

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