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BIOC 460 DR. TISCHLER LECTURE 34

BIOC 460 DR. TISCHLER LECTURE 34. SYNTHESIS & PROCESSING OF FATS. OBJECTIVES. Sequence leading from glucose to fatty acids via lipogenesis including roles of pyruvate carboxylase and pyruvate dehydrogenase . Malic enzyme and acetyl CoA carboxylase 3. For fatty acid synthase :

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BIOC 460 DR. TISCHLER LECTURE 34

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  1. BIOC 460 DR. TISCHLER LECTURE 34 SYNTHESIS & PROCESSING OF FATS

  2. OBJECTIVES • Sequence leading from glucose to fatty acids via lipogenesis including roles of pyruvate carboxylase and pyruvate dehydrogenase. • Malic enzyme and acetyl CoA carboxylase • 3. For fatty acid synthase: • a) substrates/key products; b) sources of NADPH; • c) general mechanism • Relationship: regulation of carnitine-palmitoyl transferase-I and preventing oxidation of synthesized palmitoyl CoA • 5. Eicosanoids: • a) fatty acid from which they are derived; • b) specific functions of each eicosanoid; • c) general pathway of production; effects of glucocorticoids (cortisol) and aspirin

  3. LIPOGENESIS • principally in adipose tissue and liver • lipogenesis – cytoplasm; requires acetyl CoA • adipose: FA stored as triacylglycerols via esterification • liver: produces TAG packaged into VLDL and exported • compounds metabolized to acetyl CoA can serve as a fat precursor • glucose = primary source of carbons for fat synthesis.

  4. Glucose PPP NADH, CO2 NAD, CoA Glycolysis Fatty Acids PDH Pyruvate CO2 Pyruvate Acetyl CoA ATP, CO2 NADPH ME PC FAS NADP+ Malate ADP, Pi NAD+ Malonyl CoA CS ADP, Pi MDH Oxaloacetate ACC NADH CO2, ATP Oxaloacetate Acetyl CoA ADP+Pi ATP, CoA CL Citrate Citrate CYTOPLASM MITOCHONDRIAL MATRIX Figure 1. Export of acetyl CoA as citrate for fatty acid biosynthesis, generation of NADPH and pathway of lipogenesis.

  5. KEY MITOCHONDRIAL REACTIONS PYRUVATE CARBOXYLASE pyruvate + CO2 + ATP  oxaloacetate + ADP + Pi PYRUVATE DEHYDROGENASE pyruvate + NAD + coenzyme A (CoA)  acetyl CoA + CO2 + NADH

  6. KEY CYTOPLASMIC REACTIONS INDIRECTLY NEEDED FOR LIPOGENESIS Citrate Lyase citrate + CoA + ATP acetyl CoA + oxaloacetate + ADP + Pi Malate dehydrogenase oxaloacetate+ NADH malate + NAD+ Malic Enzyme malate + NADP+pyruvate + NADPH

  7. KEY CYTOPLASMIC REACTIONS DIRECTLY NEEDED FOR LIPOGENESIS AND FATTY ACID ACTIVATION Acetyl CoA Carboxylase: acetyl CoA + HCO3- + ATP malonyl CoA + ADP + Pi Fatty 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

  8. reduction dehydration reduction condensation A C P A C P CE acp CE acp 2 NADPH 2 NADP+ C=O C=O C=O C=O C=O CH2 CH2 CH2 CH2 CH2 C=O C=O C=O C=O C=O C=O CH2 CH3 CH3 CH3 CH3 CH3 CH3 CH3 C=O CH2 C=O CH3 A C P CE acp CO2 CO2 CO2 CO2 COO- malonyl CoA acetyl CoA 4-C unit Figure 2. General mechanism for the fatty acid synthase reaction. CE is condensing enzyme. ACP is acyl carrier protein. This row represents the initial steps for priming the reaction with acetyl CoA and the addition of two carbons from malonyl CoA.

  9. reduction dehydration reduction A C P A C P A C P condensation CE acp CE acp CE acp 2 NADPH 2 NADP+ CO2 6-C unit 6-C unit malonyl CoA 4-C unit Figure 2. General mechanism for the fatty acid synthase reaction. CE is condensing enzyme. ACP is acyl carrier protein. This row depicts a typical cycle of adding two more carbons to the fatty acid chain.

  10. 5 more cycles adding 10 more carbons A C P A C P A C P 5malonyl CoA 10NADPH 16-C unit palmitate CE acp CE acp CE acp 5CO2 10NADP+ thioesterase cleavage malonyl CoA 6-C unit palmitate Figure 2. General mechanism for the fatty acid synthase reaction. CE is condensing enzyme. ACP is acyl carrier protein. This row shows the release of the finished product, palmitate, through cleavage by thioesterase.

  11. Sources of NADPH for the Biosynthesis of Fatty Acids. malic enzyme: Malate + NADP+ Pyruvate + CO2 + NADPH pentose phosphate pathway: Glucose-6-P + 2 NADP+ Ribulose-5-P + 2 NADPH + CO2

  12. Glycerol Dihydroxyacetone phosphate ATP glycerol kinase fatty acyl CoA ADP CoA Glycerol-3-P fatty acyl CoA Acyldihydroxyacetone phosphate NADPH CoA NADP+ fatty acyl CoA Pi CoA phosphatase fatty acyl CoA CoA Lysophosphatidic acid Phosphatidic acid Diacylglycerol Triacylglycerol Figure 3. Formation of phosphatidic acid from glycerol-3-P or DHAP, and its conversion to triacylglycerol

  13. EICOSANOIDS • hormones localized to tissues where they are produced. • prostaglandins, thromboxanes and leukotrienes. • derived from arachidonic acid • arachidonic acid from linoleic acid an essential fatty acid Table 1. Physiological functions of eicosanoids.

  14. Leuokotrienes Lipoxygenase Thromboxanes in platelets Prostaglandins in many cells Membrane Phospholipid Phospholipase A2 inhibited by glucocorticoids Arachidonic acid Cyclooxygenase inhibited by aspirin, ibuprofen PGH2 Figure 4. Conversion of arachidonic acid to eicosanoids.

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