CHAPTER 21 Lipid Biosynthesis

1. CHAPTER 21Lipid Biosynthesis Biosynthesis of fatty acids and eicosanoids Key topics: • Biosynthesis of triacylglycerols • Biosynthesis of cholesterol 白麗美 醫學一8F, 5520 pai@mail.cgu.edu.tw

2. Lipids Fulfill a Variety of Biological Functions Storage of energy Constituents of cellular membranes Anchors for membrane proteins Cofactors for enzymes Signaling molecules Pigments Detergents Transporters Antioxidants

3. Catabolism and Anabolic of Fatty Acids Proceed via Different Pathways Catabolism of fatty acids produced acetyl-CoA reducing power to NADH location: mitochondria • Anabolism of fatty acids • - requires malonyl-CoA and acetyl-CoA • - reducing power from NADPH • - location: cytosol in animals, chloroplast in plants

4. Fig. 21.1 The Acetyl-CoA carboxylase reaction • ACC is a bifunctional enzyme • Biotin carboxylase • Transcarboxylase

6. Fig. 21.2 Addition of two carbons Four steps

8. Fig. 21.3 Multifunctional Polypeptide Fatty acid synthase thioesterase

9. Palmitate synthesis

10. First acyl

11. Acyl carrier protein

15. Condensation with acetate -ketoacyl-ACP synthase (KS)

16. Reduction of carbonyl to hydroxyl -ketoacyl-ACP reductase (KR)

17. Dehydration of alcohol to alkene • -hydroxyacyl-ACP dehydratase (DH)

18. Reduction of alkene to alkane • enoyl-ACP reductase (ER)

19. Chain transfer • Malonyl/acetyl-CoA ACP • transferase

21. Figure 21-7 Second round of the fatty acid Synthesis cycle

22. Figure 21-8 Subcellular localization of lipid metabolism Glycolysis produce NADH, in cytosol NADH/NAD is small

23. Figure 21-9 Production of NADPH Hepatocyte and adipocyte

24. Figure 21-10 Not from fatty acid

25. Figure 21-11 Regulation of fatty acid synthesis Acetyl-CoA carboxylase Active-dephosphorylation 1. Allosteric regulation citrate, palmitoyl CoA 2. hormone- insulin-dP (activation) glucagon and epinephrine P (inactivation) 3. plant: Mg 2+ , pH, illumination 4. bacteria-cell growth guanine nucleotide 5. Gene level: polyunsaturated FA inhibit lipogenic enzyme in liver

26. Figure 21-12 synthesis of other fatty acids Elongation: smooth ER and mitochondria Acetyl CoA from Malonyl CoA Coenzyme A as acyl carrier Essential fatty acid

27. Figure 21-13 Desaturation of fatty acids in vertebrates Oxidation on both, on smooth ER

28. Box 21-1 Mixed function oxidases (fatty acyl-CoA desaturase), oxygenases, and cytochrome P450 Oxidase: O2 as electron acceptor e.g. fatty acid oxidation in peroxisomes cytochrome oxidase in mitochondria most: flavoproteins Oxygenase: O2 into substrate As hydroxyl or carboxyl group Dioxygenase

29. Box 21-1 Mixed function oxidases, oxygenases, and cytochrome P450 Monooxygenase (hydroxylases, mix-function oxidases (oxygenase)) Heme protein-cytochrome P-450 (SER) Hydroxylation –adrenocortical hormone Drug-soluble , Detoxification Figure, 21-13, 16, 30, 37, 47

30. Figure, 21-14 Action of plant desaturation ER and chloroplast Membrane fluidity

31. Figure, 21-15 (a) the cyclic pathway Eicosanoids: biological signal molecules Local hormone G-protein linked receptor (SER) COX: Prostaglandin H2 synthase

32. Figure, 21-15 (b) the cyclic pathway Cyclooxygenase: Cox-1: prostaglandins-gastric mucin (protect) Cox-2: prostaglandins-inflammation, pain, fever

33. Figure, 21-15 (b) nonsteroidal anti-inflammatory drug (NSAID) minicking the structure of the substrate or an intermediate Thromboxanesynthase PGH2 to thromboxane A2-constriction of blood vessels and platelet aggregation (under COX1 pathway) Low doses of aspirin reduce heart attacks and strokes

34. Figure21-15C Cox-2-specific drugs , 1,000 times difference to Cox-1 and Cox-2 Reduce prostacyclin (COX2) Dilates blood vessels)

35. Figure, 21-16 the linear pathway lipooxygenase (mix-function oxidases) Leukocytes, heart, brain, lung, and spleen Use cytochrome P-450 (SER)

36. Figure, 21-17 Biosynthesis of phosphatidic acid Liver and kidney

37. Figure, 21-18 Biosynthesis of triacylglycerol

38. Figure, 21-19 Regulation of triacylglycerol synthesis by insulin Reduce cAMP- reduce lipolysis: reduce free fatty acid in blood Citrate lyase ACC

39. Figure, 21-20 the triacylglycerol cycle –low when other fuels available 75% released to form TAG in liver

40. Figure, 21-21Glyceroneogenesis In adipocyte: glucagon and epinephrine Suppress glycolysis Little DHAP is available no glycerol kinase in adipocyte No glucose synthesis DHAP

41. Glucocorticoil hormones regulate PEP carboxykinase In the liver and adipose tissue

42. Figure, 21-22 regulation of glyceroneogenesis Increase flux of TAG cycle

43. High levels of free fatty acids in the blood Interfere with glucose utilization in muscle Promote insulin resistance-type 2 diabetes Thiazolidinediones-reduce fatty acids in the blood Increase sensitivity to insulin

44. Figure, 21-22 regulation of glyceroneogenesis This drug binds to and activate a nuclear hormone receptor -peroxisome proliferator activated receptor g Increase PEP carboxykinase in adipose tissue

45. Synthesis of malonyl-CoA, and fatty acyl chain 2. Regulation of fatty acid synthesis 3. Mixed function oxidase 4. Eicosanoids (NSAID) 5. Biosynthesis of triacylglycerol and the TAG cycle