Lecture Notes for Chapter 17 Lipid Metabolism

1. Essential Biochemistry Third Edition Charlotte W. Pratt | Kathleen Cornely Lecture Notes for Chapter 17 Lipid Metabolism

2. Approximately half of all deaths in the US are linked to atherosclerosis. • Atherosclerosis • A slow progressive disease • Characterized by hardening of the arteries due to lipid accumulation in blood vessel walls

3. Lipids are transported via various lipoproteins.

4. Lipoproteins transport cholesterol and other fats. HDL: orange Lipid core containingcholesterol, phospholipids,cholesterol esters: green Small angle neutron scattering of a high-density lipoprotein

5. Lipoprotein Function • Chylomicrons transport fats from intestines to tissues. • Very-low-density lipoproteins transport triacylglycerols from the liver to other tissues. • Low-density lipoproteins carry cholesterol to the tissues. • LDL levels should be relatively low. • LDL is commonly referred to as “bad cholesterol.” • High-density lipoproteins export cholesterol from the tissues to the liver. • HDL levels should be relatively high. • HDL is commonly referred to as “good cholesterol.”

6. Lipoprotein Function Illustrated

7. Lipid Metabolism In Context • Triacylglycerols contain fatty acids attached to a glycerol backbone. • Fatty acids are broken down into 2C and 3C intermediates that feed into the citric acid cycle.

8. KEY CONCEPTS: Section 17-1 • Fatty acids to be degraded are linked to coenzyme A and then transported into mitochondria. • The four reactions of each cycle of b oxidation produce acetyl-CoA, QH2, and NADH. • Additional enzymes are required to break down unsaturated fatty acids. • Fatty acids with an odd number of carbons yield propionyl-CoA that is ultimately converted to acetyl-CoA. • Peroxisomes oxidize long-chain and branched fatty acids, producing H2O2.

9. Triacylglycerols are the primary source of fatty acids.

10. Fatty acids are activated before they are degraded. • Activated fatty acids are acylated to CoA. • Reaction is driven by ATP hydrolysis.

11. Each round of β oxidation has four reactions. • Acyl groups are transferred via carnitine. • Acyl-CoA is degraded into acetyl-CoA.

12. β Oxidation is a spiral process. Let’s look at the reactions of b oxidation more closely.

13. β Oxidation

14. β Oxidation results in ATP production.

15. Fatty acids with cis double bonds pose a problem for enzymes in β oxidation.

16. Enoyl-CoA isomerase converts a cis 3,4 double bond to a trans 2,3 double bond so that β oxidation can continue.

17. When linoleate is degraded, another double bond blocks β oxidation.

18. Oxidation of odd-chain fatty acids yields propionyl-CoA.

19. Breakdown of Propionyl-CoA

20. Breakdown of Propionyl-CoA

21. Methylmalonyl-CoA mutase uses an unusual cofactor. • Co3+ forms a bond with carbon. • Cofactor comes from the vitamin cobalamin.

22. Some fatty acid oxidation occurs in peroxisomes. • Peroxisomes are organelles that are bound by a single membrane.

23. Fatty acid oxidation in peroxisomes differs from that in mitochondria. • Step 1: Electrons are transferred from FADH2 to H2O2 instead of ubiquinone

24. Peroxisomes also break down fatty acids unrecognized by mitochondrial enzymes.

25. KEY CONCEPTS: Section 17-2 • Fatty acid synthesis begins with the carboxylation of acetyl-CoA in the cytosol. • Fatty acid synthase catalyzes seven separate reactions to extend a fatty acid by two carbons. • Elongases and desaturases modify newly synthesized fatty acids. • Various metabolites contribute to the regulation of fatty acid synthesis. • Ketogenesis converts acetyl-CoA to small soluble ketone bodies.

26. Fatty acid synthesis differs from fatty acid breakdown. • For metabolic reasons, there are distinctions. • Acyl chains are carried by CoA in fatty acid oxidation. • Acyl chains are carried by acyl-carrier protein in fatty acid synthesis.

27. Acetyl-CoA carboxylase catalyzes the first step of fatty acid synthesis. • First, biotin is carboxylated. • Second, carboxyl group is transferred to acetyl-CoA. How does Acetyl-CoA get into the cytosol?

28. Acetyl groups move to the cytosol via the citrate transport system.

29. Fatty acid synthase catalyzes fatty acid synthesis. • 540-kD protein • Two identical polypeptide sequences • Six active sites per polypeptide

30. Fatty acid synthesis begins with two transacylation reactions. Then, the two products are condensed…

31. Condensation in Fatty Acid Synthesis

32. Subsequent Steps of Fatty Acid Synthesis

33. Palmitate Synthesis • Fatty acid synthesis cycles until a 16-C chain is formed. • A thioesterase releases the acyl-carrier protein.

34. Other enzymes catalyze elongation and desaturation reactions.

35. Control of Fatty Acid Metabolism Inhibition Activation

36. Acetyl-CoA can also form ketone bodies. • Formed when glucose is unavailable • Used to supply some of the brain’s energy needs

37. Catabolism of Ketone Bodies

38. KEY CONCEPTS: Section 17-3 • Acyl groups are transferred from CoA to a glycerol backbone to generate triacylglycerols and phospholipids. • Cholesterol is synthesized from acetyl-CoA. • Cholesterol can be used both inside and outside the cell.

39. Triacylglycerol synthesis requires a glycerol backbone and fatty acid activation.

40. Triacylglycerol Synthesis

41. Phospholipid Synthesis • Ethanolamine and choline are first phosphorylated. • CTP is used. • Inorganic pyrophosphate hydrolysis drives the reaction.

42. Phosphatidylserine Synthesis

43. Phosphatidylinositol Synthesis

44. Cholesterol synthesis begins with acetyl-CoA.

45. Cholesterol is derived from squalene. • Squalene is derived from the isoprenoid precursor.

46. Cholesterol can be used in several ways. • Embedded into membranes • Converted into esters for transport

47. Cholesterol can be used in several ways. • Cholesterol can be a precursor of: • Hormones such as testosterone, estrogen • Bile acids such as cholate

48. Cells can synthesize cholesterol as well as take it up from circulating low-density lipoproteins.

49. High-density lipoproteins remove excess cholesterol from cells.

50. Summary of Lipid Metabolism