1. Chapter Twenty-One
Lipid Metabolism

2. Lipids are Involved in Generation and Storage of Energy
The oxidation of fatty acids (FA)in triacylglycerols are the principal storage form of energy for most organisms
Their carbon chains are in a highly reduced form
The energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate oxidized

3. Catabolism of Lipids
Lipases catalyze hydrolysis of bonds between fatty acid and the rest of triacylglycerols
Phospholipases catalyze hydrolysis of bonds between fatty acid and the rest of phosphoacylglycerols
May have multiple sites of action

4. Fatty Acid Activation Fatty acid oxidation begins with activation
A thioester bond is formed between the carboxyl group of the FA and the thiol of CoA-SH

5. Liberation of Fatty Acids from Triacylglycerols

6. The Role of Carnitine in Acyl-CoA Transfer
The acyl-CoA crosses the outer mitochondrial membrane, but not the inner membrane
The acyl group is then transferred to carnitine, carried across the inner mitochondrial membrane, and transferred to mitochondrial CoA-SH
Carnitine Palmitoyltransferase I (CPT-I, carnitine acyltransferase I) has specificity for acyl groups between 14 and 18 carbons long

7. The Role of Carnitine in Acyl-CoA Transfer (Cont’d)
translocase

8. -Oxidation
-Oxidation: a series of reactions that cleaves carbon atoms two at a time from the carboxyl end of a fatty acid
The complete cycle of one -oxidation requires four enzymes
Reaction 1: Oxidation of the , carbon-carbon single bond to a carbon-carbon double bond
Reaction 2: Hydration of the carbon-carbon double bond
Reaction 3: Oxidation of the -hydroxyl group to a carbonyl group
Reaction 4: Cleavage of the carbon chain by a reverse Claisen reaction

9. -Oxidation (Cont’d)

10. b-Oxidation Gives Rise to Nine 2-Carbon Units

11. Summary
Fatty acids are activated and transported to the mitochondrial matrix for further catabolism
The breakdown of fatty acids takes place in the mitochondrial matrix and proceeds by successive removal of two-carbon units as acetyl-CoA
Each Cleavage of a two-carbon moiety requires a four-step reaction sequences called -oxidation

12. Energy Yield from FA Oxidation
The energy released by the oxidation of acetyl-CoA formed by -oxidation of FA can be used to produce ATP
Eight cycles of -oxidation are required for the oxidation of Stearic acid to acetyl-CoA

13. Energy Yield from FA Oxidation (Cont’d)
The overall equation for oxidation of stearic acid can be obtained by adding the equations for b-oxidation, the citric acid cycle, and oxidative phosphorylation

14. Energy Yield from FA Oxidation (Cont’d)

15. Summary
The complete oxidation of FA by the citric acid cycle and the electron transport chain releases large amounts of energy
When we include the reoxidation of NADH and FADH2 from -oxidation and the citric acid cycle, we obtain a net yield of 120 ATP for a single molecule of stearic acid

16. Catabolism of Odd-Numbered FA
Odd-numbered FA are not frequently encountered, but do also undergo -oxidation
The last -oxidation cycle of a fatty acid with an odd number of carbons gives propionyl-CoA, which can be converted to methyl malonyl-S-CoA, and succinyl-S-CoA

17. Oxidation of an Unsaturated FA
A cis-trans isomerization is needed to convert unsaturated FA to acetyl-CoA
This enzyme is known as an isomerase
Oxidation of unsaturated FA does not generate as much ATP relative to saturated FA with the same # of carbons

18. Oxidation of an Unsaturated FA (Cont’d)
FADH2

19. Summary
FA with odd number of carbons produce propionyl-CoA in the last step of the oxidation
Propionyl-CoA can be converted to succinyl-CoA, which plays a role in the citric acid cycle
The oxidation of unsaturated FA requires enzymes that catalyze isomerization around the double bonds so that oxidation can proceed

20. Ketone Bodies
Formation of ketone bodies occurs when the amount of acetyl-CoA produced is excessive compared to the amount of oxaloacetate available to react with it
Intake high in lipids and low in carbohydrates
Diabetes not suitably controlled
Starvation
Ketone bodies are: acetone, -hydroxybutyrate, and acetoacetate
Formed principally in liver mitochondria
Can be used as a fuel in most tissues and organs

21. Ketone Bodies (Cont’d)
Summary:
• If an organism has an excess of acetyl-CoA, it produces ketone bodies.
• This situation can arise from an excessive intake of fats compared to carbohydrates, or from diabetes.

22. Fatty Acid Biosynthesis
Biosynthesis is not exact reversal of oxidation
Biosynthetic reactions occur in the cytosol

23. Fatty Acid Biosynthesis (Cont’d)
Carboxylation of acetyl-CoA occurs in the cytosol
Catalyzed by acetyl-CoA carboxylase
Biotin is the carrier of the carboxyl group
Malonyl-CoA is key intermediate that is produced

25. Biosynthesis of Palmitate from Acetyl- and Malonyl-CoA

26. Biosynthesis of Palmitate from Acetyl- and Malonyl-CoA

28. Sites of Fatty Acid Metabolism in an Animal Cell

29. Comparison of FA Degradation and Biosynthesis
Summary
• Acetyl-CoA is transported to the cytosol and converted to malonyl-CoA
• The biosynthesis of FA proceeds by the addition of 2-carbon units to the hydrocarbon chain. The process is catalyzed by the fatty-acid synthase complex
Comparison of FA Degradation and Biosynthesis

30. Triacylglycerol Biosynthesis
Lipids, such as, triacylglycerols, phosphoacylglycerols, and steroids are derived from FA and metabolites of FA

31. Biosynthesis of Phosphoacylglycerols
Bacteria
Eukaryotes

33. Biosynthesis of Sphingosine/Ceramide
Require starting materials palmitoyl-CoA and serine

34. Cholesterol Biosynthesis
All carbon atoms of cholesterol and steroids synthesized from it are derived from the two-carbon acetyl group of acetyl-CoA
Involves many reaction steps
Involvement of isoprene units are key to the biosynthesis of steroids and other biomolecules known as terpenes

35. Overall View of Cholesterol Biosynthesis

36. Cholesterol Biosynthesis (Cont’d)
Synthesis begins with the condensation of two molecules of acetyl-CoA
Next, condensation with a third molecule of acetyl-CoA
The formation of mevalonate is completed by reduction of the thioester that gives a 1° alcohol
Committed step
See ketone body at p601

37. Mevalonate to Squalene
The pyrophosphorylation of the 1° alcohol of mevalonate (two moles of ATP) is followed by phosphorylation of the 3° alcohol (one mole of ATP), then the concerted decarboxylation and -elimination of phosphate ion gives isopentenyl pyrophosphate
Then there is an enzyme-catalyzed isomerization of the carbon-carbon double bond that gives dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is then reacted with isopentyl pyrophosphate, which is followed by H+ loss to give farnesyl pyrophosphate
The joining together of two units of farnesyl pyrophosphate (C15) units by a two-electron oxidation gives squalene (C30)

38. The Conversion of Mevalonate to Squalene

39. Squalene to Cholesterol

40. Cholesterol as a Precursor
Cholesterol is the precursor for a number of steroid hormones

41. Role of Cholesterol in Heart Disease
Lipids are transported in the blood stream by lipoproteins
Cholesterol and its fatty acid esters are packaged into several classes of lipoproteins for transport

42. The LDL Particle

43. The Fate of Cholesterol

44. Summary
The biosynthesis of cholesterol proceeds by the condensation of five-carbon isoprenoid units
Isoprenoid units in turn are derived from the reaction of three acetyl-CoA units
Once cholesterol is formed, it serves as a precursor for other steroids
Cholesterol must be packaged for transport in the bloodstream. Some of these forms of cholesterol play a role in heart disease

45. Problem set
1, 3, 5, 11, 12, 14, 18, 20, 21, 24, 25, 28, 30, 37, 38, 44, 47, 48
Homework (Due day: Nov, 26th)
Figure 21. 3, Figure 21. 4, Figure 21. 5, Figure 21. 6, Figure , Figure , Figure