Generation and Storage of Energy

2. Generation and Storage of Energy • The oxidation of fatty acids (FA)in triacylglycerols is the _________________________________ 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 • ____________catalyze hydrolysis of bonds between fatty acid and the rest of triacylglycerols • __________________ 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 ____________ • A thioester bond is formed between the carboxyl group of the FA and the thiol of CoA-SH

5. The Role of Carnitine in Acyl-CoA Transfer • The acyl-CoA crosses the ____________ mitochondrial membrane, but not the ____________ membrane • The acyl group is then transferred to carnitine, carried across the inner mitochondrial membrane, and transferred to mitochondrial CoA-SH • Carnitine Palmitoyltransferase (CPT-1) has specificity for acyl groups between 14 and 18 carbons long

6. The Role of Carnitine in Acyl-CoA Transfer

7. -Oxidation • -Oxidation: a series of reactions that cleaves carbon atoms __________ 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

8. -Oxidation

9. 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

10. Energy Yield from FA Oxidation • The energy released by the oxidation of acetyl-CoA formed by -oxidation of FA can drive ___ synthesis • ____________ cycles of -oxidation are required for the oxidation of stearic acid to acetyl-CoA

11. Energy Yield from FA Oxidation • The overall equation for oxidation of stearic acid can be obtained by adding the equations for b-oxidation, the ______________________, and ___________________________________

12. Energy Yield from FA Oxidation

13. 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

14. 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 ______________________________

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

16. Oxidation of an Unsaturated FA

17. 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

18. 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 _______ and low in ______________ • Diabetes not suitably controlled • Starvation • Ketone bodies are: acetone, -hydroxybutyrate, and acetoacetate • Formed principally in ___________ mitochondria • Can be used as a fuel in most tissues and organs

19. Ketone Bodies 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.

20. Fatty Acid Biosynthesis • Biosynthesis is not exact reversal of oxidation • Biosynthetic reactions occur in the ___________

21. Fatty Acid Biosynthesis • Carboxylation of acetyl-CoA occurs in the cytosol • Catalyzed by acetyl-CoA carboxylase • ___________ is the carrier of the carboxyl group • Malonyl-CoA is key intermediate that is produced

22. Biosynthesis of Palmitate

23. Sites of Fatty Acid Metabolism in an Animal Cell

24. 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

25. Triacylglycerol Biosynthesis Lipids such as triacylglycerols, phosphoacylglycerols, and steroids are derived ___________ __________________

26. Biosynthesis of Phosphoacylglycerols

27. Biosynthesis of Sphingosine/Ceramide Requires starting materials _______________and serine

28. Cholesterol Biosynthesis • All carbon atoms of cholesterol and steroids synthesized from it are derived from the two-carbon acetyl group of ___________________ • Involves many reaction steps • Involvement of ___________units are key to the biosynthesis of steroids and other biomolecules known as ________

29. Overall View of Cholesterol Biosynthesis

30. Cholesterol Biosynthesis • Synthesis begins with the condensation of 2 molecules of __________________ • Next, condensation with a 3RD molecule of __________ • The formation of mevalonate is completed by reduction of the thioester to a 1° alcohol

31. Mevalonate to Squalene • The pyrophosphosphorylation 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 ______________________ ______________________ • Then there is an enzyme-catalyzed isomerization of the carbon-carbon double bond that gives dimethylallyl pyrophosphate • Dimethylallyl pyrophosphate is then converted to 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 2-electron oxidation gives ___________ (C30)

32. The Conversion of Mevalonate to Squalene

33. Squalene to Cholesterol

34. Cholesterol as a Precursor Cholesterol is the precursor for a number of ______________________ ______________________

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

36. The LDL Particle

37. The Fate of Cholesterol

38. 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