1. September 12 Chapter 24 G&G Fatty acid catabolism
Biochemistry 432/832
September 12
Chapter 24 G&G
Fatty acid catabolism

2. Announcements:
- Exam #1 next Thursday (Sept 19)
- Chapters 23, 24
- Chapter 19 (glycolysis)
- Chapter 25, section 25.1, up to biosynthesis of complex lipids (page 819)

3. 1. Biosynthesis of ribose-5-P and NADPH
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Reducing
power
Nucleic acid
synthesis
Glyceraldehyde-3-P
Pyruvate
1. Biosynthesis of ribose-5-P and NADPH
ATP 28

4. 2. Biosynthesis of ribose-5-P
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
2. Biosynthesis of ribose-5-P
ATP 28

5. 3. Biosynthesis of NADPH Glucose Glycogen Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
3. Biosynthesis of NADPH
ATP 28

6. 4. Biosynthesis of NADPH and ATP
Glucose
Glycogen
Glucose-6-P
Ribose-5-P + NADPH
Fructose-6-P
Glyceraldehyde-3-P
Pyruvate
4. Biosynthesis of NADPH and ATP
ATP 28

7. Triacylglycerols O ||
CH2 - O - C - (CH2)n - CH3
Saturated versus unsaturated O ||
CH - O - C - (CH2)n - CH3 O ||
CH2 - O - C - (CH2)n - CH3
Glycerol Fatty acid

8. Why Fatty Acids are used for storage of energy?
Two reasons:
The carbon in fatty acids (mostly CH2) is almost completely reduced (so its oxidation yields the most energy possible).
Fatty acids are not hydrated (as mono- and polysaccharides are), so they can pack more closely in storage tissues
Result: fatty acids have ~6 more energy of the corresponding amount of proteins or glycogen 3

9. Activation of fatty acids for b-oxidation by acyl-CoA synthetase

10. Role of carnitine in transferring fatty acids across the mitochondrial membrane

11. -Oxidation of Fatty Acids
A Repeated Sequence of 4 Reactions
Strategy: create a carbonyl group on the -C
First 3 reactions do that; fourth cleaves the "-keto ester"
Products: an acetyl-CoA and a fatty acid two carbons shorter, FADH2, NADH 8

12. The b-oxidation of saturated fatty acids

13. Acyl-CoA Dehydrogenase
Oxidation of the C-C bond
A family of three soluble matrix enzymes
Mechanism involves proton abstraction, followed by double bond formation and hydride removal by FAD
Electrons are passed to an electron transfer flavoprotein, and then to the electron transport chain
Enzyme is inhibited by a metabolite of hypoglycin (from akee fruit) 9

14. The acyl-CoA dehydrogenase reaction

15. The mechanism of acyl-CoA dehydrogenase
Hydride transfer
Proton abstraction

16. Acyl-CoA dehydrogenase structure

17. Inhibition of acyl-CoA dehyrogenase by hypoglycin

18. Adds water across the double bond
Enoyl-CoA Hydratase
Adds water across the double bond
at least three forms of the enzyme are known
Normal reaction converts trans-enoyl-CoA to L--hydroxyacyl-CoA 10

19. Hydroxyacyl-CoA Dehydrogenase
Oxidizes the -Hydroxyl Group
This enzyme is completely specific for L-hydroxyacyl-CoA
D-hydroxylacyl-isomers are handled differently 11

20. The L-b-hydroxylacyl-CoA dehydrogenase reaction

21. Fourth reaction: thiolase
-ketothiolase
Cysteine thiolate on enzyme attacks the -carbonyl group
Thiol group of a new CoA attacks the shortened chain, forming a new, shorter acyl-CoA
The reaction is favorable and drives other three 12

22. Summary of -Oxidation
Repetition of the cycle yields a succession of acetate units
Thus, palmitic acid yields eight acetyl-CoAs
Complete -oxidation of one palmitic acid yields 106 molecules of ATP
Large energy yield is the consequence of the highly reduced state of the carbon and compact storage (no hydration) of fatty acids 13

23. Odd-Carbon Fatty Acids
-Oxidation yields propionyl-CoA
Odd-carbon fatty acids are metabolized normally, until the last three-C fragment - propionyl-CoA - is reached
Three reactions convert propionyl-CoA to succinyl-CoA
The involvement of biotin and B12 14

24. Oxidation of fatty acids containing odd numbers of carbons

25. Unsaturated Fatty Acids
Consider monounsaturated fatty acids:
Oleic acid, palmitoleic acid
Normal -oxidation for three cycles
cis-3 acyl-CoA cannot be utilized by acyl-CoA dehydrogenase
Enoyl-CoA isomerase converts this to trans- 2 acyl CoA
-oxidation continues from this point

27. Polyunsaturated Fatty Acids
Slightly more complicated
Same as for oleic acid, but only up to a point:
3 cycles of -oxidation
enoyl-CoA isomerase
1 more round of -oxidation
trans- 2, cis- 4 structure is a problem!
2,4-Dienoyl-CoA reductase to the rescue!

29. Peroxisomal -Oxidation
Peroxisomes - organelles that carry out flavin-dependent oxidations, regenerating oxidized flavins by reaction with O2 to produce H2O2
Similar to mitochondrial -oxidation, but initial double bond formation is by acyl-CoA oxidase
Electrons go to O2 rather than e- transport
Fewer ATPs result

30. The acyl-CoA oxidase reaction in peroxisomes

31. A special source of fuel and energy for certain tissues
Ketone Bodies
A special source of fuel and energy for certain tissues
Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrate
These are called "ketone bodies"
Source of fuel for brain, heart and muscle
Major energy source for brain during starvation
They are transportable forms of fatty acids! 19

32. Interesting Aspect of Their Synthesis
Ketone Bodies - II
Interesting Aspect of Their Synthesis
Occurs only in the mitochondrial matrix 20

33. Ketone Bodies and Diabetes
"Starvation of cells in the midst of plenty"
Glucose is abundant in blood, but uptake by cells in muscle, liver, and adipose cells is low
Type I diabetes - 10% - insufficient secretion of insulin
Type II diabetes - 90% - deficiency in insulin receptors
Cells, metabolically starved, turn to gluconeogenesis and fat/protein catabolism
Oxaloacetate is low, due to excess gluconeogenesis, so Ac-CoA from fat/protein catabolism does not go to TCA, but rather to ketone body production
Acetone can be detected in breath of diabetics 21