1. Lipid metabolism Dr. Khalid Alharthy

2. Introduction Lipids are broadly defined as any substances that are insoluble in water. In other words, anything that is non-polar or non-ionic. They are soluble in non-polar solvents for example: Hexane.

3. Introduction Fats, waxes, sterols and fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides and phospholipids are lipids. These are naturally occurring molecules.

4. Introduction Fats or fatty acids are biological molecules that are consisted of two parts: carboxylic group (polar) and hydrocarbon chain (non-polar group). Fatty acids are called amphipathic because it has polar and non-polar groups.

5. Introduction Fatty acids could be classified as saturated and unsaturated FAs. Unsaturated fatty acids has double bonds between their carbons at the hydrocarbon chain. A single double bond at the hydrocarbon chain make the fatty acids a mono-unsaturated such as oleic acid. More than one double bond at the hydrocarbon chain make the fatty acid a polyunsaturated such as linoleic acid.

7. Introduction The important functions of fatty acids are: Energy source Build up of cell membrane Synthesis of hormones (such as steroid hormone) and intracellular second messengers.

8. Fatty acids metabolism (Fatty acids oxidation) Fatty acid beta oxidation cycle is a process in which fatty acids oxidation occurs. It consists of four steps that converted the fatty acid to acetyl CoA that ultimately enter the TCA cycle to be further oxidized. Importantly, Fatty acid must be activated by attaching it with a coenzyme A molecule before going through beta oxidation cycle.

9. Activation of Fatty acid

10. Acyl is a term that means carboxyl group. Fatty acyl CoA synthetase is the enzyme that converts Fatty acid to fatty acyl CoA This reaction needs coenzyme A molecule and ATP molecule to happen. AMP that is resulted from ATP would further converted to 2Pi by adding pyrophosphate (PPi) to it. So, in this activation process we lost 2 ATP molecules. That we will subtract from the total ATP produced by fatty acid metabolism.

11. 1 st step of Beta oxidation cycle

12. In this oxidation step, Flavin adenine dinucleotide (FAD) as an oxidizing agent will be used to form a double bond between alpha and beta carbons. This oxidation step catalyzed by fatty acyl CoA dehydrogenase enzyme. A FADH2 will be resulted from this reaction.

13. 2 nd step of Beta oxidation cycle In this step, a water molecule added across the double bond to introduce an oxygen at beta carbon

14. 3 rd step of Beta oxidation cycle

15. In this oxidation step, nicotinamide adenine dinucleotide (NAD) as an oxidizing agent will be used to convert the hydroxyl molecule on beta carbon to carbonyl. This oxidation step catalyzed by beta hydroxyl fatty acyl CoA dehydrogenase enzyme. A NADH will be resulted from this reaction.

16. 4 TH or the last step of Beta oxidation cycle Beta keto fatty acyl CoA Fatty acyl CoA 2 carbons shorter than original one Acetyl CoA that is going to enter the TCA cycle

17. 4 TH or the last step of Beta oxidation cycle In this last step (cleavage step) of beta oxidation cycle, a break off of the first two carbons as acetyl CoA and the remaining of the molecule will be attached with a molecule of coenzyme A to form a fatty acyl CoA 2 carbons shorter than the original one.

18. Summary If we start with an 18 carbon fatty acid we will use two ATP to activate it to acyl CoA derivative that will enter the Beta oxidation cycle. Since the end product of beta oxidation is acetyl CoA that has two carbons, we will have 8 turns of beta oxidation cycle to convert that 18 carbon fatty acyl CoA to yield 9 acetyl CoA. (9 Acetyl CoA produced because the last turn we will get two acetyl CoA after these 8 turns) Each turn converts 1 NAD to 1 NADH and 1 FAD to 1 FADH2, for a total of 8 of each. Then each acetyl CoA is oxidized in the TCA cycle to produce 3 NADH, 1 FADH2, 1 GTP and 2 CO 2.

19. Summary An 18 carbon fatty acid oxidized through beta oxidation yields 9 acetyl CoA, 8 NADH, 8 FADH2. Then 9 acetyl CoAs oxidized through TCA cycle yielded 27 NADH, 9 FADH2, 9 GTP and 18 CO 2. The overall yield is 18 CO2, 35 NADH, 17 FADH2 and 9 GTP. We then must subtract f the 2 ATP that was used at the activation of fatty acid.

20. Summary The NADH and FADH2 are then reoxidied by electron transport and the energy released is used to synthesize ATP. Upon reoxidied each NADH gives us 3 ATP, and each FADH2 gives us 2 ATP. Therefore, 35 NADH × 3 = 105 ATP 17 FADH2 × 2 = 34 ATP

21. Adding everything up in ATP equivalents gives; 105 ATP from NADH 34 ATP from FADH2 9 ATP from GTP -2 ATP from fatty acyl CoA synthetase step Total 146 ATP from oxidation of an 18 carbon fatty acid.

22. ATP yield from Fat vs Carbohydrates To do the comparison between fat and carbohydrates in term of ATP production, we must compare the same number of carbons oxidized of each one. 3 glucose molecules have 18 carbons. 3 × 38 ATP = 114 ATP for 18 carbons from glucose. We got 146 ATP from 18 carbons from a fatty acid Approximately, 29 % more ATP per carbon from fat compared to carbohydrates!!!! WHY???

23. ATP yield from Fat vs Carbohydrates The fatty acid has two oxygen s for 18 carbons, the glucose has 18 oxygens for 18 carbons. That means fatty acid started out more reduced. Therefore, it has more energy in it. Fat, being hydrophobic is stored dry, while glucose is hydrated.

24. ATP yield from Fat vs Carbohydrates The average adult male (70 kg, 150 Ibs), has about 700 g of stored carbohydrate, primarily in his liver and skeletal muscle. This is enough to meet his energy needs for about 24 hours. The average adult male has about 14 kg of stored fat, which is enough to meet his energy needs for about 3 months.

25. ATP yield from Fat vs Carbohydrates The ability to store 3 months worth of caloric nutrients is very important for our survival. Women who have to little body fat can not get pregnant. This is nature’s way of making sure the mother can provide adequate nourishment for her fetus. Sever accident victims are less likely to survive if they have too little body fat at the time of the accident.

26. ATP yield from Fat vs Carbohydrates If we had to carry 3 months worth of caloric nutrients around with us in the form of carbohydrate the average adult male would have to weigh 182 kg. Because we are terrestrial animal we could probably handle this weight although not without difficulties. Birds, however, would never able to fly. Consider a humming bird. These birds weigh about 3 g and they migrate across the gulf of Mexico each year from the Yucatan peninsula to the US gulf coast and back. This about 1200 miles over water non-stop. If they had to store the fuel for this trip in the form of carbohydrate they would never get off the ground.