1. * Lipid Biosynthesis
- These are endergonic and reductive reactions, use ATP as source of energy and reduced electron carrier usually NADPH as reductant.
* Fatty acid synthesis:
- F.A synthesis is not the reversal of the degradative pathway, using different sets of enzymes.
1-synthesis in cytosol, degradation in mitochondria (mitochondrial matrix)
2-intermediates of F.A synthesis are covalently linked to -SH group of ACP, at higher organism single polypeptide called fatty acid synthase. (while in F.A degradation are bonded to CoA)
3-the growing F.A is elongated by sequential addition of 2-carbon units.
4-the reductant in fatty acid synthesis is NADPH, while the oxidant in F.A degradation are NAD+, FAD
5-elongation of F.A is stopped at C16 and further elongation or insertion of double bonds are carried by other enzyme systems.
* Large proportion of F.A used in the body is supplied by diet excess CHO and protein are converted into F.A.
- F.A are synthesized mainly in liver and lacting mammary gland and to lesser extent in adipose tissue and kidney.

2. -oxidation of Saturated Fatty Acids
* Fatty acids are activated and transported into mitochondria
* F.As enter to cytosol from the blood and should move to mitocondrial matrix where the enzymes are exist in three steps “CARNITINE SHUTTLE”
F.A fatty acyl CoA
This process occurs in the outer mitocondrial membrane
Found at outer mitocondrial membrane
The hydrolysis of
Pull the rxn to the formation of fatty acyl CoA

3. * Fatty acyl CoA esters : don’t cross the inner mitocondrial membrane intact.
But it binds to the -OH group of Carnitine to form fatty acyl-Carnitine complex
this complex enters the matrix by facilitated diffusion.
In the matrix Carnitine and fatty acyl CoA are regenerated.
Outer face of the membrane
Inner face of the membrane
Inner membrane
Acyl-Carnitine / Carnitine transporter
Entrance of F.A to mitocondrial matrix (Carnitine shuttle)
1- Esterification to CoA
2- Transestrification to Carnitine followed by transport.
3- Transestrification back to CoA.

4. * The -oxidation of saturated F.A has four basic steps
1- Dehydrogenation (oxidation)
- 3 isomers of AD
a) LCAD (long chain acyl-CoA dehydrogenase)
act on fatty acids carbons
b) MCAD : C
c) SAD : C
- AD bound to the inner membrane of mitochondria
- AD has FAD as prosthetic group
2- Hydration (addition of water)
- water is added to the double bond.
3- Dehydrogenation (oxidation)
- the enzyme is specific only for L-isomer
NADH NAD+ and e- are transported to O2 to produce ATP via e-transport chain
NADH NADH dehydrogenase (complex I)
4- Thiolysis
- free CoA-SH split off the carboxy terminal two carbons
1-oxidation
2e- electron transfer chain
2-Hydration
3-oxidation
4-Thiolysis
Thio ester of fatty acid carbon

5. Thio ester of fatty acid + 2 carbon
3-oxidation
1-oxidation
2-Hydration
4-Thiolysis
2e- electron transfer chain

6. -oxidation of Fatty acids

7. In each cycle of -oxidation one acetyl-CoA, 2 pairs of e- and 4H+ are removed from the fatty acid
C16-CoA + CoA + FAD + NAD+ + H2O
C14-CoA + acetyl-CoA + FADH2 + NADH + H+
Palmitoyl CoA 7 cycles of -oxidation acetyl CoA + 7 FADH2 + 7 NADH + 7H+
- The four steps are repeated 7 times

8. * Mitocondrial oxidation of F.A
- oxidation: four reactions results in shortening the F.A by 2 carbon units, and these four steps are repeated until the complete degradation of F.A
7 cycles acetyl CoA
16 C palmitic acid
Are oxidized to CO2 in the mitocondrial matrix
* The energy released by fatty acid oxidation is conserved as ATP

9. * Energy yields from complete oxidation of palmitic acid
(129 ATP resulted from complete oxidation)
Palmitoil-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O
8 acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+
acyl-CoA dehydrogenase FADH2
- hydroxyacyl-CoA dehydrogenase 7 NADH
8 acetyl CoA : citric acid cycle produce
isocitrate dehydrogenase NADH
ketoglutirate dehydrogenase NADH
succinyl CoA-CoA synthatase GTP
succinate dehydrogenase FADH2
malate dehydrogenase NADH
Total = 31 NADH + 15 FADH2 + 8 ATP
= 131 ATP
- For each fatty acid to be activated by thiokinase (fatty acyl CoA synthetase) two high energy bonds are consumed and these should be considered
So = 129 ATP
24 NADH
+ 8 FADH2
+ 8 GTP ATP

10. Energy yields from complete oxidation of palmitic acid

11. Methylmalonyl CoA epimerase
Complete oxidation of odd number of Fatty acids (require additional three reactions)
* F.A with an odd number of C are common in plants.
* Odd F.A oxidized normally by - oxidation, in the last step, Propionyl CoA and acetyl CoA are produced.
biotin
Propionyl CoA carboxylase
Methylmalonyl CoA epimerase
Coenzyme B12
Methylmalomyl CoA mutase

13. - oxidation of polyunsaturated F
- oxidation of polyunsaturated F.A (18 : 2 9,12 linoleate) need additional two enzymes
Is removed by continuing the - oxidation.
Cis 4
First oxidation step of the second cycle
FAD
Acyl CoA dehydrogenase
FADH2

14. Is not a substrate for enoyl-CoA hydratase

15. * oxidation of unsaturated Fatty acids need additional reactions
(Monounsaturated)
* F.A with double bond is in Cis- configuration can’t acted by enoyl-CoA hydratase that add H2O to the Trans double bond of 2 enoyl-CoA generated during - oxidation.
Oxidation of oleate 18 C 18 : 19
Is not a substrate for enoyl-CoA hydratase
This is a substrate for hydratase enzyme and - oxidation is continued

16. -oxidation of unsaturated F.A

17. * Regulation of fatty acid oxidation
- In the liver :
Fatty CoA formed in the cytosol has two routs
A. enter the mitochondria - oxidation for energy.
B. Synthesis of triglycerols. This depends on the rate of transfer of fatty CoA into the mitochondria.
Malonyl CoA : the first intermediate in the cytosolic synthesis of F.A from acetyl CoA
When there is no need for energy, high level of glucose increase acetyl CoA increase malonyl CoA that inhibit the Carnitine acyl transferase I.
Oxidation of fatty acid is inhibited whenever there is excess CHO and glucose and the extra glucose is converted into fatty acid. While excess fatty acid can’t be converted to glucose .
Also when NADH / NAD+ ratio is high inhibition of - hydroxyacyl CoA dehydrogenase.
When high concentration of acetyl CoA inhibition of thiolase.

18. Ketone Bodies
* Acetyl CoA in the liver cells can enter the citric acid cycle, or can be converted into ketone bodies.
synthesized in the liver to be exported to other tissues by the blood, then they can be oxidized by citric acid cycle.
Produced in smaller amounts and exhaled
The brain uses glucose as fuel
if it is not available it can use acetoacetate and -hydroxybutyrate.
* Ketone bodies can be used as fuel for heart, skeletal muscles and kidney.

19. Ketone bodies formed in the liver are exported to other organs

20. *Acetone is formed in very small amount in healthy people.
* Untreated diabetes or (starvation) large quantities of acetoacetate is produced increase acetone amount odor to the breath.
Specific for D not L
Or even spontaneous decarboxylation

21. Extra hepatic tissues use ketone bodies as fuels
Acetoacetate and - hydroxybutyrate is converted into 2 acetyl CoA that enter the citric acid cycle to produce energy.

22. Extra hepatic tissues use ketone bodies as fuels

23. Over production of ketone bodies during the diabetes and starvation
* During starvation, gluconeogenesis which depleted citric acid cycles intermediates diverting the acetyl CoA to ketone body production.
* In diabetes, low level of insulin Tissues can’t uptake glucose to use as fuel Malonyl CoA is not formed the entrance of fatty acids into mitochondria are not inhibited accumulation of acetyl CoA that can’t go through citric acid cycle accelerate the ketone body production, causing low pH and keto acidosis or ketosis.