Beta Oxidation of Fatty Acids

In detail description about beta oxidation of fatty acid with regulation and clinical importance.
easy to study and write in exams for students.

1. BETA OXIDATION OF FATTY ACIDS Dr SANA PARVEEN MBBS,MD

2. β oxidation is major pathway of oxidation of fatty acids. DEF: The oxidation of the hydrocarbon chain of Fatty acid by a sequential cleavage of two carbon atoms. It is called β oxidation, because the oxidation and splitting of two carbon units occur at the beta-carbon atom.

3. Preparative Steps for Beta Oxidation Before oxidation fatty acids require to be - 1.Activated 2.Transported into mitochondria

4. Fatty Acids Activation Fatty acids are activated to their co-enzyme A (CoA) derivative. This activation is taking place in cytoplasm Enzyme : thiokinase or fatty acyl CoA synthetase ATP is hydrolyzed to AMP and Ppi using energy of two high energy bonds . Two inorganic phosphates are used Three different enzymes, one each for short chain, medium chain and long chain fatty acids have been identified.

5. Transport of Activated Fatty acid For transport two molecules are required 1.Carnitine 2.Translocase

6. Carnitine: Carnitine is beta-hydroxy gamma trimethyl ammonium butyrate, (CH3)3–N+–CH2–CHOH–CH2–COOH. It is synthesized from lysine and methionine in liver and kidney.

7. Role of Carnitine Fatty acids are activated in the cytoplasm; but the beta oxidation is in mitochondria. Carnitine a transporter, is involved in transfer of long chain of fatty acids. Medium chain and short chain fatty acids do not require carnitine for transport across the inner mitochondrial membrane. So medium chain and short chain fatty acids are easily oxidized.

8. Carnitine Acyl Transferase The enzyme carnitine acyl transferase-I (CAT-I/CPT -I) will transfer the fatty acyl group to the hydroxyl group of carnitine to form acyl carnitine The reaction occurs on the cytosolic side of inner mitochondrial membrane.

9. Translocase A protein translocase will carry the acyl carnitine across the membrane to the matrix of mitochondria. On the matrix side of the membrane another enzyme , carnitine acyl transferase-II (CAT-II) will transfer the acyl group back to co-enzyme A molecule Carnitine is returned to the cytosolic side by the translocase.

10. Beta Oxidation After the penetration of the acyl-CoA into mitochondria, it undergoes β- oxidation. A saturated acyl-CoA is degraded by a repeated sequence of four reactions 1. O xidation by FAD 2. H ydration 3. O xidation by NAD 4. C leavage.

11. Step 1: Oxidation by FAD The first reaction is the oxidation of acyl-CoA by an acyl-CoA dehydrogenase to give an Δ 2 -trans enoyl -CoA The coenzyme for the dehydrogenase is FAD which is converted to FADH 2 . FADH 2 when oxidised in electron transport chain will produce 1.5 ATP molecules.

12. Step 2:Hydration The next step is the hydration (addition of water) of the double bond between C2 and C3 by Δ 2 - enoyl -CoA hydratase to form β- hydroxy acyl-CoA.

13. Step 3:Oxidation by NAD The β- hydroxy derivative undergoes second oxidation reaction catalyzed by β - hydroxyacyl -CoA dehydrogenase to form β- ketoacyl -CoA and generates NADH. The NADH when oxidised in electron transport chain will generate 2.5 ATPs .

14. Step 4:Cleavage Finally β- ketoacyl -CoA is split at the β-carbon by thiolase to yield acetyl-CoA and an acyl- CoA which is shorter by two carbon atoms.

15. The new acyl-CoA, containing two carbons less than the original, re-enters the β-oxidation pathway at reaction catalyzed by acyl-CoA dehydrogenase . The process continues till the fatty acid degraded completely to acetyl-CoA.

16. Energetics of Beta Oxidation ( ATPYield ) Palmitic acid (16 C) needs 7 cycles of beta oxidation . it gives rise to 8 molecules of acetyl CoA. Every molecule of acetyl CoA when oxidised in the TCA cycle gives 10 molecules of ATP . Each molecule of The energy yield from one molecule of palmitate calculated as: 8 acetyl CoA × 10 = 80 ATP 7 FADH2 × 1.5 = 10.5 ATP 7 NADH × 2.5 = 17.5 ATP Gross total = 108 ATP Net yield = 108–2 = 106 ATP In the initial activation reaction, the equivalents of 2 high energy bonds are utilised . FADH2=1.5ATP NADH2=2.5ATP

17. Regulation of Beta Oxidation The availability of free fatty acid (FFA) regulates the net utilisation through beta oxidation. The level of FFA is controlled by glucagon:insulin ratio. Glucagon increases FFA level and insulin has the opposite effect.

18. Regulation of Beta Oxidation CAT-I is the regulator of entry of fatty acid into mitochondria. Malonyl -CoA is an inhibitor of CAT-I. (intermediate of fatty acid synthesis) In well fed conditions concentration of malonyl -CoA increases which inhibits CAT-I and leads to decrease in fatty acid oxidation. In starvation, reverse occurs i.e. decreased malonyl -CoA will remove CAT I inhibition allowing more AcylCoA to be oxidized.

19. Clinical Applications Carnitine deficiency : seen in preterm infants & hemodialysis patients Dietary deficiency of essential amino acids ( lys,met ) impaired fatty acid oxidation is noticed. more glucose is utilized, resulting in episodes of hypoglycemia . Deficiency of translocase : It leads to defective metabolism of long chain fatty acids. In this condition, muscle cramps are precipitated by fasting, exercise and high fat diet .

20. CPT-I deficiency : affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis , with hypoglycemia. CPT-II deficiency : affects primarily skeletal muscle and, when severe, the liver. Oral hypoglycemic drugs ( glibenclamide and tolbutamide ), used in the treatment of type 2 diabetes mellitus may also inhibit transferases enzyme( CPT-I). Treatment is to avoid LCFA and substitute with SCFA &MCFA .

21. Jamaican vomiting syndrome Jamaican vomiting syndrome is due to a toxin called hypoglycin ,present in unripe ackee fruit Hypoglycin inhibits fatty acyl co A dehydrogenase and impairs β oxidation Hypoglycemia,vomiting ,convulsions & coma are seen.

22. Medium chain acyl CoA dehydrogenase deficiency Of all enzymes of beta oxidation MCAD deficiency is most common usually manifests early in life by 2 years Patients have vomiting, lethargy, fasting hypoglycemia etc.many ultimately go into coma Hypoglycemia is not ketotic There is compensatory increase in ω oxidation which produces small to medium chain dicarboxylic acids that are excreted in urine as glycine & carnitine conjugates Treatment is high carbohydrate diet & carnitine supplementation to compensate urinary loss. Most cases of SIDS are found to be due to MCAD deficiency .

23. References: Textbook of Biochemistry for medical students-DM Vasudevan Textbook of Medical biochemistry –Dr S.K.Gupta