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beta oxidation.pptx
- 1. Catabolism of fattyacids BETA OXIDATION OF FATTY ACIDS DR.MURALI
- 2. • This processis known as beta-oxidation, because the oxidation and splitting of two carbon units occur at the beta-carbon atom. The oxidation of the hydrocarbon chain occurs by a sequential cleavage of two carbon atoms (Fray Knoop, 1904).
- 3. Preparative Steps forBeta Oxidation • The co-enzyme A is a complex molecule containing B complex vitamin pantothenic acid and a molecule of beta mercapto ethanolamine; this SH group forms thioester bond in acyl CoA (Fig.). To emphasize the function of the SH group, the CoA is sometimes written as CoA-SH.
- 4. Preparative Step 1:Activation of Fatty Acids • Fatty acids are activated to their co-enzyme A (CoA) derivative. This activation is taking place in cytoplasm. ATP is hydrolyzed to AMP and PPi and the energy from hydrolysis of Ppi drives the reaction forward. Thus two high energy bonds are utilized in this reaction
- 5. • The enzymeis a thiokinase or fatty acyl CoA synthetase (step 0, Fig. 12.9). Acetyl group and acyl groups are different; see Box 12.3.
- 6. • Three differentenzymes, one each for short chain, medium chain and long chain fatty acids have been identified. Small chain fatty acids may also be activated by thiophorase enzyme, using succinyl CoA (see under ketone bodies).
- 7. Preparative Step 2:Role of Carnitine • Fatty acids are activated in the cytoplasm; but betaoxidation is in mitochon dria. So transport of fatty acids through the mitochondrial membrane is essential. The long chain fatty acyl CoA cannot pass through the inner mitochondrial membrane. Therefore a transporter, carnitine is involved in transfer of fatty acids. Carnitine is betahydroxy- gamma-trimethyl ammonium butyrate, (CH3)3–N+–CH2–CHOH–CH2–COOH. It is synthesized from lysine and methionine in liver and kidney.
- 8. Preparative Step 3:Carnitine Acyl Transferase • The enzyme carnitine acyl transferase-I (CAT-I) will transfer the fatty acyl group to the hydroxyl group of carnitine to form acyl carnitine (Fig. 12.8) The reaction occurs on the cytosolic side of inner mitochondrial membrane
- 9. Preparative Step 4: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 (Fig. 12.8). Carnitine is returned to the cytosolic side by the translocase.
- 11. Clinical Applications • 1.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. 2. Carnitine deficiency is reported in preterm infants, in whom impaired fatty acid oxidation is noticed. So more glucose is utilized, resulting in episodes of hypoglycemia
- 12. • 3. Deficiencyof 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.
- 13. Carnitine • Carnitine wasoriginally found as a growth factor for mealworms and labeled vitamin Bt. Carnitine is synthesized in the liver and kidneys from lysine (via trimethyllysine) and methionine. Vitamin C (ascorbic acid) is essential for the synthesis of carnitine. During growth or pregnancy, the requirement of carnitine might exceed its natural production.
- 14. • Human geneticdisorders, such as primary carnitine deficiency, carnitine palmitoyltransferase I deficiency, carnitine palmitoyltransferase II deficiency and carnitineacylcarnitine translocase deficiency affect different steps of this process.
- 16. Beta Oxidation Steps •The next 4 reactions are sequentially repeated for complete oxidation of fatty acids. After one round of four metabolic steps, one acetyl CoA unit is split off and acyl CoA with 2 carbon atoms less is generated. This would undergo the same series of reactions again until the fatty acid is completely oxidized.
- 17. Step 1: FADLinked Dehydrogenase • The fatty acyl CoA is dehydrogenated to a transenoyl CoA with FAD accepting the hydrogen atoms (Step 1, Fig. 12.9). FADH2 when oxidised in electron transport chain will produce 1.5 ATP molecules.
- 18. Step 2: Hydration •This is catalyzed by an enoyl CoA hydratase (step 2, Fig. 12.9). This step forms a beta-hydroxy fatty acyl CoA. The L isomer alone is formed during the hydration of the trans double bond.
- 19. Step 3: NAD+Dependent Dehydrogenase • The beta-hydroxy fatty acyl CoA is again oxidized to form beta-keto fatty acyl CoA. (Step 3, Fig. 12.9). • This dehydrogenase acts only on L isomer. The NADH when oxidized in electron transport chain will generate 2.5 ATPs.
- 20. Step 4: Cleavage •The beta-keto fatty acyl CoA now undergoes thiolytic cleavage, splitting off a molecule of acetyl CoA and leaving behind a fatty acid with 2 carbon atoms less (step 4, Fig. 12.9).
- 21. Fig. 12.9: Betaoxidation of fatty acids Important to remember that the first step is FAD dependent and the third step is NAD+ dependent.
- 23. Further Cycles • Thenewly formed fatty acyl CoA will sequentially undergo further cycles of steps 1, 2, 3 and 4 of beta-oxidation until the fatty acid is completely converted to acetyl CoA (Fig. 12.10). A summary is shown in Box 12.4.
- 25. Energetics of BetaOxidation (ATP Yield) • Palmitic acid (16 C) needs 7 cycles of beta oxidation (Fig. 12.10). So, it gives rise to 8 molecules of acetyl CoA (Box 12.4). Every molecule of acetyl CoA when oxidized in the TCA cycle gives 10 molecules of ATP. Each molecule of FADH2 produces 1.5 molecules of ATP and each NADH generates 2.5 molecules of ATP, when oxidized in the electron transport chain. Hence, the energy yield from one molecule of palmitate may be calculated as:
- 27. Fig. 12. 10:Summary of beta oxidation of palmitic acid (16 C) It undergoes 7 cycles, which give rise to 8 molecules of acetyl CoA.
- 28. Regulation of BetaOxidation • i. The availability of free fatty acid (FFA) regulates the net utilization through beta oxidation. ii. The level of FFA, in turn, is controlled by glucagon:insulin ratio. Glucagon increases FFA level and insulin has the opposite effect. iii. CAT-I is the regulator of entry of fatty acid into mitochondria. Malonyl CoA inhibits CAT-I activity. Thus during de novo synthesis of fatty acid, beta oxidation is inhibited.
- 29. OXIDATION OF ODDCHAIN FATTY ACIDS • The odd chain fatty acids are oxidized exactly in the same manner as even chain fatty acids. However, after successive removal of 2-carbon units, at the end, one 3 carbon unit, propionyl CoA is produced
- 30. ALPHA OXIDATION • Itis a process by which fatty acids are oxidized by removing carbon atoms, one at a time, from the carboxyl end. The process is important in brain. The fatty acid does not need activation. Hydroxylation occurs at the alpha-carbon atom.
- 32. • It isthen oxidized to alpha-keto acid. The keto acid then undergoes decarboxylation yielding a molecule of CO2 and a fatty acid with one carbon atom less. This process occurs in the endoplasmic reticulum, does not require CoA, but does not generate energy. Some fatty acids undergo alpha hydroxylation in peroxisomes also.
- 33. • Alpha-oxidation ismainly used for fatty acids that have a methyl group at the beta-carbon, which blocks beta-oxidation. A major dietary methylated fatty acid is phytanic acid (Fig. 12.12). It is derived from phytol present in chlorophyll, milk and animal fats
- 34. Refsum's Disease • Itis a metabolic error due to lack of alpha-hydroxylase (phytanic acid oxidase) so that alpha oxidation does not occur and phytanic acid accumulates in the tissues. The patient presents with severe nurological symptoms, polyneuropathy, retinitis pigmentosa, nerve deafness and cerebellar ataxia. Regression of symptoms is observed with restricted dietary intake of phytanic acid. Milk is a good source of phytanic acid, which may be avoided.
- 35. • Infantile Refsum'sDisease • It is a peroxisomal disorder, similar to Zellweger syndrome and adrenoleukodystrophy (see Chapter 41). Hence phytanic acid accumulates along with VLCFA. Children do not survive long.
- 36. OMEGA OXIDATION • Itis a minor pathway taking place in microsomes, with the help of hydroxylase enzymes involving NADPH and cytochrome P-450. The CH3 group is converted to CH2OH and subsequently oxidized with the help of NAD+ to a COOH group to produce dicarboxylic acids. ω-oxidation becomes important when β-oxidation is defective and dicarboxylic acids (6C and 8C acids) are excreted in urine causing dicarboxylic aciduria
- 37.
- 38. Inherited Disorders • Inheriteddefects in the enzymes of beta oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty liver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase.3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid. Dicarboxylic aciduria is characterized by the excretion of dicarboxylic acids and by nonketotic hypoglycemia
- 39. • It iscaused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase. Zellweger’s (cerebrohepatorenal) syndrome occurs in individuals with a rare inherited absence of peroxisomes in all tissues. They accumulate C26–C38 polyenoic acids in brain tissue and also exhibit a generalized loss of peroxisomal functions, e.g. impaired bile acid and ether lipid synthesis. More than 25 enzymes have been identified for fatty acid metabolism in humans, out of which about 15 are known to be associated with metabolic disorders.