Oxidation of Fatty Acids


Oxidation of Fatty Acids

Introduction

·         Fatty acids are aliphatic carboxylic acids containing a long hydrocarbon chain.
·         The hydrocarbon chain may be saturated (with no double bond) or unsaturated (containing double bond).
·         Triacylglycerols (fats) are the most abundant source of energy and provide energy twice as much as carbohydrates and protein.
·         Fatty acid can be obtained from diet, adipolysis and de novo synthesis.

   Mitochondrial oxidation of fatty acids takes place in 3 stages:-

1.       In 1st stage β oxidation of fatty acid undergo oxidative removal of successive 2-C units in form of acetyl Co-A.
2.       In 2nd stage of fatty acid oxidation, the acetyl group of acetyl co-A are oxidized to co2 in the citric acid cycle which also takes place in the mitochondrial matrix.
3.       The first 2 stages of fatty acid oxidation produce the reduce electron carriers NADH and FADH2 which in 3rdstage donate electron to mitochondrial respiratory chain, through which the electron pass to oxygen with the concomitant phosphorylation of ADP to ATP.

Types of Fatty Acid Oxidation

·         Alpha oxidation- predominantly takes place in brain and liver, one carbon is lost in the form of co2 per cycle
·         Beta oxidation- major mechanism, occurs in the mitochondria matrix. 2-C units are released as acetyl CoA per cycle.
·         Omega oxidation- minor mechanism, but becomes important in condition of impaired beta oxidation.

Beta oxidation overview

  A saturated acyl Co-A is degraded by recurring sequence of 4 reaction.
  4 enzyme catalyzed reaction make up the 1st stage of fatty acid oxidation.
  The fatty acid chain is shortened by 2 carbon atoms as a result of these reaction FADH2, NADH and acetyl Co-A are generated.
  Oxidation is on the β-carbon and the chain is broken between the α(2) and β (3) carbon atom, hence known as β oxidation.

Activation of Fatty Acids

  Fatty acids must first be converted to an active intermediate before they can be catabolized.
  This is the only step in the in complete degradation of fatty acid that requires energy from ATP.
  Fatty acids are activated to fatty acyl CoA in a reaction catalyzed by acyl CoA synthase.

Transport of Fatty Acids into mitochondria

  The inner mitochondrial membrane is not permeable to long chain fatty acyl CoA.
  The fatty acyl CoA group is transferred to carnitine which functions as a carrier, catalyzed by carnitine acyltransferase Ι present on the outer surface of mitochondrial membrane.
  In the mitochondrial matrix, the acyl group from acyl carnitine is transferred to CoA by the enzyme carnitine acyltransferase ΙΙ.

Steps of β oxidation

·        Step 1-α, β dehydrogenation of acyl CoA

       The first step is the removal of two hydrogen atoms from the 2(α) and 3(β) carbon atoms, catalyzed by acyl CoA dehydrogenase  and requiring FAD. This result in the formation of trans-∆² enoyl CoA and FADH2.
       The electron removal from the fatty acyl CoA are transferred to FAD and the reduced form of the dehydrogenase immediately donates its electron to an electron carrier of the mitochondrial respiratory chain, the electron transferring flavoprotein (ETF).
       The oxidation catalyzed by acyl CoA dehydrogenase is analogous to succinate dehydrogenation in the citric acid cycle. In both the reaction, the enzyme is bound to the inner membrane, a double bond is introduced into a carboxylic acid between the α and β carbon. FAD is the electron acceptor, and electron from the reaction ultimately enters the respiratory chain and pass to O2 with concomitant synthesis of about 1.5 ATP molecules.

·        Step 2 hydration of α,β unsaturated acyl CoA

       In this step, a molecule of water is added to the double bond of the Trans ∆² enoyl CoA to form the L stereoisomer of β hydroxyacyl-CoA. And reaction is catalyzed by enoyl-CoA hydratase.

·         Step 3 Oxidation of β-hydroxyacyl-CoA

       The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by L(+)-3-hydroxyacyl-CoA dehydrogenase to form the corresponding 3-ketoacyl-CoA compound. In this case, NAD+ is the coenzyme involved.

·         Step 4 Thiolysis

       3-ketoacyl-CoA is spilt at the 2, 3- position by thiolase (3-ketoacyl-CoA-thiolase), forming acetyl-CoA two carbons shorter than the original acyl-CoA molecule.
       The acyl-CoA formed in the cleavage reaction reenters the oxidative pathway at reaction 2.
       Since acetyl-CoA can be oxidized to CO2 and water via the citric acid cycle the complete oxidation of fatty acids is achieved.


Stoichiometry of β-oxidation

  The yields of NADH, FADH2 and ATP in the successive steps of palmitocyl-CoA oxidation. Because of the activation of palmitate to palmitoyl-CoA breaks both phosphoanhydride bonds in ATP, the energetic cost of activating a fatty acid is equivalent to 2ATP, and the net gain per molecule of palmitate is 106 ATP.
  The standard free-energy change for the oxidation of palmitate to CO2 and H2O is about 9800 kJ/mol. Under standard condition the energy recovered as the phosphate bond energy of ATP is 106×30.5 kJ/mol=3230 kJ/mol, about 33% of the theoretical maximum.

Energy yield

·         Energy yield by the complete oxidation of one mol of Palmitic acid-
·         The degradation of palmitoyl CoA (C 16-acyl CoA) requires seven reaction cycles. In the seventh cycle, the C4-ketoacyl CoA is thiolyzed to two molecules of acetyl CoA.
·         106 ATP are produced by the complete oxidation of one mol of Palmitic acid.

Oxidation of Unsaturated Fatty Acid

  Most of the fatty acids in the triacylglycerol and phospholipids of animal and plants are unsaturated having one or more double bonds. These bonds are in the cis configuration and cannot be acted upon by enoyl-CoA hydratase, the enzyme catalyzing the addition of H2O to the Trans double bond of the ∆²-enoyl-CoA generated during β oxidation. Two auxillarly enzymes are needed for β-oxidation of the common unsaturated fatty acids: an isomerase and a reductase.

Oxidation of Monounsaturated Fatty Acid

·         Oleate is an abundant 18-carbon monounsaturated fatty acid with a cis double bond between C-9 and C-10.
·         In the first step of oxidation, oleate is converted into oleoyl-CoA and like the saturated fatty acids, enter the mitochondrial matrix via carnitine shuttle.
·         Oleoyl-CoA then undergoes 3 passes through the fatty acid oxidation cycle to yield 3 molecule of acetyl CoA and co-enzyme A, ester of ∆³, 12-Carbon unsaturated fatty acid, cis-∆³ dodecenoyl-CoA. This product cannot serve as a substrate for enoyl-CoA hydratase, which acts only on trans double bonds.
·         The auxiliary enzyme ∆³,∆²-enoyl CoA isomerase isomerize the cis ∆³ enoyl-CoA to trans ∆²-enoyl-CoA, which is converted by enoyl-CoA hydratase into the corresponding L-β- hydroxyacyl CoA.
·         This intermediate is now acted upon by the remaining enzymes of β-oxidation to yield acetyl-CoA and the co-enzyme A ester of a 10-carbon saturated fatty acids decanoyl CoA.
·         The latter undergoes four more passes through the pathway to yield five more molecules of acetyl-CoA.
·         Altogether, 9 acetyl-CoA are produced from one molecules of the 18-Carbon oleate.

Oxidation of a Polyunsaturated Fatty Acid

·         The other auxiliary enzyme (a reductase) is required for oxidation of polyunsaturated fatty acids- for example the 18-carbon linoleate, which has a cis-∆⁹,cis-∆¹² configuration.
·         Linoleoyl-CoA undergoes three passes through the β-oxidation sequences to yield three molecules of acetyl-CoA and the coenzyme A ester of a 12-carbon unsaturated fatty acid with a cis-∆³, cis ∆⁶ configuration.
·         This intermediate cannot be used by enzymes of β-oxidation pathway; its double bonds are in the wrong position and have the wrong configuration (cis, not Trans).
·         However, the combined action of enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase allows re-entry of the intermediate into the β oxidation pathway and its degradation to 6 acetyl-CoA. The overall result is conversion of linoleate to 9 molecules of acetyl-CoA.

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