Oxidation of Fatty Acids: β-, α- and ω-Oxidation | Lipid Metabolism

The below mentioned article provides a short note on the Oxidation of Fatty Acids.

Introduction to Oxidation of Fatty Acids:

Fatty acids are oxidized by β-, α- and ω-oxidation. Quantitatively, β-oxidation is the most important pathway. The term β-oxidation means the oxida­tion takes place in the β-carbon of the fatty acid with the removal of 2 carbon atoms at a time from the carboxyl end of the molecule. The fatty acids containing even number and odd number of carbon atoms as well as the unsatur­ated fatty acids are oxidized by β-oxidation.

β-oxidation of Fatty Acids:

a. Several enzymes collectively known as “fatty acid oxidase” are found in mitochondrial ma­trix adjacent to the respiratory chain (which is found in the in­ner membrane).

b. Long chain fatty acids are first activated to “active fatty acid” or acyl-CoA in the cytosol by the enzyme acyl-CoA syn­thetase in the presence of ATP, coenzyme A and Mg⁺⁺. But activation of lower fatty acids oc­curs within the mitochondria. Thiokinases are found both in­side and outside the mitochon­dria.

c. Long chain acyl-CoA does not penetrate mitochondria without the presence of carnitine. The enzyme carnitine palmitoyl transferase i associated with the mitochondrial membranes al­lows long chain acyl groups to penetrate the mitochondria. The mechanism is shown (Fig. 18.1).

Another enzyme, carnitine acyl carnitine translocasc, present in mitochondria, catalyzes the transfer of short chain acyl groups between CoA and car­nitine.

Acyl carnitine + CoA ↔ Acyl-CoA + Carnitine

Carnitine palmitoyl transferase

Acyl carnitine combines with CoA to form acyl-CoA and carnitine which is released by the enzyme carnitine palmitoyl trans­ferase 11.

d. Acyl-CoA is then converted to α, β-unsaturated acyl-CoA by the enzyme acyl-CoA dehydrogenase in presence of the coen­zyme flavoprotein which contains FAD as prosthetic groups. The reduced coenzyme is re-oxidized by the respiratory chain.

e. Water is added to saturate the double bond and form β-hydroxy acyl-CoA, catalyzed by the enzyme enoyl-CoA hydratase (crotonase).

f. The β-hydroxy acyl-CoA undergoes dehydrogenation on the p-carbon forming β-keto acyl-CoA. The reaction is catalyzed by β- hydroxy acyl-CoA dehydrogenase in presence of NAD. The reduced coenzyme (NADH) is re-oxidized by the respiratory chain.

g. Finally, β-keto acyl-CoA is split at the β- position by thiolase (β-ketothiolase) with the addition of one molecule of CoA. The products of this reaction are acetyl-CoA (C₂-units) and an acyl-CoA containing 2 carbon less than the original acyl-CoA molecule which undergoes further-oxida­tion by β-oxidation. In this way, a long chain fatty acid is degraded completely to acetyl-CoA which is completely oxi­dized to CO₂ and water via the citric acid cycle within the mitochondria.

Fatty acids with an odd number of carbon at­oms are oxidized by the pathway of β-oxidation until propionyl-CoA is formed. This compound is converted to succinyl-CoA which is a constituent of the citric acid cycle. Unsaturated fatty acids are also oxidized fol­lowing β-oxidation. The reactions are shown in Fig. 18.3.

α- and ω-oxidation of Fatty Acids:

α-oxidation takes place by the removal of one car­bon at a time from the carboxyl end of the mol­ecule. It does not require CoA intermediates and does not lead to the generation of high-energy phos­phates.

ω-oxidation takes place by hydroxylase en­zymes involving cytochrome P-450 in microsomes. The -CH₃ group is converted to a-CH₂OH group which is ultimately oxidized to -COOH group form­ing a dicarboxylic acid.

Oxidation of Fatty Acids with an Odd Number of Carbon Atoms:

Fatty acids with odd number of carbon atoms are oxidized by the pathway of β-oxidation producing acetyl-CoA until a three carbon (Propinyl-CoA) remains. Propionyl-CoA is converted to succinyl- CoA, a constituent of citric acid cycle.

Peroxisomes Oxidize very Long Chain Fatty Acids:

The modified form of β-oxidation in Peroxisomes forms acetyl-CoA and H₂O₂ which is broken down by catalase. This first dehydrogenation is not di­rectly linked to the generation of ATP, but the ini­tial activation by a very long chain acyl-CoA syn­thetase facilitates the oxidation of very long chain fatty acids (e.g., C₂₀, C₂₂). These enzymes are induced by high fat diets and in some species by hypolipidemic drugs such as clofibrate.

The enzymes in peroxisomes do not attack shorter chain fatty acids and the β-oxidation se­quence ends at octanoyl-CoA. Octanoyl and acetyl groups are subsequently removed from the peroxi­somes in the form of octanoyl and acetylcarnitine and both are further oxidized in mitochondria.

Another role of peroxisomal β-oxidation is to shorten the side chain of cholesterol in bile acid formation.

Peroxisomes do not contain carnitine palmitoyltransferase.

Energetics of Fatty Acid Oxidation:

Palmitic acid (16 carbons) undergoes 7 times β-oxidation and produces 8 molecules of acetyl- CoA. Each time, β-oxidation produces 5 ATP: