β Oxidation of saturated and unsaturated fatty acids

β Oxidation of saturated and unsaturated fatty acids

Objective

•       At the end of this lecture, student will be able to

–      Explain catabolism of saturated fatty acids

–      Explain catabolism of unsaturated fatty acids

–      Discuss the diseases associated with enzymatic defects in metabolism of fatty acids

β Oxidation of saturated fatty acids

•       The fatty acids in the body are mostly oxidized by β-oxidation

•       β-Oxidation may be defined as the oxidation of fatty acids on the β-carbon atom.

•       This results in the sequential removal of a two carbon fragment-acetyl CoA

•       β-oxidation of fatty acids involves three stages

                l. Activation of fatty acids occurring in the cytosol

                ll. Transport of fatty acids into mitochondria

                lll. β-Oxidation in the mitochondrial matrix

l. Activation of fatty acids occurring in the cytosol

• Fatty acids are activated to acyl CoA by thiokinases or acyl CoA synthetases

•           The reaction occurs in two steps and requires ATP, coenzyme A & Mg²⁺

•           Fatty acid reacts with ATP to form acyladenylate which then combines with coenzyme A to produce acyl CoA

•           This reaction totally irreversible

II. Transport of fatty acids into mitochondria

•       This occurs in four steps

1. Acyl CoA is transferred to carnitine catalysed by carnitine acyltransferase-I (present on the outer surface of inner mitochondrial membrane)

2. The acyl-carnitine is transported across the membrane to mitochondrial matrix by a specific carrier protein

3. Carnitine acyl transferase-ll (found on the inner surface of inner mitochondrial membrane) converts acyl-carnitine to acyl CoA

4. The carnitine released returns to cytosol for reuse. Carnitine acyl transferase is inhibited by malonyl CoA

lll. β-Oxidation in the mitochondrial matrix

•       Each cycle of β-oxidation, liberating a two carbon unit- acetyl CoA, occurs in a sequence of four reactions

1. Oxidation: Acyl CoA undergoes dehydrogenation by an FAD-dependent flavoenzyme, acyl CoA dehydrogenase. A double bond is formed between α & β carbons

2. Hydration: Enoyl CoA hydratase brings about the hydration of the double bond to form p-hydroxyacyl CoA

3. Oxidation: β-hydroxyacyl CoA dehydrogenase catalyses the second oxidation and generates NADH. The product formed is β-ketoacylCoA

4. Cleavage: The final reaction in β-oxidation is the liberation of 2 carbon fragment, acetyl CoA from acyl CoA. This is by thiolytic cleavage catalysed by thiolase

•       The new acyl CoA, containing two carbons less than the original, re-enters the β-oxidation cycle

•       The process continues till the fatty acid is completely oxidized

Beta oxidation of palmitic acid

Energetics of β-oxidation of palmitic acid

Oxidation of palmitoyl CoA: Palmitoyl CoA + 7CoASH + 7FAD + 7NAD⁺ + 7H₂O - ---> 8 Acetyl CoA + 7FADH₂ + 7NADH + 7H⁺

•       It undergoes 7 cycles of β-oxidation to yield 8 acetyl CoA

•       Acetyl CoA can enter citric acid cycle and get completely oxidized to CO₂ & H₂O

•       Fatty acids are oxidized by most of the tissues in the body.

•       However, brain, erythrocytes and adrenal medulla cannot utilize fatty acids for energy requirement

Disorders of β-oxidation

•       SIDS: The sudden infant death syndrome (SIDS) is an unexpected death of healthy infants, usually overnight. It is estimated that at least 10% of SIDS is due to deficiency of medium chain acyl CoA dehydrogenase

•       Jamaican vomiting sickness: This disease is characterized by severe hypoglycemia, vomiting, convulsions, coma and death. lt is caused by eating unripe ackee fruit, which contains an unusual toxic amino acid, hypoglycin A. This inhibits the enzyme acyl CoA dehydrogenase and thus β-oxidation of fatty acids is blocked, leading to various complications.

β Oxidation of unsaturated fatty acids

•       Due to the presence of double bonds, the unsaturated fatty acids are not reduced to the same extent as saturated fatty acids. Therefore, oxidation of unsaturated fatty acids, in general, provides less energy than that of saturated fatty acids

•       Most of the reactions involved in the oxidation of unsaturated fatty acids are the same as found in the β-oxidation of saturated fatty acids. However, the presence of double bonds poses problem for β-oxidation to proceed

•       This is overcome by two additional enzymes-an isomerase and an epimerase

•       In the oxidation of unsaturated fatty acids, most of the reactions are the same as those for saturated fatty acids, however,2 additional enzymes are required

•       The combined action of isomerase and reductase are needed to degrade a wide range of unsaturated fatty acids

•       Energy yield is less for the oxidation of unsaturated fatty acids as they are less reduced

•       2 ATPs are less formed per double bond as the first step of dehydrogenation to introduce the double bond is not required

Summary

•       The fatty acids in the body are mostly oxidized by β-oxidation

•       Oxidation of palmitoyl CoA undergoes 7 cycles of β-oxidation to yield 8 acetyl CoA

•       SIDS & Jamaican vomiting sickness are due to deficiency of acyl CoA dehydrogenase

•       Additional two enzymes- isomerase and reductase required for oxidation on unsaturated fatty acid