Beta oxidation of odd chain and unsaturated fatty acids- lecture-4

Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation, producing acetyl-CoA, until a three-carbon (propionyl-CoA) residue remains. The 3- Carbon Propinyl co A is utilized in the following way:

The fate of propionyl co A

This compound is converted to Succinyl-CoA, a constituent of the citric acid cycle (figure-1).

Figure-1- Propionyl co A is carboxylated to produce D-methyl malonyl co A, which is converted to its L-isomer by the Racemase enzyme. L- Methyl malonyl co A is finally converted to Succinyl co A, an intermediate of the TCA cycle.

Biological Significance

The propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic. Acetyl CoA cannot be converted into pyruvate or Oxaloacetate in animals.

Clinical significance

Vitamin B12 deficiency leads to impaired conversion of L-methyl malonyl co A to Succinyl co A, due to reduced activity of Mutase enzyme, causing methylmalonic aciduria.

Beta oxidation of unsaturated fatty acids

• In the oxidation of unsaturated fatty acids, most of the reactions are the same as those for saturated fatty acids, only two additional enzymes an isomerase and a reductase are needed to degrade a wide range of unsaturated fatty acids.
• Energy yield is less by the oxidation of unsaturated fatty acids since they are less reduced.
• Per double bonds 2 ATP are less formed since the first step of dehydrogenation to introduce a double bond is not required, as the double already exists.

Beta oxidation of monounsaturated fatty acids

• Palmitoleoyl Co A undergoes three cycles of degradation, which are carried out by the same enzymes as in the oxidation of saturated fatty acids (Figure-2).
• The cis– Δ 3-enoyl CoA formed in the third round is not a substrate for acyl CoA dehydrogenase.
• An isomerase converts this double bond into a trans- Δ 2 double bond.
• The subsequent reactions are those of the saturated fatty acid oxidation pathway, in which the trans- Δ 2-enoyl CoA is a regular substrate.

Figure-2- Beta oxidation of Palmitoleoyl Co A(monounsaturated fatty acid)

Beta oxidation of polyunsaturated fatty acids

• A different set of enzymes is required for the oxidation of Linoleic acid, a C18 polyunsaturated fatty acid with cis-Δ 9 and cis-Δ12 double bonds.
• The cis- Δ 3 double bond formed after three rounds of β oxidation is converted into a trans- Δ 2 double bond by isomerase.
• The acyl CoA produced by another round of β oxidation contains a cis- Δ 4 double bond. Dehydrogenation of this species by acyl CoA dehydrogenase yields a 2,4-dienoyl intermediate, which is not a substrate for the next enzyme in the β -oxidation pathway.
• This impasse is circumvented by 2,4-dienoyl CoA reductase, an enzyme that uses NADPH to reduce the 2,4-dienoyl intermediate to Trans-D 3-enoyl CoA. 
•  cis-Δ 3-Enoyl CoA isomerase then converts trans– Δ 3-enoyl CoA into the trans- Δ 2 form, a customary intermediate in the beta-oxidation pathway.

Figure-3 -Beta oxidation of Linoleoyl co A (Dienoic acid- containing two double bonds)

Regulation of fatty acid oxidation

• There is regulation at the level of entry of fatty acids into the oxidative pathway by carnitine palmitoyl transferase-I (CPT-I), CPT-I activity is low in the fed state, leading to depression of fatty acid oxidation, and high in starvation, allowing fatty acid oxidation to increase.
• Malonyl-CoA, the initial intermediate in fatty acid biosynthesis (figure-4), formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CPT-I. Under these conditions, free fatty acids enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in very-low-density lipoproteins (VLDL).
• However, as the concentration of free fatty acids increases with the onset of starvation, acetyl-CoA carboxylase is inhibited directly by acyl-CoA, and [malonyl-CoA] decreases, releasing the inhibition of CPT-I and allowing more acyl-CoA to be -oxidized.
• These events are reinforced in starvation by a decrease in the [insulin]/[glucagon] ratio.
• Thus, -oxidation from free fatty acids is controlled by the CPT-I gateway into the mitochondria, and the balance of the free fatty acid uptake not oxidized is esterified.

Figure-4- CPT-1(Carnitine palmitoyl Transferase -1) is inhibited by malonyl co A, the product of the first step of the fatty acid synthesis. Active fatty acid synthesis takes place in the well-fed state under the effect of insulin, thus when fatty acid synthesis is active fatty acid oxidation is inhibited. Both processes do not occur simultaneously.