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Fatty acid oxidation – part-3 – A quick revision
Beta oxidation of odd chain fatty acids
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.
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, that is converted to its L-isomer by Racemase enzyme. L- Methyl malonyl co A is finally converted to Succinyl co A , an intermediate of TCA cycle.
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.
Vitamin B12 deficiency leads to impaired conversion of L-methyl malonyl co A to Succinyl co A, due to reduced activity of the enzyme, causing methyl malonic 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 double bond is not required, as the double already exists.
a) Beta oxidation of mono unsaturated 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 Palmitoleic acid (Mono unsaturated fatty acid)
b) Beta oxidation of polyunsaturated fatty acids (figure-3)
- 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 (figure-3) .
- 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 Linoleic acid (Dienoic acid- containing two double bonds)
Regulation of fatty acid oxidation(figure-4)
- 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 decrease in the [insulin]/[glucagon] ratio.
- Thus, β -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 first step of 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 the processes do not occur simultaneously.Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!