Fatty acid Metabolism Cont.

In the previous post of Fatty acid metabolism, we talked about first part of oxidation of fatty acids with even number of carbon atoms. SO, today we will talk about second part of oxidation relating to odd number of carbon atoms of Fatty acids, unsaturated fatty acids and ω-oxidation.

Fatty acid oxidation (odd number):

This process proceeds by the same reaction steps as that of an even number of carbon atoms until final 3 carbons are formed no 2 carbons as in even number. This compound is called Propionyl CoA. 

Propionyl CoA is metabolized on 3 pathways: 

 

a) Propionyl CoA is carboxylated into D- methylmalonyl CoA by propionyl CoA carboxylase which requires coenzyme called biotin.

b) D-methylmalonyl CoA is converted into L-methylmalonyl CoA by methylmalonyl CoA racemase.

c) Carbons of L-methylmalonyl is rearranged forming succinyl CoA which enters TCA cycle by enzyme methylmalonyl mutase which requires Coenzyme called Vitamin B12.

When there is deficiency in vitamin B12, it leads to methylmalonic acidemia (Mutase is missing or deficient) and aciduria (Patient is unable to convert vitamin B12 into coenzyme). 

Either type also leads to metabolic acidosis and neurological manifestations.  

As everyone knew that beta oxidation of Fatty acids occurs in mitochondria, but there are some exceptions for that: 

1)   

Very-long-chain- fatty acids (more than 22 carbon atoms) (VLCFAs) undergo their β-oxidation inside peroxisome as peroxisomes are the main site for synthetase enzyme that activates this length of fatty acids.

 

The initial dehydrogenation in peroxisome is catalyzed by FAD-containing acyl CoA oxidase.

FADH2 produced is oxidized by O2, which is reduced to H2O2. And No ATP is generated in this step. H2O2 is reduced to H2O by catalase. 

There are some genetic defects that lead to:

a)     Inability to target matrix proteins (proteins that form layer inside organelles) to peroxisomes resulting in Zellweger syndrome,

b)     Inability to transport VLCFAs across the peroxisomal membrane resulting in X-linked adrenoleukodystrophy, lead to accumulation of VLCFAs in the blood and tissues.

2)     α-oxidation of branched chain fatty acids like branched chain of phytanic acid which is a product of chlorophyll metabolism. this compound can't be substrate to acyl CoA dehydrogenase due to methyl group on beta carbon. 

Phytanic acid is hydroxylated at the α-carbon by phytani

c CoA alpha-hydroxylase (PhyH), so carbon 1 is released as CO2 and a product of 19 carbon atoms called Pristanal is formed which is oxidized into pristanic acid. And this acid is activated into its CoA derivatives and completes β-oxidation steps. 

There is a rare disease occurring when there is deficiency in PhyH which is called Refsum disease.  This results in the accumulation of phytanic acid in the plasma and tissues. The symptoms are primarily neurologic, and the treatment involves dietary restriction to halt disease progression.

c) ω-Oxidation which generated diacylglycerol occurs in ER. 

Oxidation of unsaturated fatty acids: 

It produces less energy than that of saturated one because unsaturated fatty acids are less reduced. 

Oxidation of monounsaturated fatty acids such as oleic acid requires one additional enzyme called 3,2 enoyl CoA isomerase to convert the 3-cis derivative obtained after three rounds of β-oxidation to the 2-trans derivative required as a substrate by the enoyl CoA hydratase.

Oxidation of polyunsaturated fatty acids such as Linoleic acid requires NADH-dependent 2,4-dienoyl reductase + isomerase