Dr. Prabhakar Singh SEM-III_Fatty Acid Oxidation

Metabolism of LipidsLipids: Introduction, hydrolysis of triacylglycerols; oxidation of fatty acids.Oxidation of odd numbered fatty acids, fate of propionate, role of carnitine, degradation ofcomplex lipids.

Lipids: Introduction

Hydrolysis of Triacylglycerols

FATTY ACID OXIDATIONA. Fatty Acid ActivationB. Transport Across the Mitochondrial

MembraneC. ẞ-Oxidation

Source ATP Total7 FADH2 x 1.5 ATP = 10.5 ATP7 NADH x 2.5 ATP = 17.5 ATP8 acetyl CoA x 10 ATP = 80 ATPActivation = -2 ATPNET = 106 ATP

Oxidation of odd numbered fatty acids/ fate of propionate,

α-Oxidation of fatty acids

Alpha-oxidation of phytanic acid is believed to take place entirely within peroxisomes.1. Phytanic acid is first attached to 

CoA to form phytanoyl-CoA.2. Phytanoyl-CoA is oxidized by 

phytanoyl-CoA dioxygenase, in a process using Fe2+ and O2, to yield 2-hydroxyphytanoyl-CoA.

3. 2-hydroxyphytanoyl-CoA is cleaved by 2-hydroxyphytanoyl-CoA lyase in a TPP-dependent reaction to form pristanal andformyl-CoA (in turn later broken down into formate and eventually CO2).

4. Pristanal is oxidized by aldehyde dehydrogenase to form pristanic acid (which can then undergo beta-oxidation).

Peroxisomes and Fatty Acids Oxidation

Peroxisomes are small, membrane-enclosed organelles (Figure 10.24) that contain enzymes involved in a variety of metabolic reactions, including several aspects of energy metabolism.

Omega oxidation

Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most distant from the carboxyl group of the fatty acid). The process is normally a minor catabolic pathway for medium-chain fatty acids (10-12 carbon atoms), but becomes more important when β oxidation is defective.In vertebrates, the enzymes for ω oxidation are located in the smooth ER of liver and kidney cells, instead of in the mitochondria as with β oxidation. The steps of the process are as follows:

Reaction type Enzyme Description

Hydroxylation mixed function oxidase

The first step introduces a hydroxyl group onto the ω carbon. The oxygen for the group comes from molecular oxygen in a complex reaction conduced by certain members of the CYP4A and CYP4F subfamilies viz., CYP4A11,CYP4F2,and CYP4F3 or by two other CYP450 enzymes, CYP2U1 andCYP4Z1, that involves cytochrome P450 and the electron donor NADPH.

Oxidation alcohol dehydrogenase

The next step is the oxidation of the hydroxyl group to an aldehyde by NAD+.

Oxidation aldehyde dehydrogenase

The third step is the oxidation of the aldehyde group to a carboxylic acid by NAD+. The product of this step is a fatty acid with a carboxyl group at each end.

BIOSYNTHESIS OF FATTY ACIDS l.' Productionof acetyl CoA and NADPHll. Conversionof acetylCoA to malonyl CoAlll. Reactionsof fatty acid synthasecomplex

Fatty acid synthase complex

FAS

Oxidation of Unsaturated fatty acids

β-Oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-Δ2 bond. These situations are handled by an additional two enzymes, Enoyl CoA isomerase or 2,4 Dienoyl CoA reductase.

Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate for acyl CoA dehydrogenase, or enoyl CoA hydratase:

•If the acyl CoA contains a cis-Δ3 bond, then cis-Δ3-Enoyl CoA isomerase will convert the bond to a trans-Δ2 bond, which is a regular substrate.•If the acyl CoA contains a cis-Δ4 double bond, then its dehydrogenation yields a 2,4-dienoyl intermediate, which is not a substrate for enoyl CoA hydratase. However, the enzyme 2,4 Dienoyl CoA reductase reduces the intermediate, using NADPH, into trans-Δ3-enoyl CoA. As in the above case, this compound is converted into a suitable intermediate by 3,2-Enoyl CoA isomerase.To summarize:•Odd-numbered double bonds are handled by the isomerase.•Even-numbered double bonds by the reductase (which creates an odd-numbered double bond)