Omega oxidation (ω-oxidation) is a process offatty acid metabolism in some species of animals. It is an alternative pathway tobeta oxidation that, instead of involving the β carbon, involves the oxidation of theω carbon (the carbon most distant from thecarboxyl 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, theenzymes for ω oxidation are located in thesmooth ER ofliver andkidney cells, instead of in themitochondria as with β oxidation. The steps of the process are as follows:
| Reaction type | Enzyme | Description | Reaction |
|---|---|---|---|
| Hydroxylation | mixed function oxidase | The first step introduces ahydroxyl 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, andCYP4F3 or by two other CYP450 enzymes,CYP2U1 andCYP4Z1, that involvescytochrome P450 and the electron donorNADPH (seeCytochrome P450 omega hydroxylase). |  |
| Oxidation | alcohol dehydrogenase | The next step is theoxidation of the hydroxyl group to analdehyde by NAD+. |  |
| Oxidation | aldehyde dehydrogenase | The third step is theoxidation of the aldehyde group to acarboxylic acid by NAD+. The product of this step is a fatty acid with a carboxyl group at each end. |  |
After these three steps, either end of the fatty acid can be attached tocoenzyme A. The molecule can then enter the mitochondrion and undergo β oxidation. The final products after successive oxidations includesuccinic acid, which can enter thecitric acid cycle, andadipic acid.
The first step in ω-oxidation, i.e. addition of a hydroxy residue to the omega carbon of short, intermediate, and long chain unsaturated or saturated fatty acids, can serve to produce or inactivate signaling molecules. In humans, a subset ofCytochrome P450 (CYP450)microsome-bound ω-hydroxylases (termedCytochrome P450 omega hydroxylases) metabolizearachidonic acid (also known as eicosatetraenoic acid) to 20-hydroxyeicosatetraenoic acid (20-HETE).[1] 20-HETE possesses a range of activities in animal and cellular model systems, e.g. it constricts blood vessels, alters the kidney's reabsorption of salt and water, and promotes the growth of cancer cells; genetic studies in humans suggest that 20-HETE contributes tohypertension,myocardial infarction, and brainstroke (see20-Hydroxyeicosatetraenoic acid). Among the CYP450 superfamily, members of the CYP4A and CYP4F subfamilies viz.,CYP4A11,CYP4F2,CYP4F3, are considered the predominant cytochrome P450 enzymes responsible in most tissues for forming 20-HETE.[2][3][4]CYP2U1[5] andCYP4Z1[6] contribute to 20-HETE production in a more limited range of tissues. The cytochrome ω-oxidases including those belonging to the CYP4A and CYP4F sub-families and CYPU21 also ω-hydroxylate and thereby reduce the activity of various fatty acid metabolites of arachidonic acid includingLTB4,5-HETE,5-oxo-eicosatetraenoic acid,12-HETE, and severalprostaglandins that are involved in regulating various inflammatory, vascular, and other responses in animals and humans.[6][7] This hydroxylation-induced inactivation may underlie the proposed roles of the cytochromes in dampening inflammatory responses and the reported associations of certain CYP4F2 and CYP4F3single nucleotide variants with humanCrohn's disease andCeliac disease, respectively.[8][9][10]