Alpha oxidation is a process that shortens fatty acid derivatives with a methyl group attached to the beta carbon. Inadequate alpha oxidation leads to phytanic acid accumulation, causing Refsum’s disease. Treatment involves diet and plasmapheresis, but enzymatic treatment is hoped to reduce phytanic acid buildup.
Alpha oxidation, or α-oxidation, is the name assigned to the enzymatic shortening of fatty acid derivatives that contain a methyl group (CH3-) attached to the carbon atom located beta (β) to the carboxylate group (-COO- ). Just one of a number of processes, alpha oxidation involves the metabolization of specific fatty acids, in the peroxisomes of eukaryotic cells. Inadequate alpha oxidation in the human body leads to severe accumulation of phytanic acid, which is closely related to Refsum’s disease. This genetic disease is known to produce a variety of ailments, many of which are not life-threatening. Most cases of Refsum’s disease are associated with mutations in the PHYH gene.
Structurally, the original carboxylate is attached to Coenzyme A, and can be drawn CH2CH(Me)CH2-COO-(CoA), or phytanoyl-CoA, where the structure of the coenzyme is not written and CH3 is attached to – the carbon atom is written as “Me” – which stands for methyl – for ease of visualization. Identifying the carbon atoms (C) – from right to left, not counting the carbons of the coenzyme CoA – there is the carboxylate carbon, after the α carbon, then the carbon and the carbon . Carbon atoms to the left of position are excluded for simplification. The biological process requires an enzyme because methyl attached specifically to the beta position hinders the metabolism.
In the first step of the multistep process, a hydrogen atom is replaced with a hydroxyl group (-OH) at the α carbon. The result is the structure ···CH2CH(Me)CH(OH)-COO-(CoA). This is followed by decarboxylation, coupled with oxidation, to give ···CH2CH(Me)-COO-(CoA). After alpha oxidation is another metabolic step called beta oxidation. Unfortunately, the failure in the alpha oxidation process is not covered by the latter process: phytanic acid is not metabolized by beta oxidation or any other fatty acid metabolic process.
Because Refsum’s disease is closely related to excess phytanic acid, and phytanic acid comes directly from the diet, much of an individual’s treatment has to do with diet. It is found specifically in dairy products, beef, lamb and some fish, including tuna, cod and haddock. For some individuals, a difficult and expensive blood filtration procedure called plasmapheresis may be used. The minor itchy skin and muscle wasting problems can be resolved with treatment, and one day it is hoped that enzymatic treatment will reduce the buildup of phytanic acid, and with it Refsum’s more serious problems. At present, however, the outcome can be as serious as death from cardiac arrhythmia.
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