A-Oxidation of phytanic acid

Fig. 7. a-Oxidation of phytanic acid. Compound I, phytanic acid compound II, phytanoyl-CoA compound III, 2-hydroxyphytanoyl-CoA compound IV, pristanal compound V, pristanic acid. 

A number of inherited deficiencies of peroxisomal enzymes have been described. Zellweger s syndrome, which results from defective peroxisomal biogenesis, leads to complex developmental and metabolic phenotypes affecting principally the liver and the brain. One of the metabolic characteristics of these diseases is an elevation of C26 0, and C26 1 fatty acid levels in plasma. Refsum s disease is caused by a deficiency in a single peroxisomal enzyme, the phytanoyl CoA hydroxylase that carries out a-oxidation of phytanic acid. Symptoms include retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy. Because phytanic acid is obtained solely from the diet, placing patients on a low-phytanic acid diet has resulted in marked improvement. 

On the left, the intermediates formed during a-oxidation of phytanic acid accord-... 

Tsai, S.-C., Avigan, J. Steinberg, D. (1969)/ Biol. Chem. 244, 2682-2692. Studies of the a-oxidation of phytanic acid by rat liver mitochondria. 

Mihalik, S.J., Solimiian, T.M., Day, RF. Watkins, P.A. (1992) Prog. Clin. Biol Res. 375, 239-244. Involvement of both peroxisomes and mitochondria in the a-oxidation of phytanic acid. In New developments in fatty acid oxidation (Coates, P.M. Tanaka, K., Eds.) Wiley-Liss, New York. 

We recently found the enzyme defect in RD to be at the level of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalysing the first step of the a-oxidation of phytanic acid, which involves conversion of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Furthermore we identified the human PHYH cDNA after purification of PhyH... 

Refsum disease, also called heredopathia atactica polyneuritiformis, is a rare hereditary neurological disease that is transmitted as an autosomal recessive. It results from the absence of an enzyme (phytanic acid oxidase) which catalyzes the a-oxidation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Because of the methyl side chain in position 3 the j8-carbon oxidation of phytanic acid is blocked and the breakdown of phytanic acid can only start through a-oxidation. The product of the a-oxidation is pristanic... 

Instead, from Steinberg s laboratory has come convincing evidence of the importance of a-oxidation of phytanic acid in normal subjects and their results point to a defect in this degradative pathway in patients [131], which has since been well reviewed [133]. 

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