PHYTANIC ACID OXIDATION IN MAN - IDENTIFICATION OF A NEW ENZYME CATALYZING THE FORMATION OF 2-KETOPHYTANIC ACID FROM 2-HYDROXYPHYTANIC ACIDAND ITS DEFICIENCY IN THE ZELLWEGER-SYNDROME

Phytanic acid (3,7,11,15-tetramethyldecanoic acid) is a saturated, bra nched-chain fatty acid that, because of the methyl group at the 3-posi tion, cannot undergo direct beta-oxidation. Instead, the terminal carb oxyl group has to be removed first by alpha-oxidation. The product, pr istanic acid (2,6,10,14-tetramethylpentadecanoic acid), which now cont ains the methyl group at the 2-position, can be beta-oxidized. This oc curs in peroxisomes (Singh et al 1990). Phytanic acid accumulates in a variety of different disorders, including classic Refsum disease (phy tanic acid storage disease), the disorders of peroxisome biogenesis (Z ellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystr ophy), rhizomelic chondrodysplasia punctata, peroxisomal disorders wit h a defect in pristanic acid beta-oxidation (see Wanders et al 1993 fo r review), and an atypical, variant form of phytanic acid storage dise ase that has been described recently (Tranchant et al 1994). The mecha nism of phytanic acid alpha-oxidation to pristanic acid has remained a n enigma through the years. Furthermore, there is great dispute on the subcellular localization of the phytanic acid alpha-oxidation pathway . Indeed, most authors have presented evidence in favour of a mitochon drial localization, whereas according to others alpha-oxidation occurs in peroxisomes (Singh et al 1993) or even in the endoplasmic reticulu m (Huang et al 1992). We earlier presented evidence suggesting that al pha-oxidation of phytanic acid proceeds via 2-hydroxyphytanic acid (Te n Brink et al 1992). On the basis of the analogy with the oxidation of L-lactate (to pyruvate and acetyl-CoA), we hypothesized that the path way of phytanic acid alpha-oxidation involves hydroxylation to 2-hydro xyphytanic acid followed by dehydrogenation to 2-ketophytanic acid and oxidative decarboxylation to pristanoyl-CoA (Wanders and Van Roermund 1993). We now report the identification of an enzyme localized in per oxisomes that reacts with 2-hydroxyphytanic to give 2-ketophytanic aci d. The other substrate turned out to be molecular oxygen. In addition, the enzyme was found to be deficient in liver from Zellweger patients , which explains our earlier findings (Ten Brink et al 1992) and provi des convincing evidence in favour of the suggested pathway of alpha-ox idation (see Wanders and Van Roermund 1993).