Fatty Acid Alphaoxidation Enzymology And Deficiencies In

6.1. Phytanic Acid Degradation

The presence of a methyl group at the third carbon atom of any fatty acid prevents its direct |3-oxidation. In principle oxidation of such 3-methyl branched clain fatty acids may then proceed via 2 mechanisms which include (i) co-oxidation or (ii) a-oxidation.

In the case of phytanic acid it has been established that co-oxidation does occur but only to a limited extent implying that a-oxidation is the major pathway. Steinberg and coworkers77 performed a series of studies to establish the structure of the phytanic acid oxidation pathway. These studies revealed that 2-hydroxyphytanic acid is an obligatory intermediate.78 This was concluded from the fact that phytanic acid was found to be oxidized to C02 both in total homogenates as well as in mitochondria from rat liver if ATP, NAD+ and NADPH were present. Gaschromatographic analysis of the reaction mixture revealed the time-dependent accumulation of 2-hydroxyphytanic, pristanic, A2-pristenic and 4,8,12-trimethyltridecanoic acid.78 These data led to the scheme proposed by Tsai et al.,78 shown in Figure 3A. Tsai et al.78 also found that the conversion of phytanic acid to 2-hydroxyphytanic acid required molecular oxygen which led them to suggest that the first step in the pathway is mediated by a mitochondrial cytochrome P450 type of hydroxylase.

It is now firmly established that the pathway proposed by Tsai et al?% is incorrect. This is concluded from the following key observations. Firstly, Poulos and coworkers79 made the important observation that formic acid and not C02 is the primary product of a-oxidation. Secondly, Watkins et al.3 presented convincing evidence showing that phytanoyl-CoA and not phytanic acid is the true substrate for phytanic acid a-oxidation.

Thirdly, Mihalik et al.4 discovered a new enzyme which converts phytanoyl-CoA into 2-hydroxyphytanoyl-CoA in a reaction involving 2-oxoglutarate, Fe^ and ascorbate. The existence of this enzyme was confirmed in subsequent studies both in rat5 and man.6 Interestingly, phytanoyl-CoA hydroxylase is localized in peroxisomes. This has been

established both in rat liver5 as well as in human liver6 which is hard to reconcile with data in the literature80 suggesting a different localization of phytanic acid a-oxidation in rat (mitochondrial) and man (peroxisomal). As discussed in detail elsewhere, all studies with homogenates or isolated organelles previous to the discovery of phytanoyl-CoA hydroxylase by Mihalik et al.4 which also includes our own studies,81'82 suffer from the fact that the wrong cofactor combination was used lacking 2-oxoglutarate, Fe" and ascorbate. The lack of appropriate cofactors in studies on fatty acid a-oxidation also explains the very low rates of phytanic acid a-oxidation described in homogenates and isolated organelles (see82).

Recent studies have led to a full resolution of the structure of the phytanic acid aoxidation pathway. Indeed independent studies by Croes et al.1 and Verhoeven83 revealed that 2-hydroxyphytanoyl-CoA undergoes cleavage to produce formyl-CoA and pristanal respectively, which is than oxidized to pristanic acid (Fig. 3B). The pristanic acid is now ready for (3-oxidation after its activation to its CoA-ester.

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