Phytanic acid degradation

Refsum s disease. This disorder, first described nearly 60 years ago, was recently been shown due to a defect in the enzyme phytanoyl-CoA hydroxylase. Phytanic acid is a 3-methyl fatty acid that because of this methyl group cannot be oxidized directly. It is degraded by a peroxisomal a-oxidation to pristanic acid, a 2-methyl fatty acid which can be degraded by P-oxidation. The principal clinical features of Refsum s disease are progressive polyneuropathy, retinal degeneration, hearing loss, cardiomyopathy and ichthyosis, beginning in late childhood or later. 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

Generally a linear hydrocarbon chain with a terminal carboxyl group, a fatty acid can be saturated or unsaturated. Branched-chain phytanic acid is found in dairy products. An inability to degrade phytanic acid causes its accumulation in plasma and tissues (Refsum disease). 

Answer Phytanic acid is degraded to pristanic acid by the pathway shown in Figure 17-17. Pristanic acid undergoes ft oxidation, with each round yielding propionyl-CoA (not acetyl-CoA, as for a straight-chain fatty acid). Degradation of uniformly labeled phytanic acid produces... 

P Oxidation focuses on the ft carbon of the fatty acid. In some instances, it is impossible to form a ketone on the P carbon, for example, if the P carbon is methylated. In such cases, the a carbon may be oxidized to initiate the oxidation process, a Oxidation is useful in the degradation of certain plant materials, such as phytol. The degradation of this compound is illustrated in Figure 19.9. In Refsum disease, caused by a genetic lesion, the enzyme hydroxylating phytanic acid is absent and phytanic acid accumulates in tissues. 

Phytanic acid is converted to pristanic acid by oxidation of the a-carbon and a decarboxylation. Pristanic acid is further degraded to generate a mixture of acetyl-CoA, propionyl-CoA, and isobutyl-CoA by the /3-oxidation pathway. 

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a component of the human diet that is derived from phytol, a constituent of chlorophyll, is not degraded by p-oxidation because its 3-methyl group interferes with this process. Instead, phytanic acid is chain-shortened by a-oxidation in peroxisomes as outlined in Fig. 7 [28]. Activation... 

Two of the most common branched-chain fatty acids in the diet are phytanic acid and pristanic acid, which are degradation products of chlorophyll and thus are consumed in green vegetables (Fig.23.15). Animals do not synthesize branched-chain fatty acids. These two multi-methylated fatty acids are oxidized in peroxisomes to the level of a branched C8 fatty acid, which is then transferred to mitochondria. The pathway thus is similar to that for the oxidation of straight very-long-chain fatty acids. 

In 1963, Klenk and Kahlke identified the lipid accumulating in Refsum s disease as phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). As a result, phytanic add is probably the best known 3-methyl-branched chain fatty acid. Over the subsequent 30 years, many groups have tried to elucidate the breakdovm of phytanic acid. The presence of the 3-methyl group in ph54anic acid prevents its degradation via P-oxidation, the... 

Mize, C.E., Avigan, J., Steinberg, D., Pittman, R.C., Fales, H.M. Milne, G.W.A. (1969) Biochim. Biophys. Acta 176, 720-739. A major pathway for the mammalian oxidative degradation of phytanic acid. 

Phytanic acid a-hydroxylase. Phytanic acid accumulates in liver and kidneys, and it may represent over 50% of total liver fatty acids. Plasma phytanic acid concentrations of 200-3,100 mg/I have been repotted (normal <2 mg/1). Peripheral neuropathy and ataxia, retinitis pigmentosa and skin and bone abnormalities. TVeatment by plasma exchange and low phytol intake. [Phytanic acid is normally formed in the body from the plant alcohol, phytol, present as an ester in chlorophyll. Ihe presence of a branch methyl group at position 3 of phytanic acid means that the normal process of p-oxidation is blocked. Oxidation of fatty acids one carbon at a time (a-oxidation) is common in plants, but also occurs to some extent in animals, especially in the brain, where it serves to initiate degradation of phytanic acid. The resulting pristanic acid is then degraded by p-oxidation]... 

Branched-chain acids, such as iso- (with an isopropyl terminal group) or anteiso- (a secondary butyl terminal group) are rarely found in food. Pristanic and phytanic acids have been detected in milk fat (Table 3.6). They are isoprenoid acids obtained from the degradation of the ph5dol side chain of chlorophyll. 

In Fig. 1, a revised pathway for the a-oxidative degradation of phytanic acid is shown. The different reactions depicted are based on experimental data obtained in rat... 

A deficiency wherein hyperkeratinization of epidermis and other epithelia occurs. The other metabolic defect is that encountered in Refsum s disease, an inherited neurological disorder biochemically characterized by accumulation of phytanic acid due to failure of tissue hydroxylases to initiate its degradation by a-hydroxylation. In this disease dry hyperkeratotic scaliness of the skin appears in variable degrees, reported to be at times sufficiently extreme to mimic ichthyosis. As in the ichthyoses, hyperkeratinization of other epithelia does not occur. 

Refsum s syndrome is inherited as an autosomal recessive trait. It is characterized by an enzymatic defect of cr-oxidation resulting in an accumulation of phytanic acid in many organs and body fluids. This fatty acid is a result of incomplete degradation of phytol, a part of the chlorophyll molecule. 

Figure 1 Fatty-acid structure and nomenclature. (A) Chemical formula and carbon atom numbering system for a 16-carbon saturated fatty acid (16 0). (B) Schematic representation of 16 0. (C) A monounsaturated fatty add, 18 1n-9, showing the double bond nine carbon atoms from the methyl end (carbon 18). (D) The essential n-6 fatty acid 18 2n-6, where the first double bond is found six carbon atoms from the methyl end. The two double bonds are separated by a methylene (-CH2-) group. (E) The essential n-3 fatty acid 18 3n-3, where the first double bond is found three carbon atoms from the methyl end. (F) Phytanic acid, a dietary / -methyl-branched-chain fatty acid (3,7,11,15-tetramethyl 16 0). The melhyl group on carbon 3 prevents this fatty acid from degradation by /3-oxidation. (G) Pristanic acid (2,6,10,14-tetramethyl 15 0) is the product of phytanic acid o-oxidation, in which a single carbon (carbon 1) is lost. The methyl group on carbon 2 does not preclude subsequent degradation by /3-oxidation.

Figure 4 Peroxisomal fatty-acid (FA) /3-oxidation pathways. While saturated long-chain fatty acids (LCFA) are preferentially degrade in mitochondria, saturated very-long-chain fatty acids (VLCFA) and some LCFA are shortened by peroxisomal /3-oxidation. Degradation of pristanic acid, the product of phytanic acid a-oxidation, and the conversion of the cholesterol-derived 27-carbon bile-acid precursors dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) to 24-carbon bile acids also require this pathway. The mechanism by which these substrates enter peroxisomes is unknown. Four enzymatic reactions serve to shorten the substrates by either two (LCFA, VLCFA) or three (pristanic acid, DHCA, THCA) carbon atoms. The 2-methyl group of the latter substrates is shown in brackets. SCPx thiolase refers to the thiolase activity of sterol carrier protein x.

Figure 5 Peroxisomal phytanic acid a-oxidation pathway. The dietary 3-methyl-branched fatty acid phytanic acid is toxic if allowed to accumulate in the tissues. Its 3-methyl group prevents degradation by /3-oxidation therefore, this fatty acid is first shortened by one carbon atom. Like the substrates for peroxisomal /3-oxidation, phytanic acid enters peroxisomes by an unknown mechanism. Activated phytanic acid is hydroxylated on carbon 2. Cleavage between carbons 1 and 2 yields a one-carbon CoA compound, formyl-CoA, and an aldehyde, pristanal. After oxidation and reactivation to the CoA derivative, pristanoyl-CoA can be degraded by /3-oxidation.

Subsequently it has been convincingly demonstrated that the primary metabolic lesion is in the degradative pathway of phytanic acid, and not on the synthetic chain. 

In considering the results of studies of oxidative metabolism of phytanic acid it must be recognized that the presence of a methyl group in the j3 position effectively prevents degradation by the normal method of j3-oxidation. 

Eldjarn [121] and his colleagues [129] considered first the possibility that co-oxidation, i.e. step-wise degradation from the opposite end of the molecule, might be blocked in Refsum s disease. Their eeurly results did indeed suggest that there was such a defect they showed that in patients with Refsum s disease there was a reduction in the excretion of sebacic acid (aCio dicarboxylic acid) after a loading dose of tricaprin [121]. However, these preliminary results were of uncertain significance because their patients did not show defects in co-oxidation of other substrates [130]. Later they showed that in patients whose serum phytanic acid was reduced by dietary treatment, the tricaprin test became normal [131], and in fact there is no direct evidence that co-oxidation is of importance in phytanic acid metabolism. 

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]. 

Using fibroblast cultures, the metabolic pathways have been delineated more clearly [134, 135]. In control cells it has been confirmed that the major pathway of phytanate degradation is by a-oxidation initially, followed by successive /J-oxidation steps shown diagrammatically in Figure 1.8. Cultured fibroblasts from skin biopsies of patients did not contain elevated levels of phytanic acid, but the rate of C-phytanate oxidation was less than 3% of that seen in cells from normal controls. Nevertheless, these cells were able to oxidize pristanic acid, the rj-1 homologue of phytanic acid at normal, or near-normal rates. 

Figure 1.8. Proposed pathway for degradation of phytanic acid in mammals. The three degradation products shown have been identified as products of phytanic acid in animals. The circled locations indicate the methylene groups that are converted to carboxyl groups in each successive oxidative step (after Steinberg etaL, [127].

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