In a-oxidation of phytanic acid

TThe presence of a methyl group on the [1 carbon of a fatty acid makes )3 oxidation impossible, and these branched fatty acids are catabolized in peroxisomes of animal cells by a oxidation. In the oxidation of phytanic acid, for example (Fig. 17-17), phytanoyl-CoA is hydroxylated on its a carbon, in a reaction that involves molecular oxygen decarboxylated to form an aldehyde one carbon shorter, and then oxidized to the... 

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. 

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... 

A hereditary neurodegenerative disorder of lipid metabolism in which the branched-chain fatty acid, phytanic acid, accumulates in the tissues, particularly the liver and kidney. It is due to a deficiency of phytanic acid a-hydroxylase, an enzyme involved in the oxidation of phytanic acid. The phytanic acid originates from dietary phytanic acid and also from dietary phytol, a component of chlorophyll. Treatment therefore consists of giving diets low in phytol and phytanic acid. 

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]. 

The branched-chain fatty acid, phytanic acid, is not a substrate for acyl CoA dehydrogenase due to the methyl group on its third (P) carbon (Figure 16.22). Instead, it is hydroxylated at the a-carbon by fatty acid a-hydroxylase. The product is decarboxylated and then activated to its CoA derivative, which is a substrate for the enzymes of P-oxidation. [Note Refsum disease is a rare, autosomal recessive disorder caused by a deficiency of a-hydroxylase. This results in the accumulation of phytanic acid in the plasma and tissues. The symptoms are primarily neurologic, and the treatment involves dietary restriction to halt disease progression.]... 

In Refsum s disease, an autosomal recessive disorder, the defect is probably in the a-hydroxylation of phytanic acid. Phytanic acid is a 20-carbon, branched-chain fatty acid derived from the plant alcohol phytol, which is present as an ester in chlorophyll. Thus, its origin in the body is from dietary sources. The oxidation of phytanic acid is shown in Figure 18-6. The clinical characteristics of Refsum s disease include peripheral neuropathy and ataxia, retinitis pigmentosa, and abnormalities of skin and bones. Significant improvement has been observed when patients are kept on low-phytanic acid diets for prolonged periods (e.g., diets that exclude dairy and ruminant fat). 

Oxidation of phytanic acid is blocked by the methyl group substituent on C-3 (the /3-position). Consequently, the first step in phytanic acid catabolism is an a-oxidation in which the molecule is converted to a a-hydroxy fatty acid. (a-Hydroxylating activity has been detected in the ER and in mitochondria.) This reaction is followed by the removal of the carboxyl group (Figure 12C). After activation to a CoA derivative, the product, pristanic acid, can be... 

Watkins, P.A. Mihalik, SJ. (1990) Biochem. Biophys. Res. Commun. S1, 580-586. Mitochondrial oxidation of phytanic acid in human and monkey liver implication that Refsum s disease is not a peroxisomal disorder. 

Pahan, K., Khan, M. Singh, I. (19%) J. LipidRes. 37, 1137-1143. Phytanic acid oxidation normal activation and transport yet defective a-hydroxylation of phytanic acid in peroxisomes Irom Refsum disease and rhizomelic chondrodysplasia punctata. 

Rhizomelic Chondrodysplasia Punctata Type 1 (RCDP Type I). Patients suffering from RCDP type I which is due to a non-fiinetional PTS2-receptor, also show deficient oxidations of phytanic acid. Recent data show that this results from a deficiency of phytanoyl-CoA hydroxylase. The deficiency of PhyH probably results from its mis-locahzation to the cytosol as a consequence of the non-functional PTS2-receptor and the apparent instability of the PhyH-protein in the cydosol. Pulse/chase experiments are underway to resolve this. 

Theories on the in vivo synthesis of phytanic acid concentrate mainly on two possibilities. One of them deals with the possible formation of phytanic acid from isopren units or four molecules of mevalonic acid (or mevalonate), (Kahlke 1964 a, Kahlke and Richterich 1965). Instead of an end-to-end condensation of two molecules of famesyl pyrophosphate which results in the formation of squalene and finally cholesterol, a fourth active isoprenoid unit might be attached to famesyl pyrophosphate. From this intermediate several steps of hydrogenation and oxidation would be required for the formation of phytanic acid. This hypothesis now appears unlikely since Steinberg (1965) was unable to detect any activity in the phytanic acid fraction after administration of labeled mevalonate to a patient with HAP (case T.E. of Refsum). 

Phytanic acid is normally present in small amounts in human tissues. Many defects in the a-oxidation pathway, including Refsum s disease, result in an accumulation of phytanic acid leading to neurological distress, deterioration of vision, deafness, loss of coordination and eventually death. 

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. 

Although /3-oxidation is universally important, there are some instances in which it cannot operate effectively. For example, branched-chain fatty acids with alkyl branches at odd-numbered carbons are not effective substrates for /3-oxidation. For such species, a-oxidation is a useful alternative. Consider phy-tol, a breakdown product of chlorophyll that occurs in the fat of ruminant animals such as sheep and cows and also in dairy products. Ruminants oxidize phytol to phytanic acid, and digestion of phytanic acid in dairy products is thus an important dietary consideration for humans. The methyl group at C-3 will block /3-oxidation, but, as shown in Figure 24.26, phytanic acid a-hydroxylase places an —OFI group at the a-carbon, and phytanic acid a-oxidase decar-boxylates it to yield pristanie add. The CoA ester of this metabolite can undergo /3-oxidation in the normal manner. The terminal product, isobutyryl-CoA, can be sent into the TCA cycle by conversion to succinyl-CoA. 

The a-oxidation pathway is defective in Refsum s disease, an inherited metabolic disorder that results in defective night vision, tremors, and other neurologic abnormalities. These symptoms are caused by accumulation of phytanic acid in the body. Treatment of Refsum s disease requires a diet free of chloro-... 

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. 

RGURE17-17 The a oxidation of a branched-chain fatty acid (phytanic add) in peroxisomes Phytanic acid has a methyl-substituted /3 carbon and therefore cannot undergo /3 oxidation. The combined action of the enzymes shown here removes the carboxyl carbon of phytanic acid, to produce pristanic acid, in which the /3 carbon is unsubstituted, allowing oxidation. Notice that /3 oxidation of pristanic acid releases propionyl-CoA, not acetyl-CoA. This is further catabolized as in Figure 17-11. (The details of the reaction that produces pristanal remain controversial.)... 

Milk fat contains small quantities of phytanic and pristanic acid. Phytanic acid is produced by bacterial cleavage of the phytol side chain of plant chlorophyll in the rumen. Some phytanic acid is converted to pristanic acid by a-oxidation in the liver. Both of these branched-chain acids are agonists for PPARa at physiological concentrations (Parodi, 2004). Milk fat from cows fed cannery fruit and vegetable waste no doubt contains other interesting phytochemicals with anti-cancer potential. 

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