A-Oxidation of phytanic add

Watkins, P.A. Mihalik, SJ. (1990) Biochem. Biophys. Res. Commun. 167, 580-586. Mitochondrial oxidation of phytanic add in human and monkey Uver impUcation that Refsum s disease is not a peroxisomal disorder. 

Pahan, K., Khan, M. Singh, I. (1996) J. Lipid Res. 37, 1137-1143. Ph5rtanic add oxidation normal activation and transport yet defective a-hydroxylation of phytanic add in paoxisomes from Refsum disease and rhizomelic chondrodysplasia punctata. 

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.)... 

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

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

Veihoeven, N.M., Schor, D.S.M., Previs, S.F., Brunengiaber, H. Jakobs, C (1997) Eur. J. Pediatr. 156, S83-S87. Stable isotope studies of phytanic add a-oxidation in vivo production of formic acid. 

Jansen, G.A., Mihalik, S.J., Watkins, P.A., Moser, H.W., Jakobs, C, Denis, S. Wanders, R.J.A. (1996) Biochem. Biophys. Res. Commun. 229, 205-210. Phytanoyl-CoA hydroxylase is present in human Uver, located in peroxisomes, and deficient in Zellweger syndrome direct, unequivocal evidence for the new, revised pathway of phytanic add alpha-oxidation in humans. 

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. 

Hence, activation precedes hydroxylation. Although 3-MBFA can be activated at different cellular sites—mitochondria, peroxisomes and endoplasmic reticulum —only the peroxisomal activity seems to supply a precursor for the hydroxylation reaction. Whether the acyl-CoA synthetase acting on phytanic acid is the same as the one activating palmitic acid and pristanic acid is a matter of controversy. Anyway, the requirement for an activation step explains the inhibition of a-oxidation by fenoprofen, an inhibitor of long chain fatty acid activation, and by different fatty adds (unpubHshed data), presumably due to competitive inhibition or by depletion of the available CoA. 

Mihalik, S.J., RainviUe, A.M. Watkins, PA. (1995) Em J. Biochem. 232, 545-551. Phytanic add a-oxidation in rat liver peroxisomes. Production of a-hydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. 

Verhoeven, N.M., Sdior, D.S., ten Brink, H.J., Wanders, RJA. Jakobs, C. (1997) Biochem. Biophys. Res. Commuti. 237, 33-36. Resolution of the phytanic add a-oxidation pathway Identification of ptis-tanal as product of the decarboxylation of 2-hydroxyphytanoyl-CoA. 

It is now firmly established that the pathway proposed by Tsai et is incorrect. This is concluded from the following key observations. Firstly, Poulos and coworkers made the important observation that formic acid and not CO2 is the primary product of a-oxidation. Secondly, Watkins et al. presented convincing evidence showing that phytanoyl-CoA and not phytanic acid is the true substrate for phytanic add a-oxidation. 

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.

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