Hepatic alpha-oxidation of phytanic acid. A revised pathway.
Synthetic 3-methyl-branched chain fatty acids were used to decipher the breakdown of phytanic acid. Based on results obtained in intact or permeabilized rat hepatocytes, rat liver homogenates or subcellular fractions, a revised alpha-oxidation pathway is proposed which appears to be functioning in man as well. In a first step, the 3-methyl-branched chain fatty acid is activated by an acyl-CoA synthetase. This reaction requires CoA, ATP and Mg2+. Subsequently, the acyl-CoA ester is hydroxylated at position 2 by a peroxisomal dioxygenase. This step is dependent on alpha-oxoglutarate, ascorbate (or glutathione), Fe2+ and O2. The 2-hydroxy-3-methylacyl-CoA intermediate is cleaved by a peroxisomal lyase to formyl-CoA and a 2-methyl-branched fatty aldehyde. Formyl-CoA is (partly enzymically) hydrolyzed to formate, which is then converted, most likely in the cytosol, to CO2. In the presence of NAD+, the aldehyde is dehydrogenated to a 2-methyl-branched fatty acid, presumably by a peroxisomal aldehyde dehydrogenase. This acid can--after activation--be degraded via a D-specific peroxisomal beta-oxidation system.
Van Veldhoven
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PP
Katholieke Universiteit Leuven, Afdeling Farmakologie Herestraat, Belgium. Paul.VanVeldhoven@med.kuleuven.ac.be
Mannaerts
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GP
Casteels
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M
Croes
K
K
D000818:Animals; D003065:Coenzyme A / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010831:Phytanic Acid / Q000378:metabolism*; D051381:Rats
D010831:Phytanic Acid; D003065:Coenzyme A