Identification of pristanal dehydrogenase activity in peroxisomes: conclusive evidence that the complete phytanic acid alpha-oxidation pathway is localized in peroxisomes.
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which, due to the methyl-group at the 3-position, can not undergo beta-oxidation unless the terminal carboxyl-group is removed by alpha-oxidation. The structure of the phytanic acid alpha-oxidation machinery in terms of the reactions involved, has been resolved in recent years and includes a series of four reactions: (1) activation of phytanic acid to phytanoyl-CoA, (2) hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA, (3) cleavage of 2-hydroxyphytanoyl-CoA to pristanal and formyl-CoA, and (4) oxidation of pristanal to pristanic acid. The subcellular localization of the enzymes involved has remained enigmatic, with the exception of phytanoyl-CoA hydroxylase and 2-hydroxyphytanoyl-CoA lyase which are both localized in peroxisomes. The oxidation of pristanal to pristanic acid has been claimed to be catalysed by the microsomal aldehyde dehydrogenase FALDH encoded by the ALDH10-gene. Making use of mutant fibroblasts deficient in FALDH activity, we show that phytanic acid alpha-oxidation is completely normal in these cells. Furthermore, we show that pristanal dehydrogenase activity is not fully deficient in FALDH-deficient cells, implying the existence of one or more additional aldehyde dehydrogenases reacting with pristanal. Using subcellular localization studies, we now show that peroxisomes contain pristanal dehydrogenase activity which leads us to conclude that the complete phytanic acid alpha-oxidation pathway is localized in peroxisomes.
Jansen
G A
GA
Department of Clinical Chemistry, Department of Pediatrics, University of Amsterdam, Academic Medical Centre, Emma Children's Hospital, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands
van den Brink
D M
DM
Ofman
R
R
Draghici
O
O
Dacremont
G
G
Wanders
R J
RJ
D000445:Aldehyde Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000201:enzymology / Q000378:metabolism*; D010831:Phytanic Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012035:Refsum Disease / Q000201:enzymology; D016111:Sjogren-Larsson Syndrome / Q000235:genetics / Q000378:metabolism
D000447:Aldehydes; D005227:Fatty Acids; C107623:pristanal; D010831:Phytanic Acid; D000445:Aldehyde Oxidoreductases; C427384:pristanal dehydrogenase; C038828:long-chain-aldehyde dehydrogenase