ARTICLE NO. RC977066 Resolution of the Phytanic Acid a-Oxidation Pathway: Identi®cation of Pristanal as Product of the

shown in both rat and human liver [1,2,3]. Phytanoyl-The structure and enzymology of the phytanic acid CoA hydroxylation was found to be de®cient in liver a-oxidation pathway have long remained an enigma. and ®broblasts from patients affected by Refsum dis-Recent studies have shown that phytanic acid ®rst un- ease, rhizomelic chondrodysplasia punctata and gener-dergoes activation to its coenzyme A ester, followed alised peroxisomal disorders like Zellweger syndrome,by hydroxylation to 2-hydroxyphytanoyl-CoA. In this providing the biochemical basis for the phytanic acidpaper we have studied the mechanism of decarboxyl-accumulation found in these disorders [1,4,5,6]. Theation of 2-hydroxyphytanoyl-CoA in human liver. To mechanism whereby 2-hydroxyphytanoyl-CoA is de-this end, human liver homogenates were incubated carboxylated to pristanic acid or pristanoyl-CoA, haswith 2-hydroxyphytanoyl-CoA in the presence or ab-remained unknown so far. A systematic study of thesence of NAD/. Hereafter, the medium was analyzed reaction mechanisms of enzymes suggested to us thefor the presence of pristanal and pristanic acid by gas possibility that the decarboxylation of 2-hydroxyphyta-chromatography mass spectrometry. Our results show noyl-CoA might occur via a mechanism resembling thethat pristanal is formed from 2-hydroxyphytanoyl-breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA. Pristanal is subsequently oxidized to pristanic CoA). This metabolite is converted into acetoacetateacid in a NAD / dependent reaction. These results ®-nally resolve the mechanism of the phytanic acid a- and acetyl-CoA by means of HMG-CoA lyase [7]. If