Cerebronic acid (2-hydroxytetracosanoic acid), an alpha-hydroxy very long-chain
fatty acid (VLCFA) and a component of
cerebrosides and
sulfatides, is unique to nervous tissues. Studies were carried out to identify the pathway and the subcellular site involved in the oxidation of
cerebronic acid. The results from these studies revealed that
cerebronic acid was catabolized by alpha-oxidation to CO2 and
tricosanoic acid (23:0). Studies with subcellular fractions indicated that
cerebronic acid was alpha-oxidized in fractions having particulate bound
catalase and
enzyme systems for the beta-oxidation of VLCFA (e.g.,
lignoceric acid), suggesting peroxisomes as the subcellular organelle responsible for alpha-oxidation of
cerebronic acid.
Etomoxir, an inhibitor of mitochondrial
fatty acid oxidation, had no effect on
cerebronic acid alpha-oxidation. Further,
cerebronic acid oxidation was found to be dependent on the presence of NAD+ but not
FAD,
NADPH,
ATP, Mg2+, or
CoASH. Intraorganellar localization studies indicated that the
enzyme system for the alpha-oxidation of
cerebronic acid was associated with the peroxisomal limiting membranes. Studies on cultured fibroblasts from normal subjects and patients with
peroxisomal disorders indicated an impairment of alpha-oxidation of
cerebronic acid in cell lines that lack peroxisomes [e.g.,
Zellweger syndrome (ZS)]. On the other hand, alpha-oxidation of
cerebronic acid was found to be normal in cell lines from
X-linked adrenoleukodystrophy,
adult Refsum disease, and
rhizomelic chondrodysplasia punctata. Our results clearly demonstrate that alpha-oxidation of alpha-hydroxy VLCFA (
cerebronic acid) is a peroxisomal function and that this oxidation is impaired in ZS. Furthermore, this alpha-oxidation
enzyme system is distinct from the one for the alpha-oxidation of beta-
carbon branched-chain
fatty acids (e.g.,
phytanic acid).