Fatty Acid Metabolism in Cultured Skin Fibroblasts from Patients with Peroxisomal Disorders: Lignoceroyl-CoA Ligase Deficiency in Childhood Adrenoleukodystrophy

Abstract

We have previously reported that the peroxisomal B-oxidation system for very long chain (>C₂₂) fatty acids is defective in the peroxisomal disorders, adrenoleukodystrophy (ALD) and Zellweger’s cerebro-hepato-renal syndrome (CHRS), (Singh, et. al. Proc. Natl. Acad. Sci. 81, 4203, 1984). In order to elucidate the specific enzyme defect, we examined the oxidation of [1-¹⁴C]lignoceric acid and [1-¹⁴C]lignoceroyl-CoA (substrates for the 1st and 2nd steps of the B-oxidation cycle). In agreement with our previous observation, we found that oxidation of lignoceric acid (substrate for the 1st step) in fibroblasts from childhood ALD was only 32% of the control. However, the rates of oxidation of lignoceroyl-CoA (substrate for the 2nd step) in cultured fibroblasts from childhood ALD and control were essential equivalent (44,853 ± 8,243 and 41,530 ± 3,708 CPM/mg protein/hr respectively). These studies indicate that oxidation of lignoceric acid is defective while degradation of lignoceroyl-CoA is normal in childhood AL. This identifies lignoceroyl-CoA ligase as the enzyme impaired in childhood ALD. Since lignoceric acid is oxidized in peroxisomes, it is likely that peroxisomal lignoceroyl- CoA ligase activity is defective in chilhood ALD. We also examined this oxidation in CHRS cells and found that degradation of both of these substrates is defective. These studies indicate that the molecular mechanism for the pathognomonic accumulation of very long chain fatty acids in X-linked childhood ALD is different from that in CHRS.