New insights in peroxisomal beta-oxidation. Implications for human peroxisomal disorders.

In mammals including man, peroxisomes play a pivotal role in the breakdown of various carboxylates via beta-oxidation. Physiological substrates include very long chain fatty acids (e.g. lignoceric acid), medium and long chain dicarboxylic acids, certain polyunsaturated fatty acids, 2-methylbranched isoprenoid-derived fatty acids (e.g. pristanic acid), prostanoids (prostaglandins, leukotrienes thromboxanes), and bile acid intermediates (di- and trihydroxycoprostanic acid). Substrate spectrum and specificity studies of the four different beta-oxidation steps in rat and man indicate that these carboxylates, in contrast to previous belief, are degraded by separate systems composed of different enzymes. Bile acid intermediates are degraded in hepatic peroxisomes via 2-methylacyl-CoA racemase, trihydroxycoprostanoyl-CoA oxidase (in rat) or branched acyl-CoA oxidase (in man), D-specific multifunctional protein 2 (MFP 2) and sterol carrier protein X/thiolase. beta-oxidation of pristanic acid can occur in all tissues and relies on the action of 2-methylacyl-CoA racemase (for the 2R-isomer), pristanoyl-CoA oxidase (in rat) or branched chain acyl-CoA oxidase (in man), D-specific multifunctional protein 2 (MFP 2) and sterol carrier protein X/thiolase. The enzymes catalyzing the breakdown of straight chain fatty acids are palmitoyl-CoA oxidase, L-specific multifunctional protein 1 (MFP 1) and the dimeric thiolase. These enzymes are present in all tissues and are identical to those initially characterized in hepatic peroxisomes. Due to the presence of peroxisome targeting signals in all the above mentioned proteins, they are localised in the cytosolic or absent (due to proteolysis) in tissues of patients with a generalized peroxisome deficiency (e.g. Zellweger syndrome). In addition to these lethal inherited disorders that are caused by defects in the biogenesis of peroxisomes, a growing number of patients with peroxisomal beta-oxidation deficiencies have been described. The implications of the presence of separate beta-oxidation systems for the latter disorders is quite profound and calls, in many cases, for a reevaluation of the diagnosis of such patients.