Further insights into peroxisomal lipid breakdown via alpha- and beta-oxidation

Mammalian peroxisomes degrade fatty carboxylates via two pathways, beta -ox idation and, as shown more recently, alpha -oxidation. The latter process c onsists of an activation step. followed by a hydroxylation at position 2 an d cleavage of the hydroxyacyl-CoA, generating formyl-CoA (precursor of form ate/CO2) and, in case of phytanic acid as substrate, pristanal (precursor o f pristanic acid). The stereochemistry of the overall pathway, cofactor req uirements and substrate specificity of the hydroxylase and the cleavage enz yme, which is homologous with bacterial oxalyl-CoA decarboxylases, will be discussed. With regard to beta -oxidation, peroxisomes contain different ac yl-CoA oxidases, multifunctional proteins and thiolases, Based on substrate spectra and stereospecificities of these enzymes, a model was proposed whe reby straight chain and branched compounds are degraded by separate pathway s. The biochemical findings in mice lacking the D-specific multifunctional protein, however, do not fully support this model. These animals, together with the Pex5(-) mice, might be useful to pinpoint the pathological factors contributing to the brain abnormalities in Zellweger patients. Apparently, the deficit in docosahexaenoic acid, presumably formed via peroxisomal bet a -oxidation, is not the major cause.