Structure-function relationships in the peroxisome: implications for human disease.
Progress relevant to human peroxisomal disorders over the past 3 years includes improved biochemical delineation of disease phenotypes and new insights into peroxisomal structure and biogenesis. Immunoblotting studies using antibodies to peroxisomal beta-oxidation enzymes have defined mutations affecting each step of the pathway, some with clinical phenotypes as severe as disorders with global peroxisome deficiency. The latter disorders, typified by Zellweger syndrome, often lack matrix proteins but retain major membrane species of 150, 70, 35, and 22 kDa in empty peroxisomal "ghost" structures. The hypothesis that peroxisomal deficiency disorders result from altered targeting or import of peroxisomal matrix proteins has been strengthened by the demonstration of a carboxy terminal peroxisome-targeting signal which is distinct from amino terminal signals directing proteins to mitochondria. A mutation which mistargets alanine/glyoxylate aminotransferase from peroxisomes to mitochondria in primary hyperoxaluria provides a graphic example of these signals. The structural significance of membrane function is supported by the primacy of membrane assembly in normal ontogeny or regenerating liver. The coordinate control, targeting, and striking inducibility of peroxisomal proteins suggests a potential vehicle for gene and enzyme therapy.
Wilson
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Division of Pediatric Genetics and Metabolism, University of Texas Southwestern Medical Center, Dallas 75235-9063.
D000595:Amino Acid Sequence; D000818:Animals; D004798:Enzymes / Q000235:genetics; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics*; D008830:Microbodies / Q000201:enzymology*; D008969:Molecular Sequence Data; D012689:Sequence Homology, Nucleic Acid
D004798:Enzymes