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Abstract

Abstract 

  1. Peroxisomes are single-membrane lined organelles present in virtually all eukaryotic cells. In most human cells, their abundance ranges from less than a hundred to more than a thousand peroxisomes per cell. The granular matrix of the organelle contains more than 50 matrix enzymes that participate in a wide variety of metabolic pathways including β-oxidation of certain fatty acids and biosynthesis of ether phospholipids, bile acids, and isoprene compounds.

  2. Peroxisome biogenesis involves synthesis of the matrix proteins on free cytosolic ribosomes followed by receptor-mediated import into the organelle. Most matrix proteins are targeted by a C-terminal peroxisome targeting sequence (PTS1) with a consensus of −S-K-L-COOH that is recognized by a cytosolic receptor, PEX5. A few matrix proteins are targeted by an N-terminal PTS2 with the consensus sequence of −R-L-XS-H-L−. Peroxisome membrane proteins are specific for the organelle. They are also synthesized on free cytosolic ribosomes and are targeted to the organelle by mechanism(s) that are separate from and less well understood than those used by matrix proteins.

  3. PEX genes encode peroxins, proteins involved in and necessary for peroxisome biogenesis. These include the PTS1 and 2 receptors, as well as additional cytosolic and integral membrane proteins that are involved in the import of peroxisomal matrix and membrane proteins. To date, 23 PEX genes have been identified, with 15 PEX genes known in humans.

  4. The peroxisome biogenesis disorders are comprised of at least 12 complementation groups. Defective biogenesis of the organelle leads to complex developmental and metabolic phenotypes that can be organized into two clinical spectra: the Zellweger spectrum with Zellweger syndrome as the most severe example and neonatal adrenoleukodystrophy and infantile Refsum disease as milder variants. The second spectrum is distinctive with classical rhizomelic chondrodysplasia punctata as its exemplar and milder variants described.

  5. The PEX genes responsible for 11 of the 12 PBD complementation groups are known with multiple mutant alleles identified. Functional analysis of the proteins encoded by these PEX genes together with careful clinical, metabolic, and cellular characterization of the mutant phenotypes has provided insight into the pathophysiology of the peroxisome biogenesis disorders as well as into the normal biology of peroxisome assembly and function.

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