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Peroxisome Biology and
Metabolism
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Peroxisomes are single membrane-bound organelles present in all
cells except for erythrocytes. In human cells, peroxisomes are spherical in
shape and range in number from a few hundred to a few thousand per
cell.1,2They contain a dense proteinaceous matrix
composed of 50 or more enzymes that participate in a variety of
metabolic processes.3 Prominent among these is
a set of enzymes catalyzing β-oxidation that are
analogous to but distinct from those catalyzing mitochondrial β-oxidation
and are encoded by different genes. The β-oxidation
systems of peroxisomes and mitochondria have distinct but overlapping
substrate specificities, with the peroxisomal system oxidizing very-long-chain
(C20–C26) and long-chain (C12–C18) fatty acids
and the mitochondrial system oxidizing long-chain (C12–C18),
medium-chain (C12–C6), and short-chain (C6–C4)
fatty acids. An additional difference is that the FAD-linked acyl-CoA
oxidase, which catalyzes the first step in the peroxisomal β-oxidation
spiral, is reoxidized by molecular oxygen to produce H2O2 while
the analogous enzymes in mitochondria transfer their electrons to
the respiratory chain via electron transport flavoprotein (ETF)
and ETF-dehydrogenase. The H2O2 produced in the
first step of the peroxisome β-oxidation spiral
and by other peroxisomal oxidases is efficiently eliminated by catalase,
another peroxisomal matrix enzyme. Additional metabolic processes
that involve peroxisomal matrix enzymes include glyoxylate transamination; β-oxidation
of phytanic acid and other β-methyl-branched fatty
acids; and synthesis of cholesterol, bile acids, and ether lipids
such as plasmalogen and lysine degradation.
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Genetic Disorders
of Peroxisomes: Overview
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Peroxisomal disorders can be divided into two classes: (1) peroxisomal
biogenesis disorders (PBD), which are characterized by deficiency
of multiple peroxisomal functions, and (2) single-function disorders
in which only one peroxisomal function is deficient.1 The
PBD are a genetically heterogeneous set of disorders comprising
at least 13 complementation groups as determined by somatic cell
hybridization studies.1,2,4 All are inherited as autosomal
recessive traits and have an aggregate frequency of about 1 in 50,000.
Zellweger syndrome (ZS) and rhizomelic chondrodysplasia punctata
(RCDP) are examples of the PBD clinical phenotypes. At the cellular
level, most PBD complementation groups demonstrate aberrant cytosolic
localization of matrix proteins with relatively empty peroxisomes
and normal import of peroxisomal membrane proteins and synthesis
of peroxisomal membranes. By contrast, a few PBD complementation
groups have no detectable peroxisomes or peroxisomal membrane vesicles.
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The single-function peroxisome disorders include at least 11
different disorders inherited either as autosomal or X-linked recessive traits,
nearly all of which are uncommon, with frequencies of less than
1 in 50,000.3,5 The clinical example for this class
of peroxisomal disorders is X-linked adrenoleukodystrophy (X-ALD),
a neurological disorder with abnormal accumulation of very-long-chain
fatty acids (VLCFA) and with an incidence in males of about 1 in
20,000.6,7 At the cellular level, peroxisomes in
the single-function disorders appear normal and have normal import
of matrix proteins.
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Clinical Phenotypes
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