Chapter 162

### Peroxisome Biology and Metabolism

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.

### Genetic Disorders of Peroxisomes: Overview

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.

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.

### Clinical Phenotypes

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