Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance

Abstract

Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for a number of important metabolic pathways, including fatty acid α- and β-oxidation, and biosynthesis of etherphospholipids and bile acids. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. Therefore, peroxisomes need specific transporter proteins to transfer these metabolites across their membranes. The mammalian peroxisomal membrane harbours three ATP-binding cassette (ABC) transporters. In recent years, significant progress has been made in unravelling the functions of these ABC transporters. There is ample evidence that they are involved in the transport of very long-chain fatty acids, pristanic acid, di- and trihydroxycholestanoic acid, dicarboxylic acids and tetracosahexaenoic acid (C24:6ω3). Surprisingly, only one disease is associated with a deficiency of a peroxisomal ABC transporter. Mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein are the cause for X-linked adrenoleukodystrophy, an inherited metabolic storage disorder. This review describes the current state of knowledge on the mammalian peroxisomal ABC transporters with a particular focus on their function in metabolite transport.

Figure 1

Hypothesized structure of the peroxisomal ABC half-transporters. The nucleotide binding domain (NBD) and Pex19p binding site (*) are indicated.

Figure 2

Schematic overview of the function of the mammalian peroxisomal ABC transporters in the import of VLCFA, pristanic acid, di- and trihydroxycholestanoic acid (DHCA and THCA), dicarboxylic acid (DCA) and tetracosahexaenoic acid (C24:6ω3) into the peroxisome. Peroxisomes contain the full enzymatic machinery to β-oxidize fatty acids, although not to completion. The enzymes involved include: two acyl-CoA oxidases (ACOX1 and ACOX2), catalysing the first step, two bifunctional proteins (LBP and DBP), catalysing the second and third step, and two peroxisomal thiolases (ACAA1 and SCPx), catalysing the last step. For complete oxidation, the end-products must be shuttled to mitochondria. There are two mechanisms by which the end-products of peroxisomal β-oxidation can be shuttled to mitochondria. The first mechanism involves four steps: (i) hydrolysis of the different CoA-esters to produce short-chain fatty acids; (ii) transfer across the peroxisomal and mitochondrial membrane probably in protonated form; (iii) activation to the corresponding CoA-esters in the mitochondrion; and (iv) further oxidation. The second mechanism involves: (i) conversion of the CoA-esters into their corresponding carnitine-esters within peroxisomes; (ii) transfer across the peroxisomal membrane, probably via a yet unidentified carrier; (iii) import into to mitochondrial matrix via the mitochondrial carnitine/acylcarnitine translocase (CACT, SLC25A20); and (iv) further oxidation. In liver peroxisomes, the bile acid intermediates THCA and DHCA undergo one cycle of β-oxidation with choloyl-CoA and chenodeoxycholoyl-CoA as end-products respectively. These two CoA-esters are then conjugated with either taurine or glycine. Subsequently, the taurine- and glycine-esters are transported out of the peroxisome into the cytosol by an unknown mechanism, followed by transport across the canalicular membrane via the bile salt efflux pump, that is, BSEP (ABCB11), to end up in bile. Figure adapted and modified from Wanders et al. (2010).

Figure 3

Expression pattern of peroxisomal ABC transporters at different developmental stages in mouse. Data were obtained from the UniGene EST profile database.

Figure 4

Comparison of the tissue-specific expression of the human and mouse peroxisomal ABC transporters as deduced from the UniGene EST profile database. Only those human and mouse tissues are included for which the total EST number in the pool is higher than 70.000.

Figure 5

Biogenesis of peroxisomal ABC transporters. After being synthesized on free cytosolic ribosomes, peroxisomal ABC transporters interact with Pex19p through the Pex19p binding motif located in the NH2-terminal region. The interaction is strengthened by sequences located downstream in the transmembrane domain. Pex19p keeps the peroxisomal ABC transporter in a soluble and proper conformation in the cytosol. Then the ABCD-Pex19p complex docks at the peroxisomal membrane via association with its docking factor Pex3p. Finally, the peroxisomal ABC transporter is inserted into the peroxisomal membrane and Pex19p shuttles back to the cytosol to initiate another import cycle. For simplicity only the ABCD monomer is depicted.