Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance
Open accessAbstract
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. LINKED ARTICLES This article is part of a themed section on Transporters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.164.issue‐7
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The ABCD1 gene encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation.
“It encodes the ABCD1/ALD protein of 745 amino acids, an ATP-binding cassette transmembrane half-transporter required for the import of coenzyme A-activated very-long-chain fatty acids (VLCFAs; >C22:0) into peroxisomes for degradation [3,4].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [4]
The high-density hotspots on exons 6 and 9 identified independently via the bioinformatics analysis of missense variants map to two specific motifs within the ATP-binding domain: Walker A and B and the ABC signature.
“At the functional level, the high-density hotspots on exons 6 and 9 identified independently via the bioinformatics analysis of missense variants map to two specific motifs within the ATP-binding domain: Walker A and B and the ABC signature (Figure 2d–f) [4].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [4]
ALDP transport involves cooperative binding of two VLCFAcyl-CoAs, ATP binding, and ALDP homodimerization, followed by outward-facing conformational change allowing release of VLCFAcylCoA into the peroxisome matrix, where VLCFAcyl-CoA undergoes peroxisomal β-oxidation.
“Transport involves cooperative binding of two VLCFAcyl-CoAs, ATP binding, and ALDP homodimerization [147], followed by outward-facing ALDP conformational change allowing for the release of VLCFAcylCoA into the peroxisome matrix [148], where VLCFAcyl-CoA undergoes peroxisomal β-oxidation [149].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [147]
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“An Abcd2 knockout mouse model has been generated and characterized (Ferrer et al., 2005).”
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“These data exclude the ABCD2 locus as a major modifier locus for X-ALD (Maier et al., 2008).”
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Self-citationAdrenoleukodystrophy—Neuroendocrine pathogenesis and redefinition of natural history
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“However, several missense variants have been reported that do not affect protein stability, but disrupt the protein’s function by decreasing ATPbinding capacity or ATPase activity [110].”
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“At the functional level, the highdensity hotspots on exons 6 and 9 identified independently via the bioinformatics analysis of missense variants map to two specific motifs within the ATP-binding domain: Walker A and B and the ABC signature (Figure 2d–f) [4].”
BackgroundSelf-citationRevisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
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- Authors
- Kemp, S., Theodoulou, F. L., & Wanders, R. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Rothamsted Research (GB)
- Corresponding author
- Kemp, Stephan
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2011-11-15
- Volume
- 164
- Issue
- 7
- Pages
- 1753-1766
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3246701
- OpenAlex
- W2133128364
- Cited by
- 115
- References
- 20
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 12 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 10 · 2013: 10 · 2012: 13
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rothamsted Repository (Rothamsted Repository) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/F007299/1, BBS/E/C/00004948, BB/F007108/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- peroxisomal ABC transporters, ABCD1, adrenoleukodystrophy, very long chain fatty acids, pristanic acid, dicarboxylic acids, fatty acid oxidation, bile acid synthesis, peroxisome biogenesis disorders
- MeSH terms
- Animals, Disease Models, Animal, Humans, Metabolic Diseases, Mutation, Tissue Distribution, ATP-Binding Cassette Transporters, Polymorphism, Single Nucleotide, Peroxisomes, Protein Transport
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