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Cited by 22Drug Transport and Resistance MechanismsLipid Membrane Structure and BehaviorPeroxisome Proliferator-Activated Receptors

How to move an amphipathic molecule across a lipid bilayer: Different mechanisms for different ABC transporters?

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Theodoulou, Frederica L., Carrier, David J., Schaedler, Theresia A., Baldwin, Stephen A., Baker, Alison·2016·Biochemical Society Transactions
DOI 10.1042/bst20160040PMC PMC4900756
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Abstract

Import of β-oxidation substrates into peroxisomes is mediated by ATP binding cassette (ABC) transporters belonging to subfamily D. In order to enter the β-oxidation pathway, fatty acids are activated by conversion to fatty acyl-CoA esters, a reaction which is catalysed by acyl-CoA synthetases (ACSs). Here, we present evidence for an unusual transport mechanism, in which fatty acyl-CoA substrates are accepted by ABC subclass D protein (ABCD) transporters, cleaved by the transporters during transit across the lipid bilayer to release CoA, and ultimately re-esterified in the peroxisome lumen by ACSs which interact with the transporter. We propose that this solves the biophysical problem of moving an amphipathic molecule across the peroxisomal membrane, since the intrinsic thioesterase activity of the transporter permits separate membrane translocation pathways for the hydrophobic fatty acid moiety and the polar CoA moiety. The cleavage/re-esterification mechanism also has the potential to control entry of disparate substrates into the β-oxidation pathway when coupled with distinct peroxisomal ACSs. A different solution to the movement of amphipathic molecules across a lipid bilayer is deployed by the bacterial lipid-linked oligosaccharide (LLO) flippase, PglK, in which the hydrophilic head group and the hydrophobic polyprenyl tail of the substrate are proposed to have distinct translocation pathways but are not chemically separated during transport. We discuss a speculative alternating access model for ABCD proteins based on the mammalian ABC transporter associated with antigen processing (TAP) and compare it to the novel mechanism suggested by the recent PglK crystal structures and biochemical data.

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  • By binding to ATP, ALDP transports VLCFAcyl-CoA into the peroxisomal matrix, where they are β-oxidized into medium-chain fatty acids (MCFAs) and MCFAcyl-carnitines, propionyl-CoA, and acetyl-CoA.

    “By binding to ATP, ALDP transports VLCFAcyl-CoA into the peroxisomal matrix [143,159,160], where they are β-oxidized into medium-chain fatty acids (MCFAs) and MCFAcyl-carnitines [161], propionyl-CoA, and acetyl-CoA.”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [160]

    The 'Fatty acid import into peroxisomes' section identifies ALDP as an ATP-binding cassette transporter that preferentially imports very-long-chain fatty acids. But the 'Transport substrates and mechanism' section describes fatty acyl-CoA as a substrate accepted at the membrane, with CoA cleaved during or after transport and the fatty acid re-activated inside the peroxisome; it does not establish transport of intact VLCFA-acyl-CoA into the matrix. The later list of β-oxidation products is not attached to this citation. (LLM, conf=0.87)

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Sorted by citations

Authors
Theodoulou, F. L., Carrier, D. J., Schaedler, T. A., Baldwin, S. A., & Baker, A.
Affiliations
  • Rothamsted Research (GB)
  • University of Leeds (GB)
Corresponding author
Theodoulou, Frederica L.
ORCID
Venue
Biochemical Society Transactions
Publisher
Portland Press Ltd.
Published
2016-06-09
Volume
44
Issue
3
Pages
774-782
ISSN
  • 0300-5127 (ISSN-L)
  • 1470-8752
DOI
10.1042/bst20160040
PMC
PMC4900756
OpenAlex
W2409627048
Cited by
22
References
7
Citations by year
2026: 4 · 2025: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 1
FWCI
0.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Society Transactions (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Rothamsted Repository (Rothamsted Repository) (submittedVersion, cc-by)
Funders
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council (BB/L001012/1, BB/L001691/1)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
fatty acid beta-oxidation, acyl-CoA synthetase, alternating access model, TAP transporter, peroxisomes
MeSH terms
Acyl Coenzyme A, Animals, Bacteria, Biological Transport, Coenzyme A Ligases, Humans, Hydrolysis, Lipid Bilayers, Lipopolysaccharides, ATP-Binding Cassette Transporters, Peroxisomes, Eukaryota, Hydrophobic and Hydrophilic Interactions

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