**1. Introduction**

ATP-binding cassette (ABC) transporters constitute a superfamily of membrane transporter proteins that actively translocate a wide range of molecules, from simple molecules (fatty acids (FAs), sugars, nucleosides, and amino acids) to complex organic compounds (lipids, oligonucleotides, polysaccharides, and proteins) [1]. Transport of substrates is dependent on the hydrolysis of ATP, which releases energy that can be used to accumulate substances in the cellular compartments or export them to the outside. ABC transporters are distributed not only in the plasma membrane of both prokaryotes and eukaryotes, but also in the membranes of the organelles of eukaryotic cells such as peroxisomes, mitochondria, lysosomes, and endoplasmic reticulum (ER). Based on their amino acid homology and structural configuration, ABC transporters in humans are classified into seven subfamilies, A to G, comprising a total of 48 ABC transporters, many of which are implicated in diseases [2]. ABC transporters of subfamily D include four proteins in mammals: ABCD1 [adrenoleukodystrophy protein (ALDP)], ABCD2 [adrenoleukodystrophy-related protein (ALDRP)], ABCD3 [70 kDa peroxisomal membrane protein (PMP70)], and ABCD4 [peroxisomal membrane protein 69 (PMP69)] [3]. ABCD1, ABCD2, and ABCD3 are located in the peroxisomal membrane. ABCD4 was identified by homology search for ALDP and PMP70 related sequences in the database of expressed sequence tags, and was initially considered peroxisomal despite the absence of a membrane peroxisomal targeting signal [4]. More recently, several studies have demonstrated that ABCD4 resides in the endoplasmic reticulum and lysosomes, and that its function is associated with cobalamin metabolism [3,5,6].

**Citation:** Tawbeh, A.; Gondcaille, C.; Trompier, D.; Savary, S. Peroxisomal ABC Transporters: An Update. *Int. J. Mol. Sci.* **2021**, *22*, 6093. https:// doi.org/10.3390/ijms22116093

Academic Editor: Thomas Falguières

Received: 28 April 2021 Accepted: 3 June 2021 Published: 5 June 2021

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The three human peroxisomal ABC transporters play an important role in the transport of various lipid substrates into the peroxisome for their shortening by β-oxidation (Figure 1). β-oxidation of FAs is a conserved process of peroxisomes by which acyl groups are degraded two carbons at a time after being activated to form the corresponding CoA derivative by a specific acyl-CoA synthetase located at the peroxisomal membrane [7]. The β-oxidation process exists in mitochondria for medium- and long-chain fatty acids (MCFAs and LCFAs) and is necessary to terminate degradation of octanoyl-CoA coming from peroxisomes. However, very long-chain fatty acids (VLCFAs, number of carbon atoms >22) are exclusively β-oxidized into the peroxisome, and this organelle is therefore essential, especially in the brain [8]. Moreover, polyunsaturated fatty acid (PUFA) synthesis may require a peroxisomal cycle of β-oxidation, as in the case of docosahexaenoic acid (DHA, C22:6 n-3) synthesis from its precursor (C24:6 n-3) [9]. It is important to note that DHA is not only of great value by itself as a component of cell membranes, but is also the source of eicosanoids associated with several key signaling functions [10]. β β β β β

**Figure 1.** Peroxisomal ABC transporters and their involvement in lipid metabolism. Peroxisomal ABC transporters are represented as homo or heterotetramers with their preferential substrates and their involvement in metabolic routes, including several enzymatic steps, catalyzed by acyl-CoA oxidase 1 and 2 (ACOX1 and ACOX2), D- and L-bifunctional protein (D-BP and L-BP), acetyl-CoA Acyltransferase 1 (3-ketoacyl-CoA thiolase, ACAA1), sterol carrier protein 2 (SCPX thiolase, SCP2), alpha-methylacyl-CoA racemase (AMACR), bile acid-CoA:amino acid N-acyltransferase (BAAT), and phytanoyl-CoA hydroxylase (PHYH).

β Thus, peroxisomal β-oxidation may not be considered a simple catabolic process of fatty acids. The role of peroxisomal ABC transporters is therefore not restricted to the catabolic function of peroxisomes, but is fully associated with their various metabolic functions including synthesis and degradation of lipids, cell signaling, inflammation control, and redox homeostasis [11–15].
