Topography of very-long-chain-fatty-acid-activating activity in peroxisomes from rat liver

Lageweg, W.; Tager, J. M.; Wanders, Ronald J. A.

doi:10.1042/bj2760053

Cited by 48 publications

(18 citation statements)

References 28 publications

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“…Similarly, ALDP could import VLCFA-CoA into peroxisomes following dimerization with itself or a partner. Whether the active site of the mammalian VLACS is located on the cytoplasmic or luminal side of peroxisomes remains unclear (33,34). If it is located within peroxisomes, this would rather support that ALDP transports VLCFA or a substrate necessary to VLACS activation.…”

Section: Discussionmentioning

confidence: 99%

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Liu¹,

Janvier²,

Berteaux‐Lecellier³

et al. 1999

Journal of Biological Chemistry

129

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The peroxisomal membrane is equipped with four ATP-binding cassette (ABC) 1 transporters, which include the adrenoleukodystrophy protein (ALDP) (1), the adrenoleukodystrophyrelated protein (ALDRP) (2), the 70-kDa peroxisomal membrane protein (PMP70) (3), and the PMP70-related protein (4, 5). Typical mammalian ABC transporters, like the multidrug-resistant P-glycoprotein, are single functional proteins with two related halves comprised of one hydrophobic transmembrane domain and one hydrophilic nucleotide-binding fold (NBF) (6). In contrast, the peroxisomal ABC transporters, as well as TAP1/TAP2 (7) and ABC7 (8), which are respectively located within the endoplasmic reticulum or mitochondria, are half-transporters with only one hydrophobic domain and one NBF.X-linked adrenoleukodystrophy (X-ALD) is the only genetic disease known to result from a peroxisomal ABC transporter gene defect. This neurodegenerative disorder is characterized by progressive demyelination within the central nervous system, adrenal insufficiency, and accumulation of very long-chain fatty acids because of an impaired peroxisomal ␤-oxidation (9 -12). Although it is firmly established that the loss of ALDP function is responsible for the abnormality in VLCFA metabolism, its precise role is unknown. Similarly, no precise function has been assigned to ALDRP, PMP70, or PMP70-related proteins. ALDRP, PMP70, and PMP70-related protein present 66, 38, and 27% amino acid identity with ALDP, respectively, suggesting functional similarity of these four transporters. These proteins display specific but sometimes overlapping patterns of expression in different cell types (13-15). Because it is likely that half-transporters need to dimerize to exert their function (6), this raises the possibility that different types of peroxisomal ABC dimers could allow the import of distinct substrates. Few ABC transporters are known to dimerize. Genetic evidence suggests that the bacterial hemolysin transporter B ABC half-transporter forms homodimers (16), whereas the Drosophila white, brown, and scarlet gene products form heterodimers (17). Heterodimerization of ABC transporters has also been reported for the transporters of antigenic peptides, TAP1 and TAP2 (18), and the two yeast peroxisomal ABC proteins, Pxa1 and Pxa2 (19,20).This study used the yeast two-hybrid assay to show that the carboxyl-terminal half of ALDP, ALDRP, and PMP70 can engage in homo-and heterodimerization. These two processes were confirmed by co-immunoprecipitation methods. We examined the effect of four different ALD patient mutations upon these interactions and attempted to map the carboxyl-terminal subdomains of ALDP allowing dimerization of the protein. EXPERIMENTAL PROCEDURESAntibodies, Yeast Strains, and Cell Lines-Monoclonal antibody 1D6 against human ALDP (hALDP) and polyclonal antibodies 1664 and 7373 raised against mouse ALDP (mALDP) and mouse ALDRP (mALDRP), respectively, have been described previously (13,15,21).

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Section: Discussionmentioning

confidence: 99%

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Liu¹,

Janvier²,

Berteaux‐Lecellier³

et al. 1999

Journal of Biological Chemistry

129

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“…An identical enzyme is present on the outer mitochondrial mem brane and the membrane of the ER (83) . Whereas Lazo et al (87) reported that the active site faces the peroxisomal interior, Lageweg et al (88) found a cytosolic orientation. A similar activity was detected in the ER but not in mitochondria (85 , 86).…”

Section: Enzymic Organizationmentioning

confidence: 99%

Biochemistry of Peroxisomes

Bosch

Schutgens²,

Wanders³

et al. 1992

Annu. Rev. Biochem.

796

233

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“…3). Whether VLCFA are activated intraperoxisomally or outside the peroxisome (and then transported into the organelle as VLCFA-CoA) has been the subject of some debate [15–19]. …”

Section: Peroxisomal Pathways Requiring Activated Fasmentioning

confidence: 99%

“…lignoceric acid; C24:0), and branched-chain FAs phytanic acid and pristanic acid [19]. The topographic orientation of ACSVL1 in the peroxisomal membrane has not completely been resolved [15–19]. Investigations into the function of the peroxisomal membrane protein ABCD1, which is defective in X-linked adrenoleukodystrophy, suggests that VLCFA are activated extraperoxisomally via ACSVL1 (or another ACS) oriented facing the cytoplasm, after which the CoA derivatives are transported into the organelle by ABCD1 [81].…”

Section: Peroxisomal Acssmentioning

confidence: 99%

Peroxisomal acyl-CoA synthetases

Watkins

Ellis

2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

117

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Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group – either a fatty acid or the acyl side chain of a steroid derivative – be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or “activation”, reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase (ACS) family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal ACSs that participate in these pathways. Of the 26 ACSs encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, ACSVL1 (FATP2), and FATP4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of ACSs in peroxisomes, much of which was obtained before the existence of multiple ACS isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific ACS isoforms in lipid metabolism.

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Topography of very-long-chain-fatty-acid-activating activity in peroxisomes from rat liver

Cited by 48 publications

References 28 publications

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Biochemistry of Peroxisomes

Peroxisomal acyl-CoA synthetases

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