Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Heinzer, Ann K.; Kemp, Stephan; Lu, Jyh-Feng; Watkins, Paul A.; Smith, Kirby D.

doi:10.1074/jbc.m203053200

Cited by 29 publications

(26 citation statements)

References 46 publications

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“…Several enzymes belonging to the VLACS family of ACSs are candidates for this role. The first identified enzyme of this family (known as VLCS, VLACS, FACVL1, and FATP2) can activate VLCFA substrates but is not highly expressed in brain (13,(31)(32)(33)(34). VLCS message was readily detectable in Neuro2a cells by reverse transcription-PCR.…”

Section: Discussionmentioning

confidence: 94%

The Acyl-CoA Synthetase “Bubblegum” (Lipidosin)

Pei

Oey

Zuidervaart

et al. 2003

Journal of Biological Chemistry

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Acyl-CoA synthetases play a pivotal role in fatty acid metabolism, providing activated substrates for fatty acid catabolic and anabolic pathways. Acyl-CoA synthetases comprise numerous proteins with diverse substrate specificities, tissue expression patterns, and subcellular localizations, suggesting that each enzyme directs fatty acids toward a specific metabolic fate. We reported that hBG1, the human homolog of the acyl-CoA synthetase mutated in the Drosophila mutant "bubblegum," belongs to a previously unidentified enzyme family and is capable of activating both long-and very longchain fatty acid substrates. We now report that when overexpressed, hBG1 can activate diverse saturated, monosaturated, and polyunsaturated fatty acids. Using in situ hybridization and immunohistochemistry, we detected expression of mBG1, the mouse homolog of hBG1, in cerebral cortical and cerebellar neurons and in steroidogenic cells of the adrenal gland, testis, and ovary. The expression pattern and ability of BG1 to activate very long-chain fatty acids implicates this enzyme in the pathogenesis of X-linked adrenoleukodystrophy. In neuron-derived Neuro2a cells, mBG1 co-sedimented with mitochondria and was found in small vesicular structures located in close proximity to mitochondria. RNA interference was used to decrease mBG1 expression in Neuro2a cells and led to a 30 -35% decrease in activation and ␤-oxidation of the long-chain fatty acid, palmitate. These results suggest that in Neuro2a cells, mBG1-activated long-chain fatty acids are directed toward mitochondrial degradation. mBG1 appears to play a minor role in very long-chain fatty acid activation in these cells, indicating that other acyl-CoA synthetases are necessary for very long-chain fatty acid metabolism in Neuro2a cells.

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Section: Discussionmentioning

confidence: 94%

The Acyl-CoA Synthetase “Bubblegum” (Lipidosin)

Pei

Oey

Zuidervaart

et al. 2003

Journal of Biological Chemistry

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“…Several of the FATP proteins were first identified as very long chain acyl-CoA synthetases (ACSVL) (31,41,42). Our laboratory and others also noted that ACSVL (43) activities were depressed in fat1⌬ strains and were increased when Fat1p was overexpressed (17,25,26,34).…”

Section: Characterization Of the Yeast Faa1⌬ Fat1⌬ Strain For Comparamentioning

confidence: 85%

“…As expected, expression of Fat1p increased the lignoceryl-CoA synthetase activities 9-fold higher compared with control cells (p Յ 0.01). Previous work has shown that Fat1p (26), mmFATP1 (27,29), mmFATP2 (21,41), mmFATP3 (40), and mmFATP4 (28,30) can activate very long-chain fatty acids, including lignocerate. More recent work from the Bernlohr laboratory (29) using purified mmFATP1 and mmFATP4 has shown that these isoforms can activate a broad range of fatty acid substrates.…”

Section: Characterization Of the Yeast Faa1⌬ Fat1⌬ Strain For Comparamentioning

confidence: 99%

Comparative Biochemical Studies of the Murine Fatty Acid Transport Proteins (FATP) Expressed in Yeast

DiRusso

Darwis

et al. 2005

Journal of Biological Chemistry

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132

127

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The fatty acid transport protein (FATP) family is a group of proteins that are predicted to be components of specific fatty acid trafficking pathways. In mammalian systems, six different isoforms have been identified, which function in the import of exogenous fatty acids or in the activation of very long-chain fatty acids. This has led to controversy as to whether these proteins function as membrane-bound fatty acid transporters or as acylCoA synthetases, which activate long-chain fatty acids concomitant with transport. The yeast FATP orthologue, Fat1p, is a dual functional protein and is required for both the import of long-chain fatty acids and the activation of very long-chain fatty acids; these activities intrinsic to Fat1p are separable functions. To more precisely define the roles of the different mammalian isoforms in fatty acid trafficking, the six murine proteins (mmFATP1-6) were expressed and characterized in a genetically defined yeast strain, which cannot transport long-chain fatty acids and has reduced long-chain acylCoA synthetase activity (fat1⌬ faa1⌬). Each isoform was evaluated for fatty acid transport, fatty acid activation (using C 18:1 , C 20:4 , and C 24:0 as substrates), and accumulation of very long-chain fatty acids. Murine FATP1, -2, and -4 complemented the defects in fatty acid transport and very long-chain fatty acid activation associated with a deletion of the yeast FAT1 gene; mmFATP3, -5, and -6 did not complement the transport function even though each was localized to the yeast plasma membrane. Both mmFATP3 and -6 activated C 20:4 and C 24:0 , while the expression of mmFATP5 did not substantially increase acyl-CoA synthetases activities using the substrates tested. These data support the conclusion that the different mmFATP isoforms play unique roles in fatty acid trafficking, including the transport of exogenous long-chain fatty acids.

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“…The finding these proteins belong to the superfamily of adenylate-forming enzymes was noted in the initial characterization of Fat1p, which suggested an enzymatic activity (54). Indeed, subsequent studies have demonstrated that increased expression of three isoforms of the murine FATP (mmFATP1, mmFATP2, and mmFATP4) and yeast Fat1p results in increased VLACS activities (36,38,50,71,72,136,140). Data from the Schaffer laboratory has shown an mmFATP1 allele carrying a single amino acid substitution in the predicted ATP-AMP binding region fails to transport fatty acids (127,128).…”

Section: Fatty Acid Transport Proteinmentioning

confidence: 97%

Transmembrane Movement of Exogenous Long-Chain Fatty Acids: Proteins, Enzymes, and Vectorial Esterification

Black

DiRusso

2003

Microbiol Mol Biol Rev

212

158

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The processes that govern the regulated transport of long-chain fatty acids across the plasma membrane are quite distinct compared to counterparts involved in the transport of hydrophilic solutes such as sugars and amino acids. These differences stem from the unique physical and chemical properties of long-chain fatty acids. To date, several distinct classes of proteins have been shown to participate in the transport of exogenous long-chain fatty acids across the membrane. More recent work is consistent with the hypothesis that in addition to the role played by proteins in this process, there is a diffusional component which must also be considered. Central to the development of this hypothesis are the appropriate experimental systems, which can be manipulated using the tools of molecular genetics. Escherichia coli and Saccharomyces cerevisiae are ideally suited as model systems to study this process in that both (i) exhibit saturable long-chain fatty acid transport at low ligand concentrations, (ii) have specific membrane-bound and membrane-associated proteins that are components of the transport apparatus, and (iii) can be easily manipulated using the tools of molecular genetics. In both systems, central players in the process of fatty acid transport are fatty acid transport proteins (FadL or Fat1p) and fatty acyl coenzyme A (CoA) synthetase (FACS; fatty acid CoA ligase [AMP forming] [EC 6.2.1.3]). FACS appears to function in concert with FadL (bacteria) or Fat1p (yeast) in the conversion of the free fatty acid to CoA thioesters concomitant with transport, thereby rendering this process unidirectional. This process of trapping transported fatty acids represents one fundamental mechanism operational in the transport of exogenous fatty acids

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Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Cited by 29 publications

References 46 publications

The Acyl-CoA Synthetase “Bubblegum” (Lipidosin)

The Acyl-CoA Synthetase “Bubblegum” (Lipidosin)

Comparative Biochemical Studies of the Murine Fatty Acid Transport Proteins (FATP) Expressed in Yeast

Transmembrane Movement of Exogenous Long-Chain Fatty Acids: Proteins, Enzymes, and Vectorial Esterification

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