Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism

Hunt, Mary C.; Alexson, Stefan E.H.

doi:10.1016/j.plipres.2008.05.001

Cited by 60 publications

(50 citation statements)

References 174 publications

(190 reference statements)

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“…Nevertheless, collectively, our data support the notion that CTS is a transporter of acyl-CoAs. It has been proposed that CTS might cleave the CoA moiety during transport, thus requiring its re-esterification inside the peroxisome (29); alternatively, cleavage may be carried out by peroxisomal thioesterases (78), which would agree with both the biochemical and genetic data. Ultimately, transport assays using purified, reconstituted CTS protein will be essential to determine unequivocally the biochemical function of this intriguing membrane protein.…”

Section: Discussionmentioning

confidence: 73%

The Arabidopsis Peroxisomal ABC Transporter, Comatose, Complements the Saccharomyces cerevisiae pxa1 pxa2Δ Mutant for Metabolism of Long-chain Fatty Acids and Exhibits Fatty Acyl-CoA-stimulated ATPase Activity

Nyathi

Lousa

Roermund

et al. 2010

Journal of Biological Chemistry

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The Arabidopsis ABC transporter Comatose (CTS; AtABCD1) is required for uptake into the peroxisome of a wide range of substrates for ␤-oxidation, but it is uncertain whether CTS itself is the transporter or if the transported substrates are free acids or CoA esters. To establish a system for its biochemical analysis, CTS was expressed in Saccharomyces cerevisiae. The plant protein was correctly targeted to yeast peroxisomes, was assembled into the membrane with its nucleotide binding domains in the cytosol, and exhibited basal ATPase activity that was sensitive to aluminum fluoride and abrogated by mutation of a conserved Walker A motif lysine residue. The yeast pxa1 pxa2⌬ mutant lacks the homologous peroxisomal ABC transporter and is unable to grow on oleic acid. Consistent with its exhibiting a function in yeast akin to that in the plant, CTS rescued the oleate growth phenotype of the pxa1 pxa2⌬ mutant, and restored ␤-oxidation of fatty acids with a range of chain lengths and varying degrees of desaturation. When expressed in yeast peroxisomal membranes, the basal ATPase activity of CTS could be stimulated by fatty acyl-CoAs but not by fatty acids. The implications of these findings for the function and substrate specificity of CTS are discussed.Peroxisomes perform a range of different functions, including ␤-oxidation of fatty acids (FA) 2 and synthesis and degradation of bioactive, lipid-derived molecules. Import of substrates for peroxisomal metabolism is mediated by ATP binding cassette (ABC) transporters belonging to subclass D (1, 2). ABC transporters are composed of a minimum of four functional domains: two transmembrane domains, involved in substrate binding and translocation, and two nucleotide binding domains (NBDs) that bind and hydrolyze ATP, providing energy for transport (3, 4). The domains may be fused into a single polypeptide, but are frequently expressed as half-size transporters composed of a transmembrane domain fused to an NBD, which hetero-or homodimerize to form a functional transporter. Bakers' yeast (Saccharomyces cerevisiae) contains two ABCD genes that encode half-size ABC proteins: Pxa1p (peroxisomal ABC-transporter 1), and Pxa2p (5-7). The single pxa1⌬ and pxa2⌬ deletion mutants are unable to grow on oleate (C18:1) as the sole carbon source and exhibit reduced ␤-oxidation of this long-chain FA. It has been proposed that Pxa1p and Pxa2p operate as a heterodimer to form a functional transporter (6,8,9), which has been shown by indirect evidence to be required for the peroxisomal transport of the C18:1-CoA, a long-chain acyl-CoA ester, but not for import of C8:0-CoA (10). In contrast, medium-chain FAs enter yeast peroxisomes as free acids independently of Pxa1p/Pxa2p, and are activated by peroxisomal acyl-CoA synthetase, Faa2p, prior to ␤-oxidation (6).The human ABCD transporter subfamily comprises four half-size members: adrenoleukodystrophy protein (ALDP), ALD-related protein, the 70-kDa peroxisomal membrane protein (PMP70), and PMP70-related protein (PMP70R/PMP69) (1, 2). Although...

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Section: Discussionmentioning

confidence: 73%

The Arabidopsis Peroxisomal ABC Transporter, Comatose, Complements the Saccharomyces cerevisiae pxa1 pxa2Δ Mutant for Metabolism of Long-chain Fatty Acids and Exhibits Fatty Acyl-CoA-stimulated ATPase Activity

Nyathi

Lousa

Roermund

et al. 2010

Journal of Biological Chemistry

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“…Four genes were identified that likely influence OxPhos metabolism (Table 1). The first, acyl-coenzyme A thioesterase, which is mitochondrially localized, affects intermediates in the citric acid cycle, which forms OxPhos substrates via lipid metabolism regulation [78–80]. A second gene, adenylate kinase, regulates mitochondrial respiration by altering ADP/ATP ratios [81] and creating feedback signal communication.…”

Section: Resultsmentioning

confidence: 99%

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

et al. 2017

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The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only pathway with both nuclear and mitochondrial encoded proteins. The importance of the interactions between these two genomes has recently received more attention because of their potential evolutionary effects and how they may affect human health and disease. In many different organisms, healthy nuclear and mitochondrial genome hybrids between species or among distant populations within a species affect fitness and OxPhos functions. However, what is less understood is whether these interactions impact individuals within a single natural population. The significance of this impact depends on the strength of selection for mito-nuclear interactions. We examined whether mito-nuclear interactions alter allele frequencies for ~11,000 nuclear SNPs within a single, natural Fundulus heteroclitus population containing two divergent mitochondrial haplotypes (mt-haplotypes). Between the two mt-haplotypes, there are significant nuclear allele frequency differences for 349 SNPs with a p-value of 1% (236 with 10% FDR). Unlike the rest of the genome, these 349 outlier SNPs form two groups associated with each mt-haplotype, with a minority of individuals having mixed ancestry. We use this mixed ancestry in combination with mt-haplotype as a polygenic factor to explain a significant fraction of the individual OxPhos variation. These data suggest that mito-nuclear interactions affect cardiac OxPhos function. The 349 outlier SNPs occur in genes involved in regulating metabolic processes but are not directly associated with the 79 nuclear OxPhos proteins. Therefore, we postulate that the evolution of mito-nuclear interactions affects OxPhos function by acting upstream of OxPhos.

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“…Current evidence in mammals and yeast indicates that acyl-CoA esters are imported across the peroxisomal membrane via a family of ATP binding-cassette transporters (Hettema et al, 1996;Verleur et al, 1997;Hunt and Alexson, 2008). However, to date there is no evidence for transport of acyl-CoA esters out of peroxisomes.…”

Section: Discussionmentioning

confidence: 99%

Contribution of CoA Ligases to Benzenoid Biosynthesis in Petunia Flowers

et al. 2012

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Biosynthesis of benzoic acid from Phe requires shortening of the side chain by two carbons, which can occur via the b-oxidative or nonoxidative pathways. The first step in the b-oxidative pathway is cinnamoyl-CoA formation, likely catalyzed by a member of the 4-coumarate:CoA ligase (4CL) family that converts a range of trans-cinnamic acid derivatives into the corresponding CoA thioesters. Using a functional genomics approach, we identified two potential CoA-ligases from petunia (Petunia hybrida) petal-specific cDNA libraries. The cognate proteins share only 25% amino acid identity and are highly expressed in petunia corollas. Biochemical characterization of the recombinant proteins revealed that one of these proteins (Ph-4CL1) has broad substrate specificity and represents a bona fide 4CL, whereas the other is a cinnamate:CoA ligase (Ph-CNL). RNA interference suppression of Ph-4CL1 did not affect the petunia benzenoid scent profile, whereas downregulation of Ph-CNL resulted in a decrease in emission of benzylbenzoate, phenylethylbenzoate, and methylbenzoate. Green fluorescent protein localization studies revealed that the Ph-4CL1 protein is localized in the cytosol, whereas Ph-CNL is in peroxisomes. Our results indicate that subcellular compartmentalization of enzymes affects their involvement in the benzenoid network and provide evidence that cinnamoyl-CoA formation by Ph-CNL in the peroxisomes is the committed step in the b-oxidative pathway.

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Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism

Cited by 60 publications

References 174 publications

The Arabidopsis Peroxisomal ABC Transporter, Comatose, Complements the Saccharomyces cerevisiae pxa1 pxa2Δ Mutant for Metabolism of Long-chain Fatty Acids and Exhibits Fatty Acyl-CoA-stimulated ATPase Activity

The Arabidopsis Peroxisomal ABC Transporter, Comatose, Complements the Saccharomyces cerevisiae pxa1 pxa2Δ Mutant for Metabolism of Long-chain Fatty Acids and Exhibits Fatty Acyl-CoA-stimulated ATPase Activity

Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions

Contribution of CoA Ligases to Benzenoid Biosynthesis in Petunia Flowers

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