IDP3 Encodes a Peroxisomal NADP-dependent Isocitrate Dehydrogenase Required for the β-Oxidation of Unsaturated Fatty Acids

Henke, B.; Girzalsky, Wolfgang; Berteaux‐Lecellier, Véronique; Erdmann, Ralf

doi:10.1074/jbc.273.6.3702

Cited by 89 publications

(108 citation statements)

References 50 publications

(71 reference statements)

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“…However, these studies did not exclude the possibility that Yhm2p is also localized to peroxisomes, notably because its transport properties make it a candidate for being involved in a peroxisomal redox shuttle that is required for the intraperoxisomal regeneration of NADPH (30,31). Also, Yhm2p was among the proteins that had been identified in a purified peroxisomal membrane fraction by mass spectrometry (32).…”

Section: Kinetic Characteristics Of Recombinant Yhm2p-the Time Coursementioning

confidence: 99%

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

Castegna

Scarcia

Agrimi

et al. 2010

Journal of Biological Chemistry

116

103

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Mitochondrial carriers are a family of transport proteins that shuttle metabolites, nucleotides, and coenzymes across the mitochondrial membrane. The function of only a few of the 35 Saccharomyces cerevisiae mitochondrial carriers still remains to be uncovered. In this study, we have functionally defined and characterized the S. cerevisiae mitochondrial carrier Yhm2p. The YHM2 gene was overexpressed in S. cerevisiae, and its product was purified and reconstituted into liposomes. Its transport properties, kinetic parameters, and targeting to mitochondria show that Yhm2p is a mitochondrial transporter for citrate and oxoglutarate. Reconstituted Yhm2p also transported oxaloacetate, succinate, and fumarate to a lesser extent, but virtually not malate and isocitrate. Yhm2p catalyzed only a counter-exchange transport that was saturable and inhibited by sulfhydrylblocking reagents but not by 1,2,3-benzenetricarboxylate (a powerful inhibitor of the citrate/malate carrier). The physiological role of Yhm2p is to increase the NADPH reducing power in the cytosol (required for biosynthetic and antioxidant reactions) and probably to act as a key component of the citrate-oxoglutarate NADPH redox shuttle between mitochondria and cytosol. This protein function is based on observations documenting a decrease in the NADPH/NADP ؉ and GSH/GSSG ratios in the cytosol of ⌬YHM2 cells as well as an increase in the NADPH/ NADP ؉ ratio in their mitochondria compared with wild-type cells. Our proposal is also supported by the growth defect displayed by the ⌬YHM2 strain and more so by the ⌬YHM2⌬ZWF1 strain upon H 2 O 2 exposure, implying that Yhm2p has an antioxidant function.Yhm2p is a protein of unknown function that has been found to be present in the inner mitochondrial membrane of Saccharomyces cerevisiae (1). This protein was shown to complement the growth defect displayed at 37°C by S. cerevisiae cells lacking ABF2, which encodes a mitochondrial DNA-binding protein involved in mitochondrial DNA replication and recombination (1, 2). In addition, the primary structure of Yhm2p exhibits all the characteristic features of the mitochondrial carrier (MC) 3 protein family, i.e. a tripartite structure consisting of three tandemly repeated homologous domains of about 100 amino acids in length, each of which contains a distinct signature motif and two hydrophobic stretches that span the membrane as ␣-helices (for reviews see Refs. 3-5). S. cerevisiae possesses 35 members of this family, one of which is localized in peroxisomes and not in mitochondria. The majority of yeast MCs has been functionally characterized and shown to transport specific metabolites, nucleotides, and coenzymes across the mitochondrial membrane (for review see Ref. 6). By contrast, the substrate(s) transported by Yhm2p have not yet been discovered, and its physiological function is yet unknown.In this study, we provide evidence that the gene product of YMR241w, named Coc1p and known as Yhm2p, is a citrateoxoglutarate carrier in S. cerevisiae. Yhm2p was overexpressed in S....

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Section: Kinetic Characteristics Of Recombinant Yhm2p-the Time Coursementioning

confidence: 99%

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

Castegna

Scarcia

Agrimi

et al. 2010

Journal of Biological Chemistry

116

103

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“…2,5-Dienoyl-CoAs form during the ␤-oxidation of unsaturated fatty acids with double bonds at odd-numbered carbons and return to the core spiral through either the NADP ϩ -independent (center) (30) or the NADP ϩ -dependent (right) (43,44) pathway as shown. Although not depicted in this figure, an intraperoxisomal NADP ϩ -dependent isocitrate dehydrogenase is required to regenerate the NADPH consumed by the 2,4-dienoylCoA reductase (10,11). Note that the final step in each pathway is catalyzed by…”

Section: Cdna Cloning Of Mammalian Eci1pmentioning

confidence: 99%

“…Pathways specific for unsaturated fatty acid metabolism. ␤-Oxidation of unsaturated fatty acids with double bonds extending from even-numbered carbons yields 2,4-dienoyl-CoAs that are metabolized as shown at left (10,11,42). 2,5-Dienoyl-CoAs form during the ␤-oxidation of unsaturated fatty acids with double bonds at odd-numbered carbons and return to the core spiral through either the NADP ϩ -independent (center) (30) or the NADP ϩ -dependent (right) (43,44) pathway as shown.…”

Section: Cdna Cloning Of Mammalian Eci1pmentioning

confidence: 99%

“…Although these enzymes are necessary for all fatty acid ␤-oxidation, the complete metabolism of unsaturated fatty acids requires one or more additional auxiliary enzymes (6). These include ⌬ 3 ,⌬ 2 -enoylCoA isomerase (Eci1p) (7,8), a 2,4-dienoyl-CoA reductase (Sps19p) (9), an NADP ϩ -dependent isocitrate dehydrogenase (Idp3p) (10,11), and a ⌬ 3,5 ,⌬ 2,4 -dienoyl-CoA isomerase (although this enzyme has yet to be identified in yeast). Among these auxiliary enzymes, ⌬ 3 ,⌬ 2 -enoyl-CoA isomerase (Eci1p) is unique in that its activity is essential for the ␤-oxidation of all unsaturated fatty acids ( Fig.…”

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confidence: 99%

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Characterization of PECI, a Novel Monofunctional Δ3,Δ2-Enoyl-CoA Isomerase of Mammalian Peroxisomes

Geisbrecht¹,

Zhang²,

Schulz³

et al. 1999

Journal of Biological Chemistry

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“…NADPH in the peroxisomal matrix, to enable the action of the peroxisomal 2,4 dienoyl-CoA reductase Sps19p, which is required for degradation of unsaturated fatty acids with double bonds at even positions (Gurvitz et al, 1997;Henke et al, 1998;van Roermund et al, 1998). The existence of an isocitrate/2-oxoglutarate redox shuttle across the peroxisomal membrane (Figure 4) is indicated by the tandem induction of both the IDP3 gene (20 c/c on oleate, Ͻ0.3 c/c on glucose) and the IDP2 gene (29 c/c on oleate, Ͻ0.3 c/c on glucose) encoding peroxisomal isocitrate dehydrogenase Idp3p and cytosolic isocitrate dehydrogenase Idp2p, respectively.…”

Section: Communication Among Peroxisomes Cytosol and Mitochondriamentioning

confidence: 99%

Dynamics of Gene Expression Revealed by Comparison of Serial Analysis of Gene Expression Transcript Profiles from Yeast Grown on Two Different Carbon Sources

Kal¹,

Zonneveld²,

Beneš

et al. 1999

MBoC

334

257

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We describe a genome-wide characterization of mRNA transcript levels in yeast grown on the fatty acid oleate, determined using Serial Analysis of Gene Expression (SAGE). Comparison of this SAGE library with that reported for glucose grown cells revealed the dramatic adaptive response of yeast to a change in carbon source. A major fraction (Ͼ20%) of the 15,000 mRNA molecules in a yeast cell comprised differentially expressed transcripts, which were derived from only 2% of the total number of ϳ6300 yeast genes. Most of the mRNAs that were differentially expressed code for enzymes or for other proteins participating in metabolism (e.g., metabolite transporters). In oleate-grown cells, this was exemplified by the huge increase of mRNAs encoding the peroxisomal ␤-oxidation enzymes required for degradation of fatty acids. The data provide evidence for the existence of redox shuttles across organellar membranes that involve peroxisomal, cytoplasmic, and mitochondrial enzymes. We also analyzed the mRNA profile of a mutant strain with deletions of the PIP2 and OAF1 genes, encoding transcription factors required for induction of genes encoding peroxisomal proteins. Induction of genes under the immediate control of these factors was abolished; other genes were up-regulated, indicating an adaptive response to the changed metabolism imposed by the genetic impairment. We describe a statistical method for analysis of data obtained by SAGE.

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IDP3 Encodes a Peroxisomal NADP-dependent Isocitrate Dehydrogenase Required for the β-Oxidation of Unsaturated Fatty Acids

Cited by 89 publications

References 50 publications

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

Characterization of PECI, a Novel Monofunctional Δ3,Δ2-Enoyl-CoA Isomerase of Mammalian Peroxisomes

Dynamics of Gene Expression Revealed by Comparison of Serial Analysis of Gene Expression Transcript Profiles from Yeast Grown on Two Different Carbon Sources

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