10 results on '"Oksana Tehlivets"'
Search Results
2. Transcriptional and antioxidative responses to endogenous polyunsaturated fatty acid accumulation in yeast
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Emma J. Collinson, Ana Čipak Gašparović, Tomislav Zarkovic, Ian W. Dawes, Neven Zarkovic, Oksana Tehlivets, Eleonora Perak, and Luka Andrisic
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Fatty Acid Desaturases ,Cell physiology ,Saccharomyces cerevisiae Proteins ,catalase ,Desaturase ,Fatty acid β-oxidation ,PUFA ,ROS ,Clinical Biochemistry ,Endogeny ,Saccharomyces cerevisiae ,Mitochondrion ,medicine.disease_cause ,Lipid peroxidation ,chemistry.chemical_compound ,medicine ,Molecular Biology ,Plant Proteins ,chemistry.chemical_classification ,biology ,food and beverages ,Fatty acid ,Cell Biology ,General Medicine ,Catalase ,Adaptation, Physiological ,Oxidative Stress ,chemistry ,Biochemistry ,Fatty Acids, Unsaturated ,biology.protein ,Hevea ,lipids (amino acids, peptides, and proteins) ,Lipid Peroxidation ,sense organs ,Reactive Oxygen Species ,Transcriptome ,Oxidative stress ,Polyunsaturated fatty acid - Abstract
Pathophysiology of polyunsaturated fatty acids (PUFAs) is associated with aberrant lipid and oxygen metabolism. In particular, under oxidative stress, PUFAs are prone to autocatalytic degradation via peroxidation, leading to formation of reactive aldehydes with numerous potentially harmful effects. However, the pathological and compensatory mechanisms induced by lipid peroxidation are very complex and not sufficiently understood. In our study, we have used yeast capable of endogenous PUFA synthesis in order to understand the effects triggered by PUFA accumulation on cellular physiology of a eukaryotic organism. The mechanisms induced by PUFA accumulation in S. cerevisiae expressing Hevea brasiliensis Δ12-fatty acid desaturase include down-regulation of components of electron transport chain in mitochondria as well as up-regulation of pentose-phosphate pathway and fatty acid β-oxidation at the transcriptional level. Interestingly, while no changes were observed at the transcriptional level, activities of two important enzymatic antioxidants, catalase and glutathione-S-transferase, were altered in response to PUFA accumulation. Increased intracellular glutathione levels further suggest an endogenous oxidative stress and activation of antioxidative defense mechanisms under conditions of PUFA accumulation. Finally, our data suggest that PUFA in cell membrane causes metabolic changes which in turn lead to adaptation to endogenous oxidative stress.
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- 2014
3. Regulation of Gene Expression through a Transcriptional Repressor that Senses Acyl-Chain Length in Membrane Phospholipids
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Harald F, Hofbauer, Florian H, Schopf, Hannes, Schleifer, Oskar L, Knittelfelder, Bartholomäus, Pieber, Gerald N, Rechberger, Heimo, Wolinski, Maria L, Gaspar, C Oliver, Kappe, Johannes, Stadlmann, Karl, Mechtler, Alexandra, Zenz, Karl, Lohner, Oksana, Tehlivets, Susan A, Henry, and Sepp D, Kohlwein
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Saccharomyces cerevisiae Proteins ,Saccharomyces cerevisiae ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Biology ,Endoplasmic Reticulum ,Article ,General Biochemistry, Genetics and Molecular Biology ,Membrane Lipids ,03 medical and health sciences ,chemistry.chemical_compound ,Acetyltransferases ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Phosphorylation ,Molecular Biology ,Phospholipids ,Derepression ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Kinase ,Fatty Acids ,030302 biochemistry & molecular biology ,AMPK ,Biological membrane ,Cell Biology ,Phosphatidic acid ,Repressor Proteins ,chemistry ,Biochemistry ,Mutation ,Myo-Inositol-1-Phosphate Synthase ,lipids (amino acids, peptides, and proteins) ,Developmental Biology - Abstract
Summary Membrane phospholipids typically contain fatty acids (FAs) of 16 and 18 carbon atoms. This particular chain length is evolutionarily highly conserved and presumably provides maximum stability and dynamic properties to biological membranes in response to nutritional or environmental cues. Here, we show that the relative proportion of C16 versus C18 FAs is regulated by the activity of acetyl-CoA carboxylase (Acc1), the first and rate-limiting enzyme of FA de novo synthesis. Acc1 activity is attenuated by AMPK/Snf1-dependent phosphorylation, which is required to maintain an appropriate acyl-chain length distribution. Moreover, we find that the transcriptional repressor Opi1 preferentially binds to C16 over C18 phosphatidic acid (PA) species: thus, C16-chain containing PA sequesters Opi1 more effectively to the ER, enabling AMPK/Snf1 control of PA acyl-chain length to determine the degree of derepression of Opi1 target genes. These findings reveal an unexpected regulatory link between the major energy-sensing kinase, membrane lipid composition, and transcription., Highlights • AMPK/Snf1 inhibition of acetyl-CoA carboxylase controls fatty acyl-chain length • Opi1 repressor preferentially binds to C16 rather than C18 acyl-chains in PA • Acyl-chain length tunes Opi1 sequestration to the ER and target gene derepression • AMPK/Snf1 thus uses its effect on acyl-chain length to control Opi1 target genes, Hofbauer et al. find that yeast Snf1/AMPK regulation of acetyl-CoA carboxylase affects acyl-chain length (C16 versus C18) in membrane phospholipids. Moreover, preferential binding of the transcriptional repressor Opi1 to C16-containing phosphatidic acid controls Opi1 sequestration and target gene derepression. Snf1/AMPK regulation of membrane-lipid composition thus determines a key transcriptional output.
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- 2014
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4. S-adenosyl-L-homocysteine hydrolase and methylation disorders: Yeast as a model system
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Oksana Tehlivets, Myriam Visram, Nermina Malanovic, Tea Pavkov-Keller, and Walter Keller
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S-Adenosylmethionine ,Hyperhomocysteinemia ,Saccharomyces cerevisiae Proteins ,Methyltransferase ,Homocysteine ,S-adenosyl-L-homocysteine hydrolase ,Review ,Saccharomyces cerevisiae ,Biology ,AdoHcy ,Methylation ,Models, Biological ,AdoMet ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hydrolase ,medicine ,Animals ,Humans ,heterocyclic compounds ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Adenosylhomocysteinase ,medicine.disease ,Molecular biology ,Enzyme ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Molecular Medicine - Abstract
S-adenosyl-L-methionine (AdoMet)-dependent methylation is central to the regulation of many biological processes: more than 50 AdoMet-dependent methyltransferases methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids. Common to all AdoMet-dependent methyltransferase reactions is the release of the strong product inhibitor S-adenosyl-L-homocysteine (AdoHcy), as a by-product of the reaction. S-adenosyl-L-homocysteine hydrolase is the only eukaryotic enzyme capable of reversible AdoHcy hydrolysis to adenosine and homocysteine and, thus, relief from AdoHcy inhibition. Impaired S-adenosyl-L-homocysteine hydrolase activity in humans results in AdoHcy accumulation and severe pathological consequences. Hyperhomocysteinemia, which is characterized by elevated levels of homocysteine in blood, also exhibits a similar phenotype of AdoHcy accumulation due to the reversal of the direction of the S-adenosyl-L-homocysteine hydrolase reaction. Inhibition of S-adenosyl-L-homocysteine hydrolase is also linked to antiviral effects. In this review the advantages of yeast as an experimental system to understand pathologies associated with AdoHcy accumulation will be discussed., Highlights ► AdoHcy is a potent product inhibitor of AdoMet-dependent methyltransferases. ► AdoHcy accumulates in hyperhomocysteinemia. ► Yeast is an advantageous system to understand AdoHcy toxicity. ► Lipid metabolism is deregulated in response to AdoHcy accumulation.
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- 2013
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5. Homocysteine as a Risk Factor for Atherosclerosis: Is Its Conversion toS-Adenosyl-L-Homocysteine the Key to Deregulated Lipid Metabolism?
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Oksana Tehlivets
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0303 health sciences ,Methyltransferase ,lcsh:QP1-981 ,Homocysteine ,030309 nutrition & dietetics ,Phospholipid ,Lipid metabolism ,Review Article ,Methylation ,Biology ,Biochemistry ,lcsh:Physiology ,lcsh:Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,S-Adenosyl-L-homocysteine ,chemistry ,Hydrolase ,Unfolded protein response ,lcsh:QD415-436 ,030304 developmental biology - Abstract
Homocysteine (Hcy) has been recognized for the past five decades as a risk factor for atherosclerosis. However, the role of Hcy in the pathological changes associated with atherosclerosis as well as the pathological mechanisms triggered by Hcy accumulation is poorly understood. Due to the reversal of the physiological direction of the reaction catalyzed byS-adenosyl-L-homocysteine hydrolase Hcy accumulation leads to the synthesis ofS-adenosyl-L-homocysteine (AdoHcy). AdoHcy is a strong product inhibitor ofS-adenosyl-L-methionine (AdoMet)-dependent methyltransferases, and to date more than 50 AdoMet-dependent methyltransferases that methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids have been identified. Phospholipid methylation is the major consumer of AdoMet, both in mammals and in yeast. AdoHcy accumulation induced either by Hcy supplementation or due toS-adenosyl-L-homocysteine hydrolase deficiency results in inhibition of phospholipid methylation in yeast. Moreover, yeast cells accumulating AdoHcy also massively accumulate triacylglycerols (TAG). Similarly, Hcy supplementation was shown to lead to increased TAG and sterol synthesis as well as to the induction of the unfolded protein response (UPR) in mammalian cells. In this review a model of deregulation of lipid metabolism in response to accumulation of AdoHcy in Hcy-associated pathology is proposed.
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- 2011
6. S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast
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Sepp D. Kohlwein, Nermina Malanovic, Ingo E. Streith, Heimo Wolinski, Oksana Tehlivets, and Gerald N. Rechberger
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Regulation of gene expression ,Methyltransferase ,Cell Biology ,Methylation ,Phosphatidic acid ,Biology ,Biochemistry ,De novo synthesis ,chemistry.chemical_compound ,chemistry ,Phosphatidylethanolamine N-methyltransferase ,S-adenosyl-L-homocysteine hydrolase ,Adenosylhomocysteinase ,Molecular Biology - Abstract
In eukaryotes, S-adenosyl-L-homocysteine hydrolase (Sah1) offers a single way for degradation of S-adenosyl-L-homocysteine, a product and potent competitive inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases. De novo phosphatidylcholine (PC) synthesis requires three AdoMet-dependent methylation steps. Here we show that down-regulation of SAH1 expression in yeast leads to accumulation of S-adenosyl-L-homocysteine and decreased de novo PC synthesis in vivo. This decrease is accompanied by an increase in triacylglycerol (TG) levels, demonstrating that Sah1-regulated methylation has a major impact on cellular lipid homeostasis. TG accumulation is also observed in cho2 and opi3 mutants defective in methylation of phosphatidylethanolamine to PC, confirming that PC de novo synthesis and TG synthesis are metabolically coupled through the efficiency of the phospholipid methylation reaction. Indeed, because both types of lipids share phosphatidic acid as a precursor, we find in cells with down-regulated Sah1 activity major alterations in the expression of the INO1 gene as well as in the localization of Opi1, a negative regulatory factor of phospholipid synthesis, which binds and is retained in the endoplasmic reticulum membrane by phosphatidic acid in conjunction with VAMP/synaptobrevin-associated protein, Scs2. The addition of homocysteine, by the reversal of the Sah1-catalyzed reaction, also leads to TG accumulation in yeast, providing an attractive model for the role of homocysteine as a risk factor of atherosclerosis in humans.
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- 2008
7. Adaptation to oxidative stress induced by polyunsaturated fatty acids in yeast
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Ana Čipak, Morana Jaganjac, Neven Zarkovic, Sepp D. Kohlwein, and Oksana Tehlivets
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chemistry.chemical_classification ,Reactive oxygen species ,Saccharomyces cerevisiae ,Cell Biology ,Biology ,Catalase ,medicine.disease_cause ,biology.organism_classification ,Adaptation, Physiological ,Yeast ,Oxidative Stress ,chemistry.chemical_compound ,Fatty acid desaturase ,fatty acid peroxidation ,fatty acid desaturase ,catalase ,chemistry ,Biochemistry ,Fatty Acids, Unsaturated ,biology.protein ,medicine ,Hydrogen peroxide ,Molecular Biology ,Oxidative stress ,Polyunsaturated fatty acid - Abstract
To create a conditional system for molecular analysis of effects of polyunsaturated fatty acids (PUFA) on cellular physiology, we have constructed a strain of yeast (Saccharomyces cerevisiae) that functionally expresses, under defined conditions, the Δ12 desaturase gene from the tropical rubber tree, Hevea brasiliensis. This strain produces up to 15% PUFA, exclusively under inducing conditions resulting in production of 4-hydroxy-2-nonenal, one of the major end products of n − 6 polyunsaturated fatty acid peroxidation. The PUFA-producing yeast was initially more sensitive to oxidative stress than the wild-type strain. However, over extended time of cultivation it became more resistant to hydrogen peroxide indicating adaptation to endogenous oxidative stress caused by the presence of PUFA. Indeed, PUFA-producing strain showed an increased concentration of endogenous ROS, while initially increased hydrogen peroxide sensitivity was followed by an increase in catalase activity and adaptation to oxidative stress. The deletion mutants constructed to be defective in the catalase activity lost the ability to adapt to oxidative stress. These data demonstrate that the cellular synthesis of PUFA induces endogenous oxidative stress which is overcome by cellular adaptation based on the catalase activity.
- Published
- 2008
8. Saccharomyces cerevisiae strain expressing a plant fatty acid desaturase produces polyunsaturated fatty acids and is susceptible to oxidative stress induced by lipid peroxidation
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Willibald Wonisch, Georg Waeg, Tanja Matijevic, Ana Čipak, Sepp D. Kohlwein, Morana Zivkovic, Oksana Tehlivets, Neven Zarkovic, Emma J. Collinson, Ian W. Dawes, and Meinhard Hasslacher
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Fatty Acid Desaturases ,Paraquat ,Free Radicals ,Molecular Sequence Data ,Saccharomyces cerevisiae ,medicine.disease_cause ,Biochemistry ,Lipid peroxidation ,chemistry.chemical_compound ,tert-Butylhydroperoxide ,Lipid oxidation ,yeast ,lipid oxidation ,PUFA ,oxidative stress ,reactive oxygen species ,Physiology (medical) ,medicine ,Amino Acid Sequence ,Cloning, Molecular ,Plant Proteins ,chemistry.chemical_classification ,Aldehydes ,biology ,Fatty acid ,Hydrogen Peroxide ,biology.organism_classification ,Yeast ,Oxidative Stress ,Fatty acid desaturase ,chemistry ,Fatty Acids, Unsaturated ,biology.protein ,Hevea ,Lipid Peroxidation ,Oxidative stress ,Polyunsaturated fatty acid - Abstract
Although oxygen is essential for aerobic organisms, it also forms potentially harmful reactive oxygen species. For its simplicity, easy manipulation, and cultivation conditions, yeast is used as an attractive model in oxidative stress research. However, lack of polyunsaturated fatty acids in yeast membranes makes yeast unsuitable for research in the field of lipid peroxidation. Therefore, we have constructed a yeast strain expressing a Delta12 desaturase gene from the tropical rubber tree, Hevea brasiliensis. This yeast strain expresses the heterologous desaturase in an active form and, consequently, produces Delta9/Delta12 polyunsaturated fatty acids under inducing conditions. The functional expression of the heterologous desaturase did not affect cellular morphology or growth, indicating no general adverse effect on cellular physiology. However, the presence of polyunsaturated fatty acids changed the yeast's sensitivity to oxidative stress induced by addition of paraquat, tert-butylhydroperoxide, and hydrogen peroxide. This difference in sensitivity to the latter was followed by the formation of 4-hydroxy-2-nonenal, one of the end products of linoleic fatty acid peroxidation, which is known to play a role in cell growth control and signaling. Here we show that this yeast strain conditionally expressing the Delta12 desaturase gene provides a novel and well-defined eukaryotic model in lipid peroxidation research. Its potential to investigate the molecular basis of responses to oxidative stress, in particular the involvement of reactive aldehydes derived from fatty acid peroxidation, especially 4-hydroxy-2-nonenal, will be addressed.
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- 2006
9. Fatty acid synthesis and elongation in yeast
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Kim Scheuringer, Oksana Tehlivets, and Sepp D. Kohlwein
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chemistry.chemical_classification ,Saccharomyces cerevisiae Proteins ,biology ,Fatty acid metabolism ,Chemistry ,Fatty Acids ,Coenzymes ,Fatty acid ,Cell Biology ,Saccharomyces cerevisiae ,Endoplasmic Reticulum ,Mitochondria ,Fatty acid synthase ,chemistry.chemical_compound ,Cytosol ,Biochemistry ,biology.protein ,Free fatty acid receptor ,Fatty acid elongation ,adipocyte protein 2 ,Fatty Acid Synthases ,Molecular Biology ,Fatty acid synthesis ,Polyunsaturated fatty acid ,Acetyl-CoA Carboxylase - Abstract
Fatty acids are essential compounds in the cell. Since the yeast Saccharomyces cerevisiae does not feed typically on fatty acids, cellular function and growth relies on endogenous synthesis. Since all cellular organelles are involved in – or dependent on – fatty acid synthesis, multiple levels of control may exist to ensure proper fatty acid composition and homeostasis. In this review, we summarize what is currently known about enzymes involved in cellular fatty acid synthesis and elongation, and discuss potential links between fatty acid metabolism, physiology and cellular regulation.
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- 2006
10. S-adenosyl-L-homocysteine hydrolase in yeast: key enzyme of methylation metabolism and coordinated regulation with phospholipid synthesis
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Sepp D. Kohlwein, Oksana Tehlivets, and Meinhard Hasslacher
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Genetic Markers ,Methyltransferase ,Saccharomyces cerevisiae Proteins ,Hydrolases ,Genes, Fungal ,Molecular Sequence Data ,Biophysics ,Phospholipid ,Saccharomyces cerevisiae ,Biology ,Biochemistry ,Methylation ,Models, Biological ,chemistry.chemical_compound ,Structural Biology ,S-adenosyl-L-homocysteine hydrolase ,Gene Expression Regulation, Fungal ,Hydrolase ,Consensus Sequence ,Genetics ,Amino Acid Sequence ,Promoter Regions, Genetic ,Molecular Biology ,Conserved Sequence ,Phospholipids ,chemistry.chemical_classification ,Sequence Homology, Amino Acid ,Lipid metabolism ,Cell Biology ,Lipid ,S-Adenosylhomocysteine ,Yeast ,Enzyme ,chemistry ,SAH1 ,Gene Deletion - Abstract
S-Adenosyl-l-homocysteine hydrolase (Sah1p, EC 3.3.1.1.) is a key enzyme of methylation metabolism. It catabolizes S-adenosyl-l-homocysteine, which is formed after donation of the activated methyl group of S-adenosyl-l-methionine (AdoMet) to an acceptor, and which acts as strong competitive inhibitor of all AdoMet-dependent methyltransferases. Sah1p is an essential enzyme in yeast and one of the most highly conserved proteins with up to 80% sequence homology throughout all kingdoms of life. SAH1 expression in yeast is subject to the general transcriptional control of phospholipid synthesis. Profound changes in cellular lipid composition upon depletion of Sah1p support the notion of a tight interaction between lipid metabolism and Sah1p function.
- Published
- 2004
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