Mutants that show increased sensitivity to hydrogen peroxide reveal an important role for the pentose phosphate pathway in protection of yeast against oxidative stress

Juhnke, H.; Krems, Bernhard; Kötter, Peter; Entian, Karl Dieter

doi:10.1007/s004380050250

Cited by 53 publications

(76 citation statements)

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“…in ER organization and biogenesis (44); and Zwf1 is required for oxidative stress response and fatty acid metabolism (45,46). One might think that most top-level TFs are involved in chromatin-remodeling complexes, because these complexes affect a large number of transcriptional events and their components have high degrees in the interaction network.…”

Section: Biochemistrymentioning

confidence: 99%

Genomic analysis of the hierarchical structure of regulatory networks

Gerstein

2006

Proc. Natl. Acad. Sci. U.S.A.

316

372

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A fundamental question in biology is how the cell uses transcription factors (TFs) to coordinate the expression of thousands of genes in response to various stimuli. The relationships between TFs and their target genes can be modeled in terms of directed regulatory networks. These relationships, in turn, can be readily compared with commonplace ''chain-of-command'' structures in social networks, which have characteristic hierarchical layouts. Here, we develop algorithms for identifying generalized hierarchies (allowing for various loop structures) and use these approaches to illuminate extensive pyramid-shaped hierarchical structures existing in the regulatory networks of representative prokaryotes (Escherichia coli) and eukaryotes (Saccharomyces cerevisiae), with most TFs at the bottom levels and only a few master TFs on top. These masters are situated near the center of the protein-protein interaction network, a different type of network from the regulatory one, and they receive most of the input for the whole regulatory hierarchy through protein interactions. Moreover, they have maximal influence over other genes, in terms of affecting expression-level changes. Surprisingly, however, TFs at the bottom of the regulatory hierarchy are more essential to the viability of the cell. Finally, one might think master TFs achieve their wide influence through directly regulating many targets, but TFs with most direct targets are in the middle of the hierarchy. We find, in fact, that these midlevel TFs are "control bottlenecks" in the hierarchy, and this great degree of control for "middle managers" has parallels in efficient social structures in various corporate and governmental settings.organization ͉ topology ͉ transcriptional regulation ͉ yeast

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Section: Biochemistrymentioning

confidence: 99%

Genomic analysis of the hierarchical structure of regulatory networks

Gerstein

2006

Proc. Natl. Acad. Sci. U.S.A.

316

372

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“…NADPH is important in the oxidative stress response as a cofactor for glutathione reductase and thioredoxin reductase, two critical activities in the cellular thiol redox control and antioxidant defense (28,29,52). The critical role of NADPH is also suggested by the H 2 O 2 hypersensitivity of strains mutated for any of the six enzymes of the pentose phosphate pathway (51,53) and by the capacity of TKL1 overexpression to suppress the oxygen sensitivity of a sod1 null mutant (54). Studies with cells carrying a genetic ablation of the pentose phosphate pathway have also suggested that other cellular mechanisms of NADPH production must exist (51,53,55).…”

Section: Strains and Growth Conditions-the Yeast Strain Yph98 (14) (Mmentioning

confidence: 99%

“…The critical role of NADPH is also suggested by the H 2 O 2 hypersensitivity of strains mutated for any of the six enzymes of the pentose phosphate pathway (51,53) and by the capacity of TKL1 overexpression to suppress the oxygen sensitivity of a sod1 null mutant (54). Studies with cells carrying a genetic ablation of the pentose phosphate pathway have also suggested that other cellular mechanisms of NADPH production must exist (51,53,55). The glycerol dissimilation pathway might be such a mechanism of NADPH regeneration.…”

Section: Strains and Growth Conditions-the Yeast Strain Yph98 (14) (Mmentioning

confidence: 99%

The H2O2 Stimulon in Saccharomyces cerevisiae

Godon¹,

Lagniel²,

Lee³

et al. 1998

Journal of Biological Chemistry

544

450

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The changes in gene expression underlying the yeast adaptive stress response to H 2 O 2 were analyzed by comparative two-dimensional gel electrophoresis of total cell proteins. The synthesis of at least 115 proteins is stimulated by H 2 O 2 , whereas 52 other proteins are repressed by this treatment. We have identified 71 of the stimulated and 44 of the repressed targets. The kinetics and dose-response parameters of the H 2 O 2 genomic response were also analyzed. Identification of these proteins and their mapping into specific cellular processes give a distinct picture of the way in which yeast cells adapt to oxidative stress. Aerobic organisms have to maintain a reduced cellular redox environment in the face of the prooxidative conditions characteristic of aerobic life. The incomplete reduction of oxygen to water during respiration leads to the formation of redox-active oxygen intermediates (ROI) 1 such as the superoxide anion radical (O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl radical (OH ⅐ ) (for review, see Refs. 1-3). ROI are also produced during the ␤-oxidation of fatty acids, and upon exposure to radiation, light, metals, and redox active drugs. Oxidative stress results from abnormally high levels of ROI which perturb the cell redox status and leads to damage to lipids, proteins, DNA, and eventually cell death. Living organisms constantly sense and adapt to such redox perturbations by the induction of batteries of genes or stimulons whose products act to maintain the cellular redox environment (4 (9,10). Yeast has the same defense mechanisms as higher eukaryotes (for review, see Refs. 11 and 12) and offers the power of genome-wide experimental approaches owing to the availability of the complete sequence of its genome. It therefore represents an ideal eukaryotic model in which to study the cellular redox control and ROI metabolism. We recently established a general method to identify yeast proteins based on two-dimensional gel electrophoresis (13). We used this genome-wide experimental approach to characterize proteins whose expression is altered upon exposure to low doses of H 2 O 2 . Such an oxidative stress challenge results in a dramatic genomic response involving at least 167 proteins. Identification of these proteins and their mapping into cellular processes give a global view of the ubiquitous cellular changes elicited by H 2 O 2 and provides the framework for understanding the mechanisms of cellular redox homeostasis and H 2 O 2 metabolism. ura3-52 lys2-801 amber ade2-101 ochre trp1-⌬1 leu2-⌬1) was used for the analysis of the H 2 O 2 response. The strain S288C (15) was used for protein spot identification. Strains were grown at 30°C in a medium containing 0.67% yeast nitrogen base without amino acids (Difco), 2% glucose, buffered to pH 5.8 with 1% succinate and 0.6% NaOH. For YPH98, uracil, adenine, lysine, tryptophan and leucine (30 mg/liter) were added to the culture medium. MATERIALS AND METHODS Strains and Growth Conditions-The yeast strain YPH98 (14) (MATaIdentification of P...

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“…During oxidative stress, NADH is thought to be dangerous because it contributes to reduction of Fe 3ϩ and, hence, to the formation of damaging hydroxy radicals through the Fenton reaction (4-6). In contrast, NADPH does not contribute to iron reduction but defends cells against oxidative stress by supporting reductive repair reactions (1)(2)(3). Cells with impaired ability to reduce NADP ϩ (as in G6PDH mutants) are sensitive to oxidative stress (2,3,42,43).…”

Section: A Model For Control Of Pyridine Pools In Response To Oxidatimentioning

confidence: 99%

“…The responsible enzyme, an NAD kinase (NadK), is expected to be essential because NADPH supports reductive biosynthetic reactions and defends cells against oxidative stress (1)(2)(3). NADH carries electrons from oxidative catabolic reactions and is toxic during oxidative stress, because it contributes electrons for iron reduction and formation of damaging hydroxyl radicals from H 2 O 2 (4)(5)(6).…”

Section: T He Pyridine Nucleotide Nadpmentioning

confidence: 99%

Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress

Grose

Joss

Velick

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

116

122

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Formation of NADP ؉ from NAD ؉ is catalyzed by NAD kinase (NadK; EC 2.7.1.23). Evidence is presented that NadK is the only NAD kinase of Salmonella enterica and is essential for growth. NadK is inhibited allosterically by NADPH and NADH. Without effectors, NadK exists as an equilibrium mixture of dimers and tetramers (K D ‫؍‬ 1.0 ؎ 0.8 mM) but is converted entirely to tetramers in the presence of the inhibitor NADPH. Comparison of NadK kinetic parameters with pool sizes of NADH and NADPH suggests that NadK is substantially inhibited during normal growth and, thus, can increase its activity greatly in response to temporary drops in the pools of inhibitory NADH and NADPH. The primary inhibitor is NADPH during aerobic growth and NADH during anaerobic growth. A model is proposed in which variation of NadK activity is central to the adjustment of pyridine nucleotide pools in response to changes in aeration, oxidative stress, and UV irradiation. It is suggested that each of these environmental factors causes a decrease in the level of reduced pyridine nucleotides, activates NadK, and increases production of NADP(H) at the expense of NAD(H). Activation of NadK may constitute a defensive response that resists loss of protective NADPH.NAD metabolism ͉ pyridine nucleotides ͉ metabolic control ͉ NADP synthesis ͉ sedimentation equilibrium

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Mutants that show increased sensitivity to hydrogen peroxide reveal an important role for the pentose phosphate pathway in protection of yeast against oxidative stress

Cited by 53 publications

References 0 publications

Genomic analysis of the hierarchical structure of regulatory networks

Genomic analysis of the hierarchical structure of regulatory networks

The H2O2 Stimulon in Saccharomyces cerevisiae

Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress

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