Yeast toxicogenomics: lessons from a eukaryotic cell model and cell factory

Santos, Sandra C. dos; Sá‐Correia, Isabel

doi:10.1016/j.copbio.2015.03.001

Cited by 46 publications

(33 citation statements)

References 69 publications

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“…These studies have helped to identify biological functions involved in the toxicity of several compounds including metals, pesticides and pharmaceutical drugs and have also proven useful to shed light on human diseases2627. In this study, a S. cerevisiae deletion collection was employed to better understand the molecular mechanisms underlying SeMet toxicity.…”

Section: Discussionmentioning

confidence: 99%

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Plateau

Saveanu

Lestini

et al. 2017

Sci Rep

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Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that selenomethionine causes a proteotoxic stress. We demonstrate that selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.

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Section: Discussionmentioning

confidence: 99%

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Plateau

Saveanu

Lestini

et al. 2017

Sci Rep

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“…Thus, appropriate engineering to upregulate the sphingolipid pathway in situ may provide a readily accessible and rational means to enhance the acetic acid tolerance of industrially valuable S. cerevisiae strains, either alone or in combination with other genetic strategies that appear to improve the acetic acid tolerance of this organism [66–68]. …”

Section: Discussionmentioning

confidence: 99%

Sphingolipid biosynthesis upregulation by TOR complex 2–Ypk1 signaling during yeast adaptive response to acetic acid stress

Guerreiro

Muir

Ramachandran

et al. 2016

Biochemical Journal

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Acetic acid-induced inhibition of yeast growth and metabolism limits the productivity of industrial fermentation processes, especially when lignocellulosic hydrolysates are used as feedstock in industrial biotechnology. Tolerance to acetic acid of food spoilage yeasts is also a problem in the preservation of acidic foods and beverages. Thus, understanding the molecular mechanisms underlying adaptation and tolerance to acetic acid stress is increasingly important in industrial biotechnology and the food industry. Prior genetic screens for S. cerevisiae mutants with increased sensitivity to acetic acid identified loss-of-function mutations in the YPK1 gene, which encodes a protein kinase activated by the Target of Rapamycin (TOR) Complex 2 (TORC2). We show here by several independent criteria that TORC2-Ypk1 signaling is stimulated in response to acetic acid stress. Moreover, we demonstrate that TORC2-mediated Ypk1 phosphorylation and activation is necessary for acetic acid tolerance, and occurs independently of Hrk1, a protein kinase previously implicated in the cellular response to acetic acid. In addition, we show that TORC2-Ypk1-mediated activation of L-serine: palmitoyl-CoA acyltransferase, the enzyme complex that catalyzes the first committed step of sphingolipid biosynthesis, is required for acetic acid tolerance. Furthermore, analysis of the sphingolipid pathway using inhibitors and mutants indicates that it is production of certain complex sphingolipids that contributes to conferring acetic acid tolerance. Consistent with that conclusion, promoting sphingolipid synthesis by adding exogenous long-chain base precursor phytosphingosine to the growth medium enhanced acetic acid tolerance. Thus, appropriate modulation of the TORC2-Ypk1-sphingolipid axis in industrial yeast strains may have utility in improving fermentations of acetic acid-containing feedstocks.

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“…Known ones include those for dipeptides [340], antibiotics [132,133,135,136], and solvents [133,341,342]. Broadly similar statements are true in S. cerevisiae, where a variety of efflux pumps help remove intracellular toxicants of all kinds [343][344][345][346][347][348]. Given the importance of horizontal gene transfer in natural evolution (e.g.…”

Section: Directed Evolution: Changing the Sequence Of The Target Tranmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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Yeast toxicogenomics: lessons from a eukaryotic cell model and cell factory

Cited by 46 publications

References 69 publications

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae

Sphingolipid biosynthesis upregulation by TOR complex 2–Ypk1 signaling during yeast adaptive response to acetic acid stress

Control of metabolite efflux in microbial cell factories: current advances and future prospects

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