Effect ofhxk2deletion andHAP4overexpression on fermentative capacity inSaccharomyces cerevisiae

Schuurmans, J. Merijn; Rossell, Sergio; Tuijl, Arjen van; Bakker, Barbara M.; Hellingwerf, Klaas J.; Mattos, M. Joost Teixeira de

doi:10.1111/j.1567-1364.2007.00319.x

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…Transcriptional analysis of a hxk2Δ -strain showed significant upregulation of genes with binding sites for Mig1p and/or Cat8p (e.g. FBP1 , MDH2 , MDH3, MLS1 , ICL1 , IDP2 and PCK1 ) [17], [18]. This confirms the significant role of Hxk2p in the Snf1p circuit of the glucose signalling mechanism.…”

Section: Introductionsupporting

confidence: 60%

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Engineering Yeast Hexokinase 2 for Improved Tolerance Toward Xylose-Induced Inactivation

et al. 2013

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Hexokinase 2 (Hxk2p) from Saccharomyces cerevisiae is a bi-functional enzyme being both a catalyst and an important regulator in the glucose repression signal. In the presence of xylose Hxk2p is irreversibly inactivated through an autophosphorylation mechanism, affecting all functions. Consequently, the regulation of genes involved in sugar transport and fermentative metabolism is impaired. The aim of the study was to obtain new Hxk2p-variants, immune to the autophosphorylation, which potentially can restore the repressive capability closer to its nominal level. In this study we constructed the first condensed, rationally designed combinatorial library targeting the active-site in Hxk2p. We combined protein engineering and genetic engineering for efficient screening and identified a variant with Phe159 changed to tyrosine. This variant had 64% higher catalytic activity in the presence of xylose compared to the wild-type and is expected to be a key component for increasing the productivity of recombinant xylose-fermenting strains for bioethanol production from lignocellulosic feedstocks.

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Section: Introductionsupporting

confidence: 60%

“…This confirms the significant role of Hxk2p in the Snf1p circuit of the glucose signalling mechanism. In addition, Hxk2p also participates in the control of genes encoding sugar transporters [17], [18], [19]. The presence of Hxk2p is required to fully induce HXT1 at high glucose concentrations and HXT2 and HXT4 at low concentrations [19].…”

Section: Introductionmentioning

confidence: 99%

Engineering Yeast Hexokinase 2 for Improved Tolerance Toward Xylose-Induced Inactivation

et al. 2013

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“…NAD+ dependent changes in gene expression levels could also be mediated by the action of PGC-1α and SIRT1 complex, which have important roles in regulation of glucose homeostasis [48]. Additional regulatory links, between glycolytic flux, energy metabolism, TCA cycle flux and fatty acid metabolism are also known in other eukaryotic systems such as baker's yeast [49]–[51]. Furthermore, several of the enzymes from central carbon metabolism may be regulated to a large extent at the post-transcriptional level [52],[53].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

et al. 2010

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Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM.

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“…Another strategy entails of direct manipulation of transcription factors (TFs), since these proteins have the potential of controlling several fluxes in an organism. Modulation of TFs as a strategy for metabolic engineering has been demonstrated by Schuurmans et al 2008, where the authors deleted one TF and overexpressed another to improve ethanol production in Saccharomyces cerevisiae [2]. A different approach is to use site directed mutagenesis on a TF, an approach that was applied to improve ethanol tolerance and production in S. cerevisiae [3].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Transcription Factor Controlling pH-Dependent Organic Acid Response in Aspergillus niger

Poulsen¹,

Andersen²,

Lantz³

et al. 2012

PLoS ONE

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Acid formation in Aspergillus niger is known to be subjected to tight regulation, and the acid production profiles are fine-tuned to respond to the ambient pH. Based on transcriptome data, putative trans-acting pH responding transcription factors were listed and through knock out studies, mutants exhibiting an oxalate overproducing phenotype were identified. The yield of oxalate was increased up to 158% compared to the wild type and the corresponding transcription factor was therefore entitled Oxalic Acid repression Factor, OafA. Detailed physiological characterization of one of the ΔoafA mutants, compared to the wild type, showed that both strains produced substantial amounts of gluconic acid, but the mutant strain was more efficient in re-uptake of gluconic acid and converting it to oxalic acid, particularly at high pH (pH 5.0). Transcriptional profiles showed that 241 genes were differentially expressed due to the deletion of oafA and this supported the argument of OafA being a trans-acting transcription factor. Furthermore, expression of two phosphoketolases was down-regulated in the ΔoafA mutant, one of which has not previously been described in fungi. It was argued that the observed oxalate overproducing phenotype was a consequence of the efficient re-uptake of gluconic acid and thereby a higher flux through glycolysis. This results in a lower flux through the pentose phosphate pathway, demonstrated by the down-regulation of the phosphoketolases. Finally, the physiological data, in terms of the specific oxygen consumption, indicated a connection between the oxidative phosphorylation and oxalate production and this was further substantiated through transcription analysis.

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Effect ofhxk2deletion andHAP4overexpression on fermentative capacity inSaccharomyces cerevisiae

Cited by 13 publications

References 17 publications

Engineering Yeast Hexokinase 2 for Improved Tolerance Toward Xylose-Induced Inactivation

Engineering Yeast Hexokinase 2 for Improved Tolerance Toward Xylose-Induced Inactivation

Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

Identification of a Transcription Factor Controlling pH-Dependent Organic Acid Response in Aspergillus niger

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