Direct Evidence That Genetic Variation in Glycerol-3-Phosphate and Malate Dehydrogenase Genes (Gpdh and Mdh1) Affects Adult Ethanol Tolerance in Drosophila melanogaster

Eanes, Walter F.; Merritt, Thomas J. S.; Flowers, Jonathan M.; Kumagai, Seiji; Zhu, Chen Tseh

doi:10.1534/genetics.108.089383

Cited by 20 publications

(16 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In each gene, we have an excision allele with impaired activity and an excision allele with normal activity. Enzyme activities were assayed as in earlier work [44,[46][47][48][49] and are shown in units of change in optical density per minute (DOD). The Men 9D allele is a perfect excision.…”

Section: Materials and Methods (A) Lifespan Designmentioning

confidence: 99%

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Talbert¹,

Barnett²,

Hoff³

et al. 2015

Proc. R. Soc. B.

View full text Add to dashboard Cite

There is a connection between nutrient inputs, energy-sensing pathways, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as an energy sensor in regulating lifespan and mediating caloric restriction. These genes possess significant expression variation in natural populations, and our experimental genotypes span this level of natural activity variation. Our studies link the readout of energy state with the perturbation of the genes of central metabolism and demonstrate their effect on lifespan.

show abstract

Section: Materials and Methods (A) Lifespan Designmentioning

confidence: 99%

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Talbert¹,

Barnett²,

Hoff³

et al. 2015

Proc. R. Soc. B.

View full text Add to dashboard Cite

show abstract

“…There is a growing appreciation that this has resulted in geographical selection for many traits, especially those associated with the ability to withstand the stresses associated with overwintering in temperate populations (Schmidt et al, 2005;Schmidt and Paaby, 2008;Reaume and Sokolowski, 2006;Mitrovski and Hoffmann, 2001;Hoffmann et al, 2001;Umina et al, 2005). From an experimental standpoint, the genetic tools of D. melanogaster are unparalleled and methods are available to permanently knockout or modify activity in many genes (Bellen et al, 2004;Venken and Bellen, 2005) and to control metabolic function (Merritt et al, 2005;Merritt et al, 2006;Eanes et al, 2006;Eanes et al, 2008;Merritt et al, 2009). In addition, D. melanogaster has been a focal model in the study of energy partitioning and aging, where differential expression of the energyproducing and energy-consuming pathways has come under intense scrutiny as a response to dietary restriction (Gershman et al, 2007;Baker and Thummel, 2007).…”

Section: Introductionmentioning

confidence: 99%

Molecular population genetics and selection in the glycolytic pathway

Eanes

2011

Journal of Experimental Biology

View full text Add to dashboard Cite

SummaryIn this review, I discuss the evidence for differential natural selection acting across enzymes in the glycolytic pathway in Drosophila. Across the genome, genes evolve at very different rates and possess markedly varying levels of molecular polymorphism, codon bias and expression variation. Discovering the underlying causes of this variation has been a challenge in evolutionary biology. It has been proposed that both the intrinsic properties of enzymes and their pathway position have direct effects on their molecular evolution, and with the genomic era the study of adaptation has been taken to the level of pathways and networks of genes and their products. Of special interest have been the energy-producing pathways. Using both population genetic and experimental approaches, our laboratory has been engaged in a study of molecular variation across the glycolytic pathway in Drosophila melanogaster and its close relatives. We have observed a pervasive pattern in which genes at the top of the pathway, especially around the intersection at glucose 6-phosphate, show evidence for both contemporary selection, in the form of latitudinal allele clines, and inter-specific selection, in the form of elevated levels of amino acid substitutions between species. To further explore this question, future work will require corroboration in other species, expansion into tangential pathways, and experimental work to better characterize metabolic control through the pathway and to examine the pleiotropic effects of these genes on other traits and fitness components.

show abstract

“…It has been shown that PCK1 is involved in the processes of small molecule biochemistry, carbohydrate metabolism, molecular transport, and response to drugs including 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD), 3H-1,2-dithiole-3-thione (D3T), and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) [63]. MDH1 (malate dehydrogenase 1) in this pathway has been reported to be relevant with drug toxicity [64, 65]. Another gene in this pathway worth mentioning is AQP1 (Aquaporin-1), which was highly expressed in endothelial cell membranes and involved in water transfer across or into these cells.…”

Section: Resultsmentioning

confidence: 99%

Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

Lei

Zheng

et al. 2013

BioMed Research International

View full text Add to dashboard Cite

Drug combinatorial therapy could be more effective in treating some complex diseases than single agents due to better efficacy and reduced side effects. Although some drug combinations are being used, their underlying molecular mechanisms are still poorly understood. Therefore, it is of great interest to deduce a novel drug combination by their molecular mechanisms in a robust and rigorous way. This paper attempts to predict effective drug combinations by a combined consideration of: (1) chemical interaction between drugs, (2) protein interactions between drugs' targets, and (3) target enrichment of KEGG pathways. A benchmark dataset was constructed, consisting of 121 confirmed effective combinations and 605 random combinations. Each drug combination was represented by 465 features derived from the aforementioned three properties. Some feature selection techniques, including Minimum Redundancy Maximum Relevance and Incremental Feature Selection, were adopted to extract the key features. Random forest model was built with its performance evaluated by 5-fold cross-validation. As a result, 55 key features providing the best prediction result were selected. These important features may help to gain insights into the mechanisms of drug combinations, and the proposed prediction model could become a useful tool for screening possible drug combinations.

show abstract

Direct Evidence That Genetic Variation in Glycerol-3-Phosphate and Malate Dehydrogenase Genes (Gpdh and Mdh1) Affects Adult Ethanol Tolerance in Drosophila melanogaster

Cited by 20 publications

References 44 publications

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Molecular population genetics and selection in the glycolytic pathway

Prediction of Effective Drug Combinations by Chemical Interaction, Protein Interaction and Target Enrichment of KEGG Pathways

Contact Info

Product

Resources

About