NADPH-generating systems in bacteria and archaea

Spaans, Sebastiaan K.; Weusthuis, Ruud A.; Oost, John eVan Der; Kengen, Servé W. M.

doi:10.3389/fmicb.2015.00742

Cited by 280 publications

(240 citation statements)

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“…Both our uniformly labeled [U- 13 C 6 ]glucose and dual-labeled [ 13 C 1,2 ]glucose experiments clearly demonstrate a strong increase in the PPP activity upon PTL treatment, presumably for the production of NADPH. Notably, NADPH is also known to be produced by other metabolic steps including the conversion of malate into pyruvate catalyzed by the NADP-dependent malic enzyme 1 (ME1) and the conversion of citrate into ␣-ke- OCTOBER 14, 2016 • VOLUME 291 • NUMBER 42 toglutarate catalyzed by the isocitrate dehydrogenase 1 enzyme (IDH1) (46). In our current study, although we cannot exclude the possibility that these processes may also contribute to NADPH generation, given the strong increase of the PPP activity shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

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Section: Discussionmentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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“…Glucose-6-phosphate dehydrogenase, for example, is one of the primary reactions forming NADPH in bacteria (19). The hydrogen transferred to NADP + comes from glucose.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen isotopes in individual amino acids reflect differentiated pools of hydrogen from food and water in Escherichia coli

Fogel

Griffin

Newsome

2016

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

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Hydrogen isotope (δ 2 H) analysis is widely used in animal ecology to study continental-scale movement because δ 2 H can trace precipitation and climate. To understand the biochemical underpinnings of how hydrogen is incorporated into biomolecules, we measured the δ 2 H of individual amino acids (AAs) in Escherichia coli cultured in glucose-based or complex tryptone-based media in waters with δ 2 H values ranging from −55‰ to +1,070‰. The δ 2 H values of AAs in tryptone spanned a range of ∼250‰. In E. coli grown on glucose, the range of δ 2 H among AAs was nearly 200‰. The relative distributions of δ 2 H of AAs were upheld in cultures grown in enriched waters. In E. coli grown on tryptone, the δ 2 H of nonessential AAs varied linearly with the δ 2 H of media water, whereas δ 2 H of essential AAs was nearly identical to δ 2 H in diet. Model calculations determined that as much as 46% of hydrogen in some nonessential AAs originated from water, whereas no more than 12% of hydrogen in essential AAs originated from water. These findings demonstrate that δ 2 H can route directly at the molecular level. We conclude that the patterns and distributions in δ 2 H of AAs are determined through biosynthetic reactions, suggesting that δ 2 H could become a new biosignature for studying novel microbial pathways. Our results also show that δ 2 H of AAs in an organism's tissues provides a dual tracer for food and environmental (e.g., drinking) water.hydrogen isotopes | aminio acids | diet | Escherichia coli

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“…Citric acid and its lyase are the intermediate product and critical enzyme of the tricarboxylic acid (TCA) cycle, respectively. The TCA cycle is critical for carbon metabolism and energy generation [27]. In a previous study, a lyase gene mutant E. tarda was unable to proliferate and cause fatal infection in a fish model [28].…”

Section: Discussionmentioning

confidence: 99%

Deep Sequencing Analysis of the Eha-Regulated Transcriptome of Edwardsiella tarda Following Acidification

Gao¹,

Liu²,

Y³

et al. 2017

Metabolomics

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In response to stresses in host cells, several transcriptional regulators described in E. tarda can activate a series of interacting signaling networks [13]. Our previous study found that Eha is a transcriptional regulator of the MarR family [14]. Eha could also regulate the mRNA levels of some surface structures like the type III secretion system to affect the intracellular survival and virulence of E. tarda [15]. We found that Eha is required for the bacteria to resist oxidative stress and survive in macrophages [16]. As the type III secretion system in E. tarda disturbs the formation of the acidic environment in phagosomes [9], we hypothesized that Eha may be required for the bacteria to resist the acid stress in macrophages.Next generation sequencing technology, RNA-Sequencing (RNAseq), has been used in bacterial transcriptome analyses [17]. We performed a high-throughput RNA-seq study, which has firstly been applied in the transcriptome analyses of E. tarda, to detect and compare the differentially-expressed genes (DEGs) between the ET13 wild type bacterium and its eha mutant following exposure to acid stress. Our present study provides the gene expression profiles and sheds light on the molecular mechanism by which E. tarda survival is regulated by Eha under acid stress conditions. Key words: Eha gene; E. tarda; RNA-seq; Macrophage; Acidification IntroductionEdwardsiella tarda (E. tarda) is a facultative intracellular pathogen that causes Edwardsiellosis in freshwater and marine fish worldwide and a Salmonella-like gastroenteritis in humans [1,2]. Macrophages play critical roles in the defense against invading bacteria. Zhang et al. showed that E. tarda can utilize macrophages as a niche to initiate its virulence and spread systemic infections [3]. However, there are various stressful conditions such as nutrition deprivation, low pH and high reactive oxygen species (ROS) present in the intracellular niche of the phagocytes [4]. There are the strategies that virulent bacterial strains use to evade phagosomes and escape into the cytosol to enable their survival in the cells [5]. E. tarda could live and multiply in macrophages, and escape from the cells. It is important for the bacterium to lead to extra intestinal diseases and systemic infections [6]. E. tarda is capable to detoxify ROS by generating catalase (Kat) and superoxide dismutase (Sod) to survive within macrophages [7,8]. Okuda et al. suggested that the bacterial type III secretion system is able to interfere with the formation of acid stress in phagosomes to facilitate its replication in macrophages [9]. However, little other information is available about how E. tarda is affected by an acidic environment.Some findings have been reported about the changes that occur in other intracellular pathogens in response to acid stress in macrophages. For example, Rathman et al. suggested that an acidic environment in Salmonella-containing phagosomes is necessary for the bacterial survival and replication within the macrophage [10]. Supporting this finding, ...

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NADPH-generating systems in bacteria and archaea

Cited by 280 publications

References 383 publications

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Hydrogen isotopes in individual amino acids reflect differentiated pools of hydrogen from food and water in Escherichia coli

Deep Sequencing Analysis of the Eha-Regulated Transcriptome of Edwardsiella tarda Following Acidification

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