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Metabolites, Volume 3, Issue 4 (December 2013), Pages 853-1129

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Research

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Open AccessArticle A Computational Framework for High-Throughput Isotopic Natural Abundance Correction of Omics-Level Ultra-High Resolution FT-MS Datasets
Metabolites 2013, 3(4), 853-866; doi:10.3390/metabo3040853
Received: 21 July 2013 / Revised: 26 August 2013 / Accepted: 10 September 2013 / Published: 25 September 2013
Cited by 2 | PDF Full-text (1000 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
New metabolomics applications of ultra-high resolution and accuracy mass spectrometry can provide thousands of detectable isotopologues, with the number of potentially detectable isotopologues increasing exponentially with the number of stable isotopes used in newer isotope tracing methods like stable isotope-resolved metabolomics (SIRM) [...] Read more.
New metabolomics applications of ultra-high resolution and accuracy mass spectrometry can provide thousands of detectable isotopologues, with the number of potentially detectable isotopologues increasing exponentially with the number of stable isotopes used in newer isotope tracing methods like stable isotope-resolved metabolomics (SIRM) experiments. This huge increase in usable data requires software capable of correcting the large number of isotopologue peaks resulting from SIRM experiments in a timely manner. We describe the design of a new algorithm and software system capable of handling these high volumes of data, while including quality control methods for maintaining data quality. We validate this new algorithm against a previous single isotope correction algorithm in a two-step cross-validation. Next, we demonstrate the algorithm and correct for the effects of natural abundance for both 13C and 15N isotopes on a set of raw isotopologue intensities of UDP-N-acetyl-D-glucosamine derived from a 13C/15N-tracing experiment. Finally, we demonstrate the algorithm on a full omics-level dataset. Full article
(This article belongs to the Special Issue Data Processing in Metabolomics)
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Open AccessArticle Comparative Pharmacokinetics of Naringin in Rat after Oral Administration of Chaihu-Shu-Gan-San Aqueous Extract and Naringin Alone
Metabolites 2013, 3(4), 867-880; doi:10.3390/metabo3040867
Received: 12 July 2013 / Revised: 20 August 2013 / Accepted: 11 September 2013 / Published: 30 September 2013
Cited by 3 | PDF Full-text (716 KB) | HTML Full-text | XML Full-text
Abstract
Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine (TCM) formula containing seven herbal medicines, has been used in the clinical treatment of gastritis, peptic ulcer, irritable bowel syndrome and depression in China. In order to explore the interaction between naringin and other constituents in [...] Read more.
Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine (TCM) formula containing seven herbal medicines, has been used in the clinical treatment of gastritis, peptic ulcer, irritable bowel syndrome and depression in China. In order to explore the interaction between naringin and other constituents in CSGS, the pharmacokinetic difference of naringin in rats after oral administration of CSGS aqueous extract and naringin alone was investigated. The pharmacokinetic parameters of naringin in rats were achieved by quantification of its aglycone, naringenin by LC-MS/MS method. The double peaks phenomenon was observed in both serum profiles of rats after orally administered CSGS aqueous extract and naringin alone. However, the T1/2b was significantly decreased in rats given CSGS aqueous extract compared with naringin alone, and the mean residence time (MRT) and the area under the serum concentration–time curve (AUC0-τ) were higher than those of naringin, which indicated that naringin in CSGS had higher bioavailability, longer term efficacy and somewhat faster metabolism and excretion than those of naringin. The results suggested that certain ingredients co-exist in CSGS could influence pharmacokinetic behavior of naringin. This also provides a reference for human studies. Full article
Open AccessArticle Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains
Metabolites 2013, 3(4), 881-911; doi:10.3390/metabo3040881
Received: 28 June 2013 / Revised: 23 September 2013 / Accepted: 25 September 2013 / Published: 11 October 2013
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Abstract
Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common [...] Read more.
Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common metabolic markers affected by CR is still lacking. Using a system biology approach comprising metabonomics and liver transcriptomics we revealed the effect of CR across multiple mouse strains (129S1/SvlmJ, C57BL6/J, C3H/HeJ, CBA/J, DBA/2J, JC3F1/J). Oligonucleotide microarrays identified 76 genes as differentially expressed in all six strains confirmed. These genes were subjected to quantitative RT-PCR analysis in the C57BL/6J mouse strain, and a CR-induced change expression was confirmed for 14 genes. To fully depict the metabolic pathways affected by CR and complement the changes observed through differential gene expression, the metabolome of C57BL6/J was further characterized in liver tissues, urine and plasma levels using a combination or targeted mass spectrometry and proton nuclear magnetic resonance spectroscopy. Overall, our integrated approach commonly confirms that energy metabolism, stress response, lipids regulators and the insulin/IGF-1 are key determinants factors involved in CR regulation. Full article
(This article belongs to the Special Issue Integrative Metabolomics)
Open AccessArticle A Rapid Method for the Extraction and Analysis of Carotenoids and Other Hydrophobic Substances Suitable for Systems Biology Studies with Photosynthetic Bacteria
Metabolites 2013, 3(4), 912-930; doi:10.3390/metabo3040912
Received: 23 August 2013 / Revised: 26 September 2013 / Accepted: 27 September 2013 / Published: 11 October 2013
Cited by 1 | PDF Full-text (1575 KB) | HTML Full-text | XML Full-text
Abstract
A simple, rapid, and inexpensive extraction method for carotenoids and other non-polar compounds present in phototrophic bacteria has been developed. The method, which has been extensively tested on the phototrophic purple non-sulphur bacterium Rhodospirillum rubrum, is suitable for extracting large numbers [...] Read more.
A simple, rapid, and inexpensive extraction method for carotenoids and other non-polar compounds present in phototrophic bacteria has been developed. The method, which has been extensively tested on the phototrophic purple non-sulphur bacterium Rhodospirillum rubrum, is suitable for extracting large numbers of samples, which is common in systems biology studies, and yields material suitable for subsequent analysis using HPLC and mass spectroscopy. The procedure is particularly suitable for carotenoids and other terpenoids, including quinones, bacteriochlorophyll a and bacteriopheophytin a, and is also useful for the analysis of polar phospholipids. The extraction procedure requires only a single step extraction with a hexane/methanol/water mixture, followed by HPLC using a Spherisorb C18 column, with a mobile phase consisting of acetone-water and a non-linear gradient of 50%–100% acetone. The method was employed for examining the carotenoid composition observed during microaerophilic growth of R. rubrum strains, and was able to determine 18 carotenoids, 4 isoprenoid-quinones, bacteriochlorophyll a and bacteriopheophytin a as well as four different phosphatidylglycerol species of different acyl chain compositions. The analytical procedure was used to examine the dynamics of carotenoid biosynthesis in the major and minor pathways operating simultaneously in a carotenoid biosynthesis mutant of R. rubrum. Full article
Open AccessArticle Counting and Correcting Thermodynamically Infeasible Flux Cycles in Genome-Scale Metabolic Networks
Metabolites 2013, 3(4), 946-966; doi:10.3390/metabo3040946
Received: 6 August 2013 / Revised: 18 September 2013 / Accepted: 24 September 2013 / Published: 14 October 2013
Cited by 8 | PDF Full-text (595 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Thermodynamics constrains the flow of matter in a reaction network to occur through routes along which the Gibbs energy decreases, implying that viable steady-state flux patterns should be void of closed reaction cycles. Identifying and removing cycles in large reaction networks can [...] Read more.
Thermodynamics constrains the flow of matter in a reaction network to occur through routes along which the Gibbs energy decreases, implying that viable steady-state flux patterns should be void of closed reaction cycles. Identifying and removing cycles in large reaction networks can unfortunately be a highly challenging task from a computational viewpoint. We propose here a method that accomplishes it by combining a relaxation algorithm and a Monte Carlo procedure to detect loops, with ad hoc rules (discussed in detail) to eliminate them. As test cases, we tackle (a) the problem of identifying infeasible cycles in the E. coli metabolic network and (b) the problem of correcting thermodynamic infeasibilities in the Flux-Balance-Analysis solutions for 15 human cell-type-specific metabolic networks. Results for (a) are compared with previous analyses of the same issue, while results for (b) are weighed against alternative methods to retrieve thermodynamically viable flux patterns based on minimizing specific global quantities. Our method, on the one hand, outperforms previous techniques and, on the other, corrects loopy solutions to Flux Balance Analysis. As a byproduct, it also turns out to be able to reveal possible inconsistencies in model reconstructions. Full article
(This article belongs to the Special Issue Data Processing in Metabolomics)
Open AccessArticle Off-the-Vine Ripening of Tomato Fruit Causes Alteration in the Primary Metabolite Composition
Metabolites 2013, 3(4), 967-978; doi:10.3390/metabo3040967
Received: 14 August 2013 / Revised: 22 September 2013 / Accepted: 27 September 2013 / Published: 16 October 2013
Cited by 4 | PDF Full-text (427 KB) | HTML Full-text | XML Full-text
Abstract
The influence of postharvest fruit ripening in the composition of metabolites, transcripts and enzymes in tomato (Solanum lycopersicum L.) is poorly understood. The goal of this work was to study the changes in the metabolite composition of the tomato fruit ripened [...] Read more.
The influence of postharvest fruit ripening in the composition of metabolites, transcripts and enzymes in tomato (Solanum lycopersicum L.) is poorly understood. The goal of this work was to study the changes in the metabolite composition of the tomato fruit ripened off-the-vine using the cultivar Micro-Tom as model system. Proton nuclear magnetic resonance (1H NMR) was used for analysis of the metabolic profile of tomato fruits ripened on- and off-the-vine. Significant differences under both ripening conditions were observed principally in the contents of fructose, glucose, aspartate and glutamate. Transcript levels and enzyme activities of -amino butyrate transaminase (EC 2.6.1.19) and glutamate decarboxylase (EC 4.1.1.15) showed differences in fruits ripened under these two conditions. These data indicate that the contents of metabolites involved in primary metabolism, and conferring the palatable properties of fruits, are altered when fruits are ripened off-the-vine. Full article
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Open AccessArticle Limited Influence of Oxygen on the Evolution of Chemical Diversity in Metabolic Networks
Metabolites 2013, 3(4), 979-992; doi:10.3390/metabo3040979
Received: 31 July 2013 / Revised: 9 October 2013 / Accepted: 11 October 2013 / Published: 16 October 2013
Cited by 3 | PDF Full-text (317 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Oxygen is thought to promote species and biomolecule diversity. Previous studies have suggested that oxygen expands metabolic networks by acquiring metabolites with different chemical properties (higher hydrophobicity, for example). However, such conclusions are typically based on biased evaluation, and are therefore non-conclusive. [...] Read more.
Oxygen is thought to promote species and biomolecule diversity. Previous studies have suggested that oxygen expands metabolic networks by acquiring metabolites with different chemical properties (higher hydrophobicity, for example). However, such conclusions are typically based on biased evaluation, and are therefore non-conclusive. Thus, we re-investigated the effect of oxygen on metabolic evolution using a phylogenetic comparative method and metadata analysis to reduce the bias as much as possible. Notably, we found no difference in metabolic network expansion between aerobes and anaerobes when evaluating phylogenetic relationships. Furthermore, we showed that previous studies have overestimated or underestimated the degrees of differences in the chemical properties (e.g., hydrophobicity) between oxic and anoxic metabolites in metabolic networks of unicellular organisms; however, such overestimation was not observed when considering the metabolic networks of multicellular organisms. These findings indicate that the contribution of oxygen to increased chemical diversity in metabolic networks is lower than previously thought; rather, phylogenetic signals and cell-cell communication result in increased chemical diversity. However, this conclusion does not contradict the effect of oxygen on metabolic evolution; instead, it provides a deeper understanding of how oxygen contributes to metabolic evolution despite several limitations in data analysis methods. Full article
Open AccessArticle 2-Hydrazinoquinoline as a Derivatization Agent for LC-MS-Based Metabolomic Investigation of Diabetic Ketoacidosis
Metabolites 2013, 3(4), 993-1010; doi:10.3390/metabo3040993
Received: 31 August 2013 / Revised: 21 September 2013 / Accepted: 10 October 2013 / Published: 31 October 2013
Cited by 8 | PDF Full-text (730 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Short-chain carboxylic acids, aldehydes and ketones are products and regulators of many important metabolic pathways. Their levels in biofluids and tissues reflect the status of specific metabolic reactions, the homeostasis of the whole metabolic system and the wellbeing of a biological entity. [...] Read more.
Short-chain carboxylic acids, aldehydes and ketones are products and regulators of many important metabolic pathways. Their levels in biofluids and tissues reflect the status of specific metabolic reactions, the homeostasis of the whole metabolic system and the wellbeing of a biological entity. In this study, the use of 2-hydrazinoquinoline (HQ) as a novel derivatization agent was explored and optimized for simultaneous liquid chromatography-mass spectrometry (LC-MS) analysis of carboxylic acids, aldehydes and ketones in biological samples. The formation of carboxylic acid derivative is attributed to the esterification reaction between HQ and a carboxyl group, while the production of aldehyde and ketone derivatives is through the formation of Schiff bases between HQ and a carbonyl group. The compatibility of HQ with biological samples was demonstrated by derivatizing urine, serum and liver extract samples. Using this HQ-based approach, the kinetics of type 1 diabetes-induced metabolic changes was characterized by the LC-MS-based metabolomic analysis of urine samples from streptozotocin (STZ)-treated mice. Subsequently, carboxylic acid, aldehyde and ketone metabolites associated with STZ-elicited disruption of nutrient and energy metabolism were conveniently identified and elucidated. Overall, HQ derivatization of carboxylic acids, aldehydes and ketones could serve as a useful tool for the LC-MS-based metabolomic investigation of endogenous metabolism. Full article
(This article belongs to the Special Issue Response to Environment and Stress Metabolism)
Open AccessArticle Studies of Secondary Melanoma on C57BL/6J Mouse Liver Using 1H NMR Metabolomics
Metabolites 2013, 3(4), 1011-1035; doi:10.3390/metabo3041011
Received: 23 August 2013 / Revised: 24 September 2013 / Accepted: 10 October 2013 / Published: 31 October 2013
Cited by 6 | PDF Full-text (722 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
NMR metabolomics, consisting of solid state high resolution magic angle spinning (HR-MAS) 1H-NMR, liquid state high resolution 1H-NMR, and principal components analysis (PCA) has been used to study secondary metastatic B16-F10 melanoma in C57BL/6J mouse liver. The melanoma group can [...] Read more.
NMR metabolomics, consisting of solid state high resolution magic angle spinning (HR-MAS) 1H-NMR, liquid state high resolution 1H-NMR, and principal components analysis (PCA) has been used to study secondary metastatic B16-F10 melanoma in C57BL/6J mouse liver. The melanoma group can be differentiated from its control group by PCA analysis of the estimates of absolute concentrations from liquid state 1H-NMR spectra on liver tissue extracts or by the estimates of absolute peak intensities of metabolites from 1H HR-MAS-NMR data on intact liver tissues. In particular, we found that the estimates of absolute concentrations of glutamate, creatine, fumarate and cholesterol are elevated in the melanoma group as compared to controls, while the estimates of absolute concentrations of succinate, glycine, glucose, and the family of linear lipids including long chain fatty acids, total choline and acyl glycerol are decreased. The ratio of glycerophosphocholine (GPC) to phosphocholine (PCho) is increased by about 1.5 fold in the melanoma group, while the estimate of absolute concentration of total choline is actually lower in melanoma mice. These results suggest the following picture in secondary melanoma metastasis: Linear lipid levels are decreased by beta oxidation in the melanoma group, which contributes to an increase in the synthesis of cholesterol, and also provides an energy source input for TCA cycle. These findings suggest a link between lipid oxidation, the TCA cycle and the hypoxia-inducible factors (HIF) signal pathway in tumor metastases. Thus, this study indicates that the metabolic profile derived from NMR analysis can provide a valuable bio-signature of malignancy and cell hypoxia in metastatic melanoma. Full article
(This article belongs to the Special Issue NMR-based Metabolomics and Its Application)
Open AccessArticle Computational Analyses of Spectral Trees from Electrospray Multi-Stage Mass Spectrometry to Aid Metabolite Identification
Metabolites 2013, 3(4), 1036-1050; doi:10.3390/metabo3041036
Received: 6 August 2013 / Revised: 7 October 2013 / Accepted: 16 October 2013 / Published: 31 October 2013
Cited by 5 | PDF Full-text (351 KB) | HTML Full-text | XML Full-text
Abstract
Mass spectrometry coupled with chromatography has become the major technical platform in metabolomics. Aided by peak detection algorithms, the detected signals are characterized by mass-over-charge ratio (m/z) and retention time. Chemical identities often remain elusive for the majority of the [...] Read more.
Mass spectrometry coupled with chromatography has become the major technical platform in metabolomics. Aided by peak detection algorithms, the detected signals are characterized by mass-over-charge ratio (m/z) and retention time. Chemical identities often remain elusive for the majority of the signals. Multi-stage mass spectrometry based on electrospray ionization (ESI) allows collision-induced dissociation (CID) fragmentation of selected precursor ions. These fragment ions can assist in structural inference for metabolites of low molecular weight. Computational investigations of fragmentation spectra have increasingly received attention in metabolomics and various public databases house such data. We have developed an R package “iontree” that can capture, store and analyze MS2 and MS3 mass spectral data from high throughput metabolomics experiments. The package includes functions for ion tree construction, an algorithm (distMS2) for MS2 spectral comparison, and tools for building platform-independent ion tree (MS2/MS3) libraries. We have demonstrated the utilization of the package for the systematic analysis and annotation of fragmentation spectra collected in various metabolomics platforms, including direct infusion mass spectrometry, and liquid chromatography coupled with either low resolution or high resolution mass spectrometry. Assisted by the developed computational tools, we have demonstrated that spectral trees can provide informative evidence complementary to retention time and accurate mass to aid with annotating unknown peaks. These experimental spectral trees once subjected to a quality control process, can be used for querying public MS2 databases or de novo interpretation. The putatively annotated spectral trees can be readily incorporated into reference libraries for routine identification of metabolites. Full article
(This article belongs to the Special Issue Data Processing in Metabolomics)
Open AccessArticle Glycerophosphoglycerol, Beta-Alanine, and Pantothenic Acid as Metabolic Companions of Glycolytic Activity and Cell Migration in Breast Cancer Cell Lines
Metabolites 2013, 3(4), 1084-1101; doi:10.3390/metabo3041084
Received: 20 August 2013 / Revised: 16 October 2013 / Accepted: 24 October 2013 / Published: 27 November 2013
Cited by 2 | PDF Full-text (903 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In cancer research, cell lines are used to explore the molecular basis of the disease as a substitute to tissue biopsies. Breast cancer in particular is a very heterogeneous type of cancer, and different subgroups of cell lines have been established according [...] Read more.
In cancer research, cell lines are used to explore the molecular basis of the disease as a substitute to tissue biopsies. Breast cancer in particular is a very heterogeneous type of cancer, and different subgroups of cell lines have been established according to their genomic profiles and tumor characteristics. We applied GCMS metabolite profiling to five selected breast cancer cell lines and found this heterogeneity reflected on the metabolite level as well. Metabolite profiles of MCF-7 cells belonging to the luminal gene cluster proved to be more different from those of the basal A cell line JIMT-1 and the basal B cell lines MDA-MB-231, MDA-MB-435, and MDA-MB-436 with only slight differences in the intracellular metabolite pattern. Lactate release into the cultivation medium as an indicator of glycolytic activity was correlated to the metabolite profiles and physiological characteristics of each cell line. In conclusion, pantothenic acid, beta-alanine and glycerophosphoglycerol appeared to be related to the glycolytic activity designated through high lactate release. Other physiological parameters coinciding with glycolytic activity were high glyoxalase 1 (Glo1) and lactate dehydrogenase (LDH) enzyme activity as well as cell migration as an additional important characteristic contributing to the aggressiveness of tumor cells. Metabolite profiles of the cell lines are comparatively discussed with respect to known biomarkers of cancer progression. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
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Open AccessArticle Global LC/MS Metabolomics Profiling of Calcium Stressed and Immunosuppressant Drug Treated Saccharomyces cerevisiae
Metabolites 2013, 3(4), 1102-1117; doi:10.3390/metabo3041102
Received: 15 October 2013 / Revised: 20 November 2013 / Accepted: 25 November 2013 / Published: 6 December 2013
Cited by 4 | PDF Full-text (992 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Previous studies have shown that calcium stressed Saccharomyces cerevisiae, challenged with immunosuppressant drugs FK506 and Cyclosporin A, responds with comprehensive gene expression changes and attenuation of the generalized calcium stress response. Here, we describe a global metabolomics workflow for investigating the [...] Read more.
Previous studies have shown that calcium stressed Saccharomyces cerevisiae, challenged with immunosuppressant drugs FK506 and Cyclosporin A, responds with comprehensive gene expression changes and attenuation of the generalized calcium stress response. Here, we describe a global metabolomics workflow for investigating the utility of tracking corresponding phenotypic changes. This was achieved by efficiently analyzing relative abundance differences between intracellular metabolite pools from wild-type and calcium stressed cultures, with and without prior immunosuppressant drugs exposure. We used pathway database content from WikiPathways and YeastCyc to facilitate the projection of our metabolomics profiling results onto biological pathways. A key challenge was to increase the coverage of the detected metabolites. This was achieved by applying both reverse phase (RP) and aqueous normal phase (ANP) chromatographic separations, as well as electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) sources for detection in both ion polarities. Unsupervised principle component analysis (PCA) and ANOVA results revealed differentiation between wild-type controls, calcium stressed and immunosuppressant/calcium challenged cells. Untargeted data mining resulted in 247 differentially expressed, annotated metabolites, across at least one pair of conditions. A separate, targeted data mining strategy identified 187 differential, annotated metabolites. All annotated metabolites were subsequently mapped onto curated pathways from YeastCyc and WikiPathways for interactive pathway analysis and visualization. Dozens of pathways showed differential responses to stress conditions based on one or more matches to the list of annotated metabolites or to metabolites that had been identified further by MS/MS. The purine salvage, pantothenate and sulfur amino acid pathways were flagged as being enriched, which is consistent with previously published literature for transcriptomics analysis. Thus, broad discovery-based data mining combined with targeted pathway projections can be an important asset for rapidly distilling, testing and evaluating a large amount of information for further investigation. Full article
(This article belongs to the Special Issue Microbial Metabolomics)
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Open AccessArticle Metabolomic Analysis of Fission Yeast at the Onset of Nitrogen Starvation
Metabolites 2013, 3(4), 1118-1129; doi:10.3390/metabo3041118
Received: 8 November 2013 / Revised: 3 December 2013 / Accepted: 6 December 2013 / Published: 13 December 2013
Cited by 6 | PDF Full-text (1069 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Microorganisms naturally respond to changes in nutritional conditions by adjusting their morphology and physiology. The cellular response of the fission yeast S. pombe to nitrogen starvation has been extensively studied. Here, we report time course metabolomic analysis during one hour immediately after [...] Read more.
Microorganisms naturally respond to changes in nutritional conditions by adjusting their morphology and physiology. The cellular response of the fission yeast S. pombe to nitrogen starvation has been extensively studied. Here, we report time course metabolomic analysis during one hour immediately after nitrogen starvation, prior to any visible changes in cell morphology except for a tiny increase of cell length per division cycle. We semi-quantitatively measured 75 distinct metabolites, 60% of which changed their level over 2-fold. The most significant changes occurred during the first 15 min, when trehalose, 2-oxoglutarate, and succinate increased, while purine biosynthesis intermediates rapidly diminished. At 30–60 min, free amino acids decreased, although several modified amino acids—including hercynylcysteine sulfoxide, a precursor to ergothioneine—accumulated. Most high-energy metabolites such as ATP, S-adenosyl-methionine or NAD+ remained stable during the whole time course. Very rapid metabolic changes such as the shut-off of purine biosynthesis and the rise of 2-oxoglutarate and succinate can be explained by the depletion of NH4Cl. The changes in the levels of key metabolites, particularly 2-oxoglutarate, might represent an important mechanistic step to trigger subsequent cellular regulations. Full article
(This article belongs to the Special Issue Microbial Metabolomics)

Review

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Open AccessReview The Complex Role of Branched Chain Amino Acids in Diabetes and Cancer
Metabolites 2013, 3(4), 931-945; doi:10.3390/metabo3040931
Received: 31 July 2013 / Revised: 3 September 2013 / Accepted: 8 October 2013 / Published: 14 October 2013
Cited by 18 | PDF Full-text (253 KB) | HTML Full-text | XML Full-text
Abstract
The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched [...] Read more.
The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched chain amino acids (BCAAs) appear to play a significant role in both of these diseases. These essential amino acids participate in a wide variety of metabolic pathways, but it is now recognized that they are also critical regulators of a number of cell signaling pathways. An elevation in branched chain amino acids has recently been shown to be significantly correlated with insulin resistance and the future development of diabetes. In cancer, the normal demands for BCAAs are complicated by the conflicting needs of the tumor and the host. The severe muscle wasting syndrome experience by many cancer patients, known as cachexia, has motivated the use of BCAA supplementation. The desired improvement in muscle mass must be balanced by the need to avoid providing materials for tumor proliferation. A better understanding of the complex functions of BCAAs could lead to their use as biomarkers of the progression of certain cancers in diabetic patients. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
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Open AccessReview Metformin: On Ongoing Journey across Diabetes, Cancer Therapy and Prevention
Metabolites 2013, 3(4), 1051-1075; doi:10.3390/metabo3041051
Received: 10 July 2013 / Revised: 27 September 2013 / Accepted: 31 October 2013 / Published: 7 November 2013
Cited by 6 | PDF Full-text (320 KB) | HTML Full-text | XML Full-text
Abstract
Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also [...] Read more.
Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide. Full article
(This article belongs to the Special Issue Cancer Metabolomics)
Open AccessReview Metabolomics for Secondary Metabolite Research
Metabolites 2013, 3(4), 1076-1083; doi:10.3390/metabo3041076
Received: 24 September 2013 / Revised: 25 October 2013 / Accepted: 1 November 2013 / Published: 11 November 2013
Cited by 7 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
Abstract
Metabolomics, the global characterization of metabolite profiles, is becoming an increasingly powerful tool for research on secondary metabolite discovery and production. In this review we discuss examples of recent technological advances and biological applications of metabolomics in the search for chemical novelty [...] Read more.
Metabolomics, the global characterization of metabolite profiles, is becoming an increasingly powerful tool for research on secondary metabolite discovery and production. In this review we discuss examples of recent technological advances and biological applications of metabolomics in the search for chemical novelty and the engineered production of bioactive secondary metabolites. Full article
(This article belongs to the Special Issue Microbial Metabolomics)
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