http://www.mdpi.com/journal/metabolites Latest open access articles published in Metabolites at http://www.mdpi.com/journal/metabolites http://www.mdpi.com/2218-1989/2/2/337 A complex structurally diverse series of eicosanoids arises from the metabolism of arachidonic acid. The metabolic profile is further complicated by the enantioselectivity of eicosanoid formation and the variety of regioisomers that arise. In order to investigate the metabolism of arachidonic acid in vitro or in vivo, targeted methods are advantageous in order to distinguish between the complex isomeric mixtures that can arise by different metabolic pathways. Over the last several years this targeted approach has become more popular, although there are still relatively few examples where chiral targeted approaches have been employed to directly analyze complex enantiomeric mixtures. To efficiently conduct targeted eicosanoid analyses, LC separations are coupled with collision induced dissociation (CID) and tandem mass spectrometry (MS/MS). Product ion profiles are often diagnostic for particular regioisomers. The highest sensitivity that can be achieved involves the use of selected reaction monitoring/mass spectrometry (SRM/MS); whereas the highest specificity is obtained with an SRM transitions between an intense parent ion, which contains the intact molecule (M) and a structurally significant product ion. This review article provides an overview of arachidonic acid metabolism and targeted chiral methods that have been utilized for the analysis of the structurally diverse eicosanoids that arise. http://www.mdpi.com/2218-1989/2/2/337 Fri, 20 Apr 2012 00:00:00 CEST Metabolites 2012-04-20 2 2 Review 337 365 2218-1989 Targeted Chiral Analysis of Bioactive Arachidonic Acid Metabolites Using Liquid-Chromatography-Mass Spectrometry 2012-04-20 doi: 10.3390/metabo2020337 Clementina Mesaros Ian A. Blair http://www.mdpi.com/2218-1989/2/2/303 Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed. http://www.mdpi.com/2218-1989/2/2/303 Mon, 16 Apr 2012 00:00:00 CEST Metabolites 2012-04-16 2 2 Review 303 336 2218-1989 A Historical Overview of Natural Products in Drug Discovery 2012-04-16 doi: 10.3390/metabo2020303 Daniel A. Dias Sylvia Urban Ute Roessner http://www.mdpi.com/2218-1989/2/2/292 AICAR (5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate) is a natural metabolic intermediate of purine biosynthesis that is present in all organisms. In yeast, AICAR plays important regulatory roles under physiological conditions, notably through its direct interactions with transcription factors. In humans, AICAR accumulates in several metabolic diseases, but its contribution to the symptoms has not yet been elucidated. Further, AICAR has highly promising properties which have been recently revealed. Indeed, it enhances endurance of sedentary mice. In addition, it has antiproliferative effects notably by specifically inducing apoptosis of aneuploid cells. Some of the effects of AICAR are due to its ability to stimulate the AMP-activated protein kinase but some others are not. It is consequently clear that AICAR affects multiple targets although only few of them have been identified so far. This review proposes an overview of the field and suggests future directions. http://www.mdpi.com/2218-1989/2/2/292 Fri, 23 Mar 2012 00:00:00 CET Metabolites 2012-03-23 2 2 Review 292 302 2218-1989 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects 2012-03-23 doi: 10.3390/metabo2020292 Bertrand Daignan-Fornier Benoît Pinson http://www.mdpi.com/2218-1989/2/1/268 The liver has many complex physiological functions, including lipid, protein and carbohydrate metabolism, as well as bile and urea production. It detoxifies toxic substances and medicinal products. It also plays a key role in the onset and maintenance of abnormal metabolic patterns associated with various disease states, such as burns, infections and major traumas. Liver cells have been commonly used in in vitro experiments to elucidate the toxic effects of drugs and metabolic changes caused by aberrant metabolic conditions, and to improve the functions of existing systems, such as bioartificial liver. More recently, isolated liver perfusion systems have been increasingly used to characterize intrinsic metabolic changes in the liver caused by various perturbations, including systemic injury, hepatotoxin exposure and warm ischemia. Metabolic engineering tools have been widely applied to these systems to identify metabolic flux distributions using metabolic flux analysis or flux balance analysis and to characterize the topology of the networks using metabolic pathway analysis. In this context, hepatic metabolic models, together with experimental methodologies where hepatocytes or perfused livers are mainly investigated, are described in detail in this review. The challenges and opportunities are also discussed extensively. http://www.mdpi.com/2218-1989/2/1/268 Wed, 14 Mar 2012 00:00:00 CET Metabolites 2012-03-14 2 1 Review 268 291 2218-1989 Stoichiometry Based Steady-State Hepatic Flux Analysis: Computational and Experimental Aspects 2012-03-14 doi: 10.3390/metabo2010268 Mehmet A. Orman John Mattick Ioannis P. Androulakis Francois Berthiaume Marianthi G. Ierapetritou http://www.mdpi.com/2218-1989/2/1/254 Glycerophospholipids (GP) are the building blocks of cellular membranes and play essential roles in cell compartmentation, membrane fluidity or apoptosis. In addition, GPs are sources for multifunctional second messengers. Whereas the genome and proteome of the most intensively studied eukaryotic model organism, the baker’s yeast (Saccharomyces cerevisiae), are well characterized, the analysis of its lipid composition is still at the beginning. Moreover, different yeast species can be distinguished on the DNA, RNA and protein level, but it is currently unknown if they can also be differentiated by determination of their GP pattern. Therefore, the GP compositions of five different yeast strains, grown under identical environmental conditions, were elucidated using high performance liquid chromatography coupled to negative electrospray ionization-hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectrometry in single and multistage mode. Using this approach, relative quantification of more than 100 molecular species belonging to nine GP classes was achieved. The comparative lipidomic profiling of Saccharomyces cerevisiae, Saccharomyces bayanus, Kluyveromyces thermotolerans, Pichia angusta, and Yarrowia lipolytica revealed characteristic GP profiles for each strain. However, genetically related yeast strains show similarities in their GP compositions, e.g., Saccharomyces cerevisiae and Saccharomyces bayanus. http://www.mdpi.com/2218-1989/2/1/254 Fri, 02 Mar 2012 00:00:00 CET Metabolites 2012-03-02 2 1 Article 254 267 2218-1989 Comparative Lipidomic Profiling of S. cerevisiae and Four Other Hemiascomycetous Yeasts 2012-03-02 doi: 10.3390/metabo2010254 Eva-Maria Hein Heiko Hayen http://www.mdpi.com/2218-1989/2/1/242 Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system. http://www.mdpi.com/2218-1989/2/1/242 Fri, 02 Mar 2012 00:00:00 CET Metabolites 2012-03-02 2 1 Review 242 253 2218-1989 Human Metabolic Network: Reconstruction, Simulation, and Applications in Systems Biology 2012-03-02 doi: 10.3390/metabo2010242 Ming Wu Christina Chan http://www.mdpi.com/2218-1989/2/1/221 Heat is one of the most fundamental and ancient environmental stresses, and response mechanisms are found in prokaryotes and shared among most eukaryotes. In the budding yeast Saccharomyces cerevisiae, the heat stress response involves coordinated changes at all biological levels, from gene expression to protein and metabolite abundances, and to temporary adjustments in physiology. Due to its integrative multi-level-multi-scale nature, heat adaptation constitutes a complex dynamic process, which has forced most experimental and modeling analyses in the past to focus on just one or a few of its aspects. Here we review the basic components of the heat stress response in yeast and outline what has been done, and what needs to be done, to merge the available information into computational structures that permit comprehensive diagnostics, interrogation, and interpretation. We illustrate the process in particular with the coordination of two metabolic responses, namely the dramatic accumulation of the protective disaccharide trehalose and the substantial change in the profile of sphingolipids, which in turn affect gene expression. The proposed methods primarily use differential equations in the canonical modeling framework of Biochemical Systems Theory (BST), which permits the relatively easy construction of coarse, initial models even in systems that are incompletely characterized. http://www.mdpi.com/2218-1989/2/1/221 Mon, 27 Feb 2012 00:00:00 CET Metabolites 2012-02-27 2 1 Article 221 241 2218-1989 Canonical Modeling of the Multi-Scale Regulation of the Heat Stress Response in Yeast 2012-02-27 doi: 10.3390/metabo2010221 Luis L. Fonseca Po-Wei Chen Eberhard O. Voit http://www.mdpi.com/2218-1989/2/1/214 Atlantinone A has been isolated from the psychrotolerant fungus Penicillium ribeum. The exact structure of the compound was confirmed by mass spectrometric and 1- and 2D NMR experiments. Atlantinone A was originally only produced upon chemical epigenetic manipulation of P. hirayamae, however in this study the compound was found to be produced at standard growth conditions by the following species; P. solitum, P. discolor, P. commune, P. caseifulvum, P. palitans, P. novae-zeelandiae and P. monticola. A biosynthetic pathway to atlantinone A starting from andrastin A is proposed. http://www.mdpi.com/2218-1989/2/1/214 Thu, 23 Feb 2012 00:00:00 CET Metabolites 2012-02-23 2 1 Article 214 220 2218-1989 Atlantinone A, a Meroterpenoid Produced by Penicillium ribeum and Several Cheese Associated Penicillium Species 2012-02-23 doi: 10.3390/metabo2010214 Petur W. Dalsgaard Bent O. Petersen Jens Ø. Duus Christian Zidorn Jens C. Frisvad Carsten Christophersen Thomas O. Larsen http://www.mdpi.com/2218-1989/2/1/195 Shotgun lipidomics has evolved into a myriad of multi-dimensional strategies for molecular lipid characterization, including bioinformatics tools for mass spectrum interpretation and quantitative measurements to study systems-lipidomics in complex biological extracts. Taking advantage of spectral mass accuracy, scan speed and sensitivity of improved quadrupole linked time-of-flight mass analyzers, we developed a bias-free global lipid profiling acquisition technique of sequential precursor ion fragmentation called MS/MSALL. This generic information-independent tandem mass spectrometry (MS) technique consists of a Q1 stepped mass isolation window through a set mass range in small increments, fragmenting and recording all product ions and neutral losses. Through the accurate MS and MS/MS information, the molecular lipid species are resolved, including distinction of isobaric and isomeric species, and composed into more precise lipidomic outputs. The method demonstrates good reproducibility and at least 3 orders of dynamic quantification range for isomeric ceramides in human plasma. More than 400 molecular lipids in human plasma were uncovered and quantified in less than 12 min, including acquisitions in both positive and negative polarity modes. We anticipate that the performance of sequential precursor ion fragmentation both in quality and throughput will lead to the uncovering of new avenues throughout the biomedical research community, enhance biomarker discovery and provide novel information target discovery programs as it will prospectively shed new insight into affected metabolic and signaling pathways. http://www.mdpi.com/2218-1989/2/1/195 Mon, 20 Feb 2012 00:00:00 CET Metabolites 2012-02-20 2 1 Article 195 213 2218-1989 Shotgun Lipidomics by Sequential Precursor Ion Fragmentation on a Hybrid Quadrupole Time-of-Flight Mass Spectrometer 2012-02-20 doi: 10.3390/metabo2010195 Brigitte Simons Dimple Kauhanen Tuulia Sylvänne Kirill Tarasov Eva Duchoslav Kim Ekroos http://www.mdpi.com/2218-1989/2/1/178 A metabolite profiling study of the antibiotic producing bacterium Streptomyces coelicolor A3(2) has been performed. The aim of this study was to monitor intracellular metabolite pool changes occurring as strains of S. coelicolor react to nutrient depletion with metabolic re-modeling, so-called metabolic switching, and transition from growth to secondary metabolite production phase. Two different culture media were applied, providing depletion of the key nutrients phosphate and L-glutamate, respectively, as the triggers for metabolic switching. Targeted GC-MS and LC-MS methods were employed to quantify important primary metabolite groups like amino acids, organic acids, sugar phosphates and other phosphorylated metabolites, and nucleotides in time-course samples withdrawn from fully-controlled batch fermentations. A general decline, starting already in the early growth phase, was observed for nucleotide pools and phosphorylated metabolite pools for both the phosphate and glutamate limited cultures. The change in amino acid and organic acid pools were more scattered, especially in the phosphate limited situation while a general decrease in amino acid and non-amino organic acid pools was observed in the L-glutamate limited situation. A phoP deletion mutant showed basically the same metabolite pool changes as the wild-type strain M145 when cultivated on phosphate limited medium. This implies that the inactivation of the phoP gene has only little effect on the detected metabolite levels in the cell. The energy charge was found to be relatively constant during growth, transition and secondary metabolite production phase. The results of this study and the employed targeted metabolite profiling methodology are directly relevant for the evaluation of precursor metabolite and energy supply for both natural and heterologous production of secondary metabolites in S. coelicolor. http://www.mdpi.com/2218-1989/2/1/178 Fri, 17 Feb 2012 00:00:00 CET Metabolites 2012-02-17 2 1 Article 178 194 2218-1989 Intracellular Metabolite Pool Changes in Response to Nutrient Depletion Induced Metabolic Switching in Streptomyces coelicolor 2012-02-17 doi: 10.3390/metabo2010178 Alexander Wentzel Havard Sletta Stream Consortium Trond E. Ellingsen Per Bruheim http://www.mdpi.com/2218-1989/2/1/165 Vitis vinifera c.v. Muscat de Frontignan (grape) contains various high valuable bioactive phenolic compounds with pharmaceutical properties and industrial interest which are not fully exploited. The focus of this investigation consists in testing the effects of various biological elicitors on a non-morphogenic callus suspension culture of V. vinifera. The investigated elicitors: Indanoyl-isoleucine (IN), N-linolenoyl-L-glutamine (LG), insect saliva (IS) and malonyl coenzyme A (MCoA) were aimed at mimicking the influence of environmental pathogens on plants in their natural habitats and at provoking exogenous induction of the phenylpropanoid pathway. The elicitors’ indanoyl-isoleucine (IN), N-linolenoyl-L-glutamine (LG) and insect saliva (IS), as well as malonyl coenzyme A (MCoA), were independently inoculated to stimulate the synthesis of phenylpropanoids. All of the enhancers positively increased the concentration of phenolic compounds in grape cells. The highest concentration of phenolic acids was detected after 2 h for MCoA, after 48 h for IN and after 24 h for LG and IS respectively. At the maximum production time, treated grape cells had a 3.5-fold (MCoA), 1.6-fold (IN) and 1.5-fold (IS) higher phenolic acid content compared to the corresponding control samples. The HPLC results of grape cells showed two major resveratrol derivatives: 3-O-Glucosyl-resveratrol and 4-(3,5-dihydroxyphenyl)-phenol. Their influences of the different elicitors, time of harvest and biomass concentration (p < 0.0001) were statistically significant on the synthesis of phenolic compounds. The induction with MCoA was found to demonstrate the highest statistical effect corresponding to the strongest stress response within the phenylpropanoid pathway in grape cells. http://www.mdpi.com/2218-1989/2/1/165 Wed, 15 Feb 2012 00:00:00 CET Metabolites 2012-02-15 2 1 Article 165 177 2218-1989 Investigation of Phenolic Acids in Suspension Cultures of Vitis vinifera Stimulated with Indanoyl-Isoleucine, N-Linolenoyl-L-Glutamine, Malonyl Coenzyme A and Insect Saliva 2012-02-15 doi: 10.3390/metabo2010165 Heidi Riedel Divine N. Akumo Nay Min Min Thaw Saw Iryna Smetanska Peter Neubauer http://www.mdpi.com/2218-1989/2/1/134 Glycosphingolipids (GSLs) contain one or more sugars that are attached to a sphingolipid moiety, usually to a ceramide, but in rare cases also to a sphingoid base. A large structural heterogeneity results from differences in number, identity, linkage, and anomeric configuration of the carbohydrate residues, and also from structural differences within the hydrophobic part. GSLs form complex cell-type specific patterns, which change with the species, the cellular differentiation state, viral transformation, ontogenesis, and oncogenesis. Although GSL structures can be assigned to only a few series with a common carbohydrate core, their structural variety and the complex pattern are challenges for their elucidation and quantification by mass spectrometric techniques. We present a general overview of the application of lipidomics for GSL determination. This includes analytical procedures and instrumentation together with recent correlations of GSL molecular species with human diseases. Difficulties such as the structural complexity and the lack of standard substances for complex GSLs are discussed. http://www.mdpi.com/2218-1989/2/1/134 Thu, 02 Feb 2012 00:00:00 CET Metabolites 2012-02-02 2 1 Review 134 164 2218-1989 Lipidomics of Glycosphingolipids 2012-02-02 doi: 10.3390/metabo2010134 Hany Farwanah Thomas Kolter http://www.mdpi.com/2218-1989/2/1/100 Secondary metabolites are small molecules that show large structural diversity and a broad range of bioactivities. Some metabolites are attractive as drugs or pigments while others act as harmful mycotoxins. Filamentous fungi have the capacity to produce a wide array of secondary metabolites including polyketides. The majority of genes required for production of these metabolites are mostly organized in gene clusters, which often are silent or barely expressed under laboratory conditions, making discovery and analysis difficult. Fortunately, the genome sequences of several filamentous fungi are publicly available, greatly facilitating the establishment of links between genes and metabolites. This review covers the attempts being made to trigger the activation of polyketide metabolism in the fungal model organism Aspergillus nidulans. Moreover, it will provide an overview of the pathways where ten polyketide synthase genes have been coupled to polyketide products. Therefore, the proposed biosynthesis of the following metabolites will be presented; naphthopyrone, sterigmatocystin, aspyridones, emericellamides, asperthecin, asperfuranone, monodictyphenone/emodin, orsellinic acid, and the austinols. http://www.mdpi.com/2218-1989/2/1/100 Mon, 30 Jan 2012 00:00:00 CET Metabolites 2012-01-30 2 1 Review 100 133 2218-1989 Genetics of Polyketide Metabolism in Aspergillus nidulans 2012-01-30 doi: 10.3390/metabo2010100 Marie L. Klejnstrup Rasmus J. N. Frandsen Dorte K. Holm Morten T. Nielsen Uffe H. Mortensen Thomas O. Larsen Jakob B. Nielsen http://www.mdpi.com/2218-1989/2/1/77 The metabolic composition of plasma is affected by time passed since the last meal and by individual variation in metabolite clearance rates. Rat plasma in fed and fasted states was analyzed with liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF) for an untargeted investigation of these metabolite patterns. The dataset was used to investigate the effect of data preprocessing on biomarker selection using three different softwares, MarkerLynxTM, MZmine, XCMS along with a customized preprocessing method that performs binning of m/z channels followed by summation through retention time. Direct comparison of selected features representing the fed or fasted state showed large differences between the softwares. Many false positive markers were obtained from custom data preprocessing compared with dedicated softwares while MarkerLynxTM provided better coverage of markers. However, marker selection was more reliable with the gap filling (or peak finding) algorithms present in MZmine and XCMS. Further identification of the putative markers revealed that many of the differences between the markers selected were due to variations in features representing adducts or daughter ions of the same metabolites or of compounds from the same chemical subclasses, e.g., lyso-phosphatidylcholines (LPCs) and lyso-phosphatidylethanolamines (LPEs). We conclude that despite considerable differences in the performance of the preprocessing tools we could extract the same biological information by any of them. Carnitine, branched-chain amino acids, LPCs and LPEs were identified by all methods as markers of the fed state whereas acetylcarnitine was abundant during fasting in rats. http://www.mdpi.com/2218-1989/2/1/77 Wed, 18 Jan 2012 00:00:00 CET Metabolites 2012-01-18 2 1 Article 77 99 2218-1989 The Effect of LC-MS Data Preprocessing Methods on the Selection of Plasma Biomarkers in Fed vs. Fasted Rats 2012-01-18 doi: 10.3390/metabo2010077 Gözde Gürdeniz Mette Kristensen Thomas Skov Lars O. Dragsted http://www.mdpi.com/2218-1989/2/1/57 Lipids, such as phosphoinositides (PIPs) and diacylglycerol (DAG), are important signaling intermediates involved in cellular processes such as T cell receptor (TCR)-mediated signal transduction. Here we report identification and quantification of PIP, PIP2 and DAG from crude lipid extracts. Capitalizing on the different extraction properties of PIPs and DAGs allowed us to efficiently recover both lipid classes from one sample. Rapid analysis of endogenous signaling molecules was performed by nano-electrospray ionization tandem mass spectrometry (nano-ESI MS/MS), employing lipid class-specific neutral loss and multiple precursor ion scanning for their identification and quantification. Profiling of DAG, PIP and PIP2 molecular species in primary human T cells before and after TCR stimulation resulted in a two-fold increase in DAG levels with a shift towards 1-stearoyl-2-arachidonoyl-DAG in stimulated cells. PIP2 levels were slightly reduced, while PIP levels remained unchanged. http://www.mdpi.com/2218-1989/2/1/57 Mon, 16 Jan 2012 00:00:00 CET Metabolites 2012-01-16 2 1 Article 57 76 2218-1989 Quantification of Signaling Lipids by Nano-Electrospray Ionization Tandem Mass Spectrometry (Nano-ESI MS/MS) 2012-01-16 doi: 10.3390/metabo2010057 Mathias Haag Angelika Schmidt Timo Sachsenheimer Britta Brügger http://www.mdpi.com/2218-1989/2/1/39 Aspergillus oryzae and A. flavus are important species in industrial biotechnology and food safety and have been some of the first aspergilli to be fully genome sequenced. Bioinformatic analysis has revealed 99.5% gene homology between the two species pointing towards a large coherence in the secondary metabolite production. In this study we report on the first comparison of secondary metabolite production between the full genome sequenced strains of A. oryzae (RIB40) and A. flavus (NRRL 3357). Surprisingly, the overall chemical profiles of the two strains were mostly very different across 15 growth conditions. Contrary to previous studies we found the aflatrem precursor 13-desoxypaxilline to be a major metabolite from A. oryzae under certain growth conditions. For the first time, we additionally report A. oryzae to produce parasiticolide A and two new analogues hereof, along with four new alkaloids related to the A. flavus metabolites ditryptophenalines and miyakamides. Generally the secondary metabolite capability of A. oryzae presents several novel end products likely to result from the domestication process from A. flavus. http://www.mdpi.com/2218-1989/2/1/39 Thu, 05 Jan 2012 00:00:00 CET Metabolites 2012-01-05 2 1 Article 39 56 2218-1989 Comparative Chemistry of Aspergillus oryzae (RIB40) and A. flavus (NRRL 3357) 2012-01-05 doi: 10.3390/metabo2010039 Christian Rank Marie Louise Klejnstrup Lene Maj Petersen Sara Kildgaard Jens Christian Frisvad Charlotte Held Gotfredsen Thomas Ostenfeld Larsen http://www.mdpi.com/2218-1989/2/1/19 One decade after the genomic and the proteomic life science revolution, new ‘omics’ fields are emerging. The metabolome encompasses the entity of small molecules—Most often end products of a catalytic process regulated by genes and proteins—with the lipidome being its fat soluble subdivision. Within recent years, lipids are more and more regarded not only as energy storage compounds but also as interactive players in various cellular regulation cycles and thus attain rising interest in the bio-medical community. The field of lipidomics is, on one hand, fuelled by analytical technology advances, particularly mass spectrometry and chromatography, but on the other hand new biological questions also drive analytical technology developments. Compared to fairly standardized genomic or proteomic high-throughput protocols, the high degree of molecular heterogeneity adds a special analytical challenge to lipidomic analysis. In this review, we will take a closer look at various mass spectrometric platforms for lipidomic analysis. We will focus on the advantages and limitations of various experimental setups like ‘shotgun lipidomics’, liquid chromatography—Mass spectrometry (LC-MS) and matrix assisted laser desorption ionization-time of flight (MALDI-TOF) based approaches. We will also examine available software packages for data analysis, which nowadays is in fact the rate limiting step for most ‘omics’ workflows. http://www.mdpi.com/2218-1989/2/1/19 Thu, 05 Jan 2012 00:00:00 CET Metabolites 2012-01-05 2 1 Review 19 38 2218-1989 Mass Spectrometry Based Lipidomics: An Overview of Technological Platforms 2012-01-05 doi: 10.3390/metabo2010019 Harald C. Köfeler Alexander Fauland Gerald N. Rechberger Martin Trötzmüller http://www.mdpi.com/2218-1989/2/1/1 The lipidome of the liver and the secreted circulating lipoproteins can now be interrogated conveniently by automated mass spectrometric methods. Multivariate analysis of the liver and serum lipid composition in various animal modes or in human patients has pointed to specific molecular species markers. The perturbations of lipid metabolism can be categorized on the basis of three basic pathological mechanisms: (1) an accelerated rate of de novo lipogenesis; (2) perturbation of the peroxisome pathway of ether-lipid and very-long-chain fatty acid biosynthesis; (3) a change in the rate of interconversion of essential omega-3 and -6 polyunsaturated fatty acids. This review provides examples to illustrate the practicalities of lipidomic studies in biomedicine. http://www.mdpi.com/2218-1989/2/1/1 Wed, 04 Jan 2012 00:00:00 CET Metabolites 2012-01-04 2 1 Review 1 18 2218-1989 Perturbations of Lipid Metabolism Indexed by Lipidomic Biomarkers 2012-01-04 doi: 10.3390/metabo2010001 Antonin Lamaziere Claude Wolf Peter J. Quinn http://www.mdpi.com/2218-1989/1/1/64 Cereal crops such as wheat, rice and barley underpin the staple diet for human consumption globally. A multitude of threats to stable and secure yields of these crops exist including from losses caused by pathogens, particularly fungal. Plants have evolved complex mechanisms to resist pathogens including programmed cell death responses, the release of pathogenicity-related proteins and oxidative bursts. Another such mechanism is the synthesis and release of secondary metabolites toxic to potential pathogens. Several classes of these compounds have been identified and their anti-fungal properties demonstrated. However the lack of suitable analytical techniques has hampered the progress of identifying and exploiting more of these novel metabolites. In this review, we summarise the role of the secondary metabolites in cereal crop diseases and briefly touch on the analytical techniques that hold the key to unlocking their potential in reducing yield losses. http://www.mdpi.com/2218-1989/1/1/64 Thu, 15 Dec 2011 00:00:00 CET Metabolites 2011-12-15 1 1 Review 64 78 2218-1989 Role of Cereal Secondary Metabolites Involved in Mediating the Outcome of Plant-Pathogen Interactions 2011-12-15 doi: 10.3390/metabo1010064 Lauren A. Du Fall Peter S. Solomon http://www.mdpi.com/2218-1989/1/1/41 Volatile organic compounds (volatiles) comprise a chemically diverse class of low molecular weight organic compounds having an appreciable vapor pressure under ambient conditions. Volatiles produced by plants attract pollinators and seed dispersers, and provide defense against pests and pathogens. For insects, volatiles may act as pheromones directing social behavior or as cues for finding hosts or prey. For humans, volatiles are important as flavorants and as possible disease biomarkers. The marine environment is also a major source of halogenated and sulfur-containing volatiles which participate in the global cycling of these elements. While volatile analysis commonly measures a rather restricted set of analytes, the diverse and extreme physical properties of volatiles provide unique analytical challenges. Volatiles constitute only a small proportion of the total number of metabolites produced by living organisms, however, because of their roles as signaling molecules (semiochemicals) both within and between organisms, accurately measuring and determining the roles of these compounds is crucial to an integrated understanding of living systems. This review summarizes recent developments in volatile research from a metabolomics perspective with a focus on the role of recent technical innovation in developing new areas of volatile research and expanding the range of ecological interactions which may be mediated by volatile organic metabolites. http://www.mdpi.com/2218-1989/1/1/41 Fri, 25 Nov 2011 00:00:00 CET Metabolites 2011-11-25 1 1 Review 41 63 2218-1989 Volatile Metabolites 2011-11-25 doi: 10.3390/metabo1010041 Daryl D. Rowan http://www.mdpi.com/2218-1989/1/1/21 Electrospray ionization mass spectrometry (ESI-MS) has become one of the most popular and powerful technologies to identify and quantify individual lipid species in lipidomics. Meanwhile, quantitative analysis of lipid species by ESI-MS has also become a major obstacle to meet the challenges of lipidomics. Herein, we discuss the principles, advantages, and possible limitations of different mass spectrometry-based methodologies for lipid quantification, as well as a few practical issues important for accurate quantification of individual lipid species. Accordingly, accurate quantification of individual lipid species, one of the key challenges in lipidomics, can be practically met. http://www.mdpi.com/2218-1989/1/1/21 Fri, 11 Nov 2011 00:00:00 CET Metabolites 2011-11-11 1 1 Review 21 40 2218-1989 Accurate Quantification of Lipid Species by Electrospray Ionization Mass Spectrometry — Meets a Key Challenge in Lipidomics 2011-11-11 doi: 10.3390/metabo1010021 Kui Yang Xianlin Han http://www.mdpi.com/2218-1989/1/1/3 Gas chromatography–mass spectrometry (GC-MS) is a widely used analytical technique in metabolomics. GC provides the highest resolution of any standard chromatographic separation method, and with modern instrumentation, retention times are very consistent between analyses. Electron impact ionization and fragmentation is generally reproducible between instruments and extensive libraries of spectra are available that enhance the identification of analytes. The major limitation is the restriction to volatile analytes, and hence the requirement to convert many metabolites to volatile derivatives through chemical derivatization. Here we compared the analytical performance of two derivatization techniques, silylation (TMS) and alkylation (MCF), used for the analysis of amino and non-amino organic acids as well as nucleotides in microbial-derived samples. The widely used TMS derivatization method showed poorer reproducibility and instability during chromatographic runs while the MCF derivatives presented better analytical performance. Therefore, alkylation (MCF) derivatization seems to be preferable for the analysis of polyfunctional amines, nucleotides and organic acids in microbial metabolomics studies. http://www.mdpi.com/2218-1989/1/1/3 Mon, 17 Jan 2011 00:00:00 CET Metabolites 2011-01-17 1 1 Article 3 20 2218-1989 Alkylation or Silylation for Analysis of Amino and Non-Amino Organic Acids by GC-MS? 2011-01-17 doi: 10.3390/metabo1010003 Silas G. Villas-Bôas Kathleen F. Smart Subathira Sivakumaran Geoffrey A. Lane http://www.mdpi.com/2218-1989/1/1/1 Technological advances in analytical instrumentation and advances in data modeling are working in synergy to open up new perspectives and research agendas in metabolic research. Thanks to the legacy of the Human Genome Project and its continued impact in the post-genomic era, metabolism is now thought of in a whole-genome context, even when the focus is on a single metabolite and individual metabolic reactions. For a few model organisms we now have extensive, and in some cases complete, information about components that perform integrated metabolic functions. This promises a true paradigm shift in our understanding of the processes of metabolism, but also poses new challenges. As complex and coordinated global behaviors are observed in what were thought to be "simple" organisms, many challenges remain in the experimental domain, as well as in the integration of data generated by increasingly high-throughput analytical techniques. Indeed, in the new era of metabolic research, mathematical and computational modeling is expected to play an increasingly important role. For many complex biochemical phenomena, use of mathematical models may be the best way to build a consistent picture and generate testable hypotheses based on complex yet inevitably incomplete data sets.[...] http://www.mdpi.com/2218-1989/1/1/1 Tue, 07 Dec 2010 00:00:00 CET Metabolites 2010-12-07 1 1 Editorial 1 2 2218-1989 Metabolites: A Novel Platform for Converging Research on Metabolism and Metabolomics 2010-12-07 doi: 10.3390/metabo1010001 Vladimir A. Likić