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See detailImmune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, Alessandro UL; Cordes, Thekla UL; Ghelfi, Jenny UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an ... [more ▼]

Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. [less ▲]

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See detailNTFD - A stand-alone application for the non-targeted detection of stable isotope labeled compounds in GC/MS data.
Hiller, Karsten UL; Wegner, André UL; Weindl, Daniel UL et al

in Bioinformatics (2013), 29(9), 1226-8

SUMMARY: Most current stable isotope-based methodologies are targeted and focus only on the well-described aspects of metabolic networks. Here, we present NTFD (non-targeted tracer fate detection), a ... [more ▼]

SUMMARY: Most current stable isotope-based methodologies are targeted and focus only on the well-described aspects of metabolic networks. Here, we present NTFD (non-targeted tracer fate detection), a software for the non-targeted analysis of all detectable compounds derived from a stable isotope-labeled tracer present in a GC/MS dataset. In contrast to traditional metabolic flux analysis approaches, NTFD does not depend on any a priori knowledge or library information. To obtain dynamic information on metabolic pathway activity, NTFD determines mass isotopomer distributions for all detected and labeled compounds. These data provide information on relative fluxes in a metabolic network. The graphical user interface allows users to import GC/MS data in netCDF format and export all information into a tab-separated format. AVAILABILITY: NTFD is C++- and Qt4-based, and it is freely available under an open-source license. Pre-compiled packages for the installation on Debian- and Redhat-based Linux distributions, as well as Windows operating systems, along with example data, are provided for download at http://ntfd.mit.edu/. CONTACT: gregstep@mit.edu. [less ▲]

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See detailA biomolecular isolation framework for eco-systems biology
Roume, Hugo UL; Muller, Emilie UL; Cordes, Thekla UL et al

in ISME Journal (The) (2013), 7(1), 110-121

Mixed microbial communities are complex, dynamic and heterogeneous. It is therefore essential that biomolecular fractions obtained for high-throughput omic analyses are representative of single samples to ... [more ▼]

Mixed microbial communities are complex, dynamic and heterogeneous. It is therefore essential that biomolecular fractions obtained for high-throughput omic analyses are representative of single samples to facilitate meaningful data integration, analysis and modeling. We have developed a new methodological framework for the reproducible isolation of high-quality genomic DNA, large and small RNA, proteins, and polar and non-polar metabolites from single unique mixed microbial community samples. The methodology is based around reproducible cryogenic sample preservation and cell lysis. Metabolites are extracted first using organic solvents, followed by the sequential isolation of nucleic acids and proteins using chromatographic spin columns. The methodology was validated by comparison to traditional dedicated and simultaneous biomolecular isolation methods. To prove the broad applicability of the methodology, we applied it to microbial consortia of biotechnological, environmental and biomedical research interest. The developed methodological framework lays the foundation for standardized molecular eco-systematic studies on a range of different microbial communities in the future. [less ▲]

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See detailThe Application of Stable Isotope Assisted Metabolomics in Biomedicine
Wegner, André UL; Cordes, Thekla UL; Michelucci, Alessandro UL et al

in Current Biotechnology (2012), 1

During the last years, metabolomics has been established as a standard technique in biomedical research to analyze changes in metabolite levels. Currently, mass spectrometry (MS) and nuclear magnetic ... [more ▼]

During the last years, metabolomics has been established as a standard technique in biomedical research to analyze changes in metabolite levels. Currently, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) are the two major technologies to acquire metabolomics data. These technologies have been proven to be invaluable tools for the detection of disease related metabolic biomarkers. However, the obtained data only describe static metabolite concentrations and do not provide information about the dynamics of the system. Based on stable-isotope assisted metabolomics experiments, metabolic flux analysis (MFA) intends to quantitatively analyze intracellular metabolite conversion rates, thus providing a readout of enzyme activities. Although many studies have been published about disease related metabolomics, only a few publications about stable-isotope assisted metabolomics related to biomedicine are available. Especially in the context of personalized medicine, stable-isotope assisted technologies will become more important, since they provide patient and disease specific information about the metabolic state of the patient. In the following review we will point out the importance of stable-isotope related technologies for biomedical sciences. First, we will introduce analytical techniques required for metabolomics and MFA. In the second part, two biomedicine related stable-isotope based studies are summarized. [less ▲]

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