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Geist J.G.,ETH Zurich | Lauw S.,TU Munich | Illarionova V.,University of Hamburg | Illarionov B.,Ikosatec GmbH | And 12 more authors.
ChemMedChem | Year: 2010

A library of 40 000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A. thaliana with IC 50 values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M. tuberculosis and P. falciparum with IC50 values in the low micromolar range. Several compounds act as weak inhibitors in the P. falciparum red blood cell assay. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Kim R.-R.,University of Hamburg | Illarionov B.,Ikosatec GmbH | Joshi M.,TU Munich | Cushman M.,Purdue University | And 5 more authors.
Journal of the American Chemical Society | Year: 2010

Riboflavin synthase catalyzes the transfer of a four-carbon fragment between two molecules of the substrate, 6,7-dimethyl-8-ribityllumazine, resulting In the formation of riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)- pyrimidinedione. Earlier, a pentacyclic adduct formed from two substrate molecules was shown to be a catalytically competent Intermediate, but the mechanism of its formation is still poorly understood. The present study shows that the recombinant N-terminal domain of riboflavin synthase from Escherichia coli interacts specifically with the exomethylene-type anion of 6,7-dimethyl-8-ribityllumazine but not with any of the tricyclic adduct-type anions that dominate the complex anion equilibrium in aqueous solution. Whereas these findings can be implemented into previously published mechanistic hypotheses, we also present a novel, hypothetical reaction sequence that starts with the transfer of a hydride ion from the 6,7-dimethyl-8-ribiltyllumazine exomethylene anion to an electroneutral 6,7-dimethyl-8-ribityllumazine molecule. The pair of dehydrolumazine and dihydrolumazine molecules resulting from this hydride transfer is proposed to undergo a 4 + 2 cycloaddition, affording the experimentally documented pentacyclic intermediate. In contrast to earlier mechanistic concepts requiring the participation of a nucleophilic agent, which is not supported by structural and mutagenesis data, the novel concept has no such requirement. Moreover, it requires fewer reaction steps and is consistent with all experimental data. © 2010 American Chemical Society.


Marsch S.,TU Munich | Bacher A.,TU Munich | Bacher A.,Ikosatec GmbH | Ettenhuber C.,TU Munich | And 11 more authors.
Isotopes in Environmental and Health Studies | Year: 2015

The positional distributions of stable isotopes in metabolites provide specific fingerprints of the pathways and fluxes that have occurred in the organisms under study. In particular, modern nuclear magnetic resonance (NMR) spectroscopy enables the detailed assignment of isotope patterns in natural products, for example, in metabolites obtained from labelling experiments using 13C-enriched precursors, such as glucose, acetate or CO2. In this study, the transient 13C-isotopologue composition of blood glucose from an adult human volunteer after intravenous supply of [U-13C6]glucose was determined by high-resolution 13C NMR spectroscopy. The non-linear progression curves displaying the relative amounts of eight 13C-glucose isotopologues reflected the contributions of glucose metabolism by glycolytic cycling, the pentose phosphate pathway and anaplerotic reactions involving the citric acid cycle. The pilot study suggests that the experimental setting can be useful in analysing under non-invasive conditions the impact of physiological and pharmacological constraints on glucose turnover in humans. © 2015, © 2015 Taylor & Francis.


Fischer M.,University of Hamburg | Fischer M.,Ikosatec GmbH | Bacher A.,University of Hamburg | Bacher A.,Ikosatec GmbH
Advances in Botanical Research | Year: 2011

Riboflavin (vitamin B2) derivatives serve as cofactors for a very wide variety of redox enzymes but are now also known to participate in the catalysis of certain non-redox reactions and as cofactors of blue-light photoreceptors. In parallel with the unique features of its chemical reactivity, the vitamin is biosynthesised from one molecule of GTP and two molecules of ribulose phosphate by a mechanistically unique series of enzyme-catalysed reactions. Although the work on its biosynthesis has predominantly involved microorganisms, a reasonably detailed picture is now also emerging for plants. A central topic of this review is the emerging role of riboflavin biosynthesis enzymes in connection with plant's iron acquisition and pathogen resistance. © 2011 Elsevier Ltd.


Fischer M.,University of Hamburg | Fischer M.,Ikosatec GmbH | Bacher A.,University of Hamburg | Bacher A.,Ikosatec GmbH
ChemBioChem | Year: 2011

The biosynthesis of one riboflavin (vitamin B2) molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate as substrates. In the final step, the tricyclic isoalloxazine chromophore, which is the hallmark of flavocoenzymes, arises from a highly unusual dismutation of bicyclic 6,7-dimethyl-8-ribityllumazine that is catalyzed by riboflavin synthase but can also proceed without catalysis. The reaction proceeds via a pentacyclic adduct of two 6,7-dimethyl-8-ribityllumazine molecules, whose cleavage into riboflavin and a pyrimidine derivative (by a sequence of two elimination steps) is mechanistically straightforward. Recently, the formation of the pentacyclic adduct has been proposed to involve a hydride transfer step followed by a [4+2] cycloaddition. Surprisingly, two different classes of riboflavin synthases utilize different diastereomers of the pentacyclic adduct, but the newly generated chiral centers are lost upon the intermediates' subsequent fragmentation. The tricyclic isoalloxazine chromophore, which is the hallmark of flavocoenzymes, arises from a highly unusual dismutation of two 6,7-dimethyl-8-ribityllumazine molecules via a pentacyclic adduct. Two different classes of riboflavin synthases utilize different diastereomers of the pentacyclic adduct whose formation has been proposed to involve a hydride transfer step followed by a [4+2] cycloaddition. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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