Activities of the reported diphenyl urea derivatives.

<p>Activities of the reported diphenyl urea derivatives.</p

Comparison of transketolase model with crystal structure.

<p>A) Superimposition of the homology model of human transketolase (in pink) with the recently released crystal structure (in white). B) Close view of the residues used for pharmacophore definition, in the homology model (in pink and thin residues) and in the crystal structure (in white and thick residues).</p

Structures of the reported diphenyl urea derivatives.

<p>In the upper part, compounds which showed good inhibitory activity. In the bottom part, compounds which showed poor activity. The pharmacophoric points are also shown; in red for hydrogen acceptor points, in blue for hydrogen donor points and in green for hydrophobic points.</p

Proposed binding mode of compound T2 and its derivatives (T2A–T2F).

<p>Black dots represent hydrogen bonds.</p

Transketolase structure model.

<p>A) Homology model of human transketolase showing the antiparallel alpha helices involved in dimerization. B) Close view of the alpha helix D200-G210 showing the selected residues of the 5-point pharmacophore. HY: hydrophobic contact, HA: hydrogen acceptor, HD: hydrogen donor.</p

Dynamic behavior of model 272 in the neighborhood of the point of Hopf bifurcation indicated in Figure 7.

<p> Small-amplitude oscillations monitored by ΔΨ are stable at external pyruvate concentrations 0.279 mM (A), but the increase of amplitude induced by increase of pyruvate concentration to 0.28 mM results in the switch to another branch of steady states (B).The inset in B zooms the interval of oscillations of ΔΨ (ordinates, ΔΨ (mV); abscissa, Time (min)).</p

Quantitative Proteomic Approach to Understand Metabolic Adaptation in Non-Small Cell Lung Cancer

KRAS mutations in non-small cell lung cancer (NSCLC) are a predictor of resistance to EGFR-targeted therapies. Because approaches to target RAS signaling have been unsuccessful, targeting lung cancer metabolism might help to develop a new strategy that could overcome drug resistance in such cancer. In this study, we applied a large screening quantitative proteomic analysis to evidence key enzymes involved in metabolic adaptations in lung cancer. We carried out the proteomic analysis of two KRAS-mutated NSCLC cell lines (A549 and NCI-H460) and a non tumoral bronchial cell line (BEAS-2B) using an iTRAQ (isobaric tags for relative and absolute quantitation) approach combined with two-dimensional fractionation (OFFGEL/RP nanoLC) and MALDI–TOF/TOF mass spectrometry analysis. Protein targets identified by our iTRAQ approach were validated by Western blotting analysis. Among 1038 proteins identified and 834 proteins quantified, 49 and 82 proteins were respectively found differently expressed in A549 and NCI-H460 cells compared to the BEAS-2B non tumoral cell line. Regarding the metabolic pathways, enzymes involved in glycolysis (GAPDH/PKM2/LDH-A/LDH-B) and pentose phosphate pathway (PPP) (G6PD/TKT/6PGD) were up-regulated. The up-regulation of enzyme expression in PPP is correlated to their enzyme activity and will be further investigated to confirm those enzymes as promising metabolic targets for the development of new therapeutic treatments or biomarker assay for NSCLC

List of Linnaeus's herbarium

<p>Units for the rate constants of monomolecular reactions of electron transition inside the complex and reactions of dissociation are s⁻¹. For bimolecular reactions of ubiquinone/ubiquinol binding units are (nmol/mg)⁻¹s⁻¹. The reactions simulated and abbreviations used in the names of constants are explained in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#s4" target="_blank">Methods</a>, part “Complex III model”.</p

Multiple steady state solutions for the model of complex III consisting of 257 ODEs.

<p>The solutions for ÄØ are given as a function of succinate concentration defining Vm_SDH (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi.1002700.e001" target="_blank">eq (1)</a>). The values of other parameters are shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi-1002700-t001" target="_blank">Table 1</a> (column “257”).</p

Multiple steady states for the integrated models of complex I and III (model 267).

<p>The solutions for ΔΨ are given as a function of succinate concentration defining Vm_SDH (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi.1002700.e001" target="_blank">eq (1)</a>). The rate constant of electron transport from cytochrome c1 to cytochrome c (k_c1c) was 735 s⁻¹. The values of other parameters, which correspond to the best fit to measured dynamics of NADH and oxygen consumption under states 4 and 3 of mitochondrial respiration <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi.1002700-Selivanov2" target="_blank">[12]</a>, are shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi-1002700-t001" target="_blank">Table 1</a> (column “267/272”) and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002700#pcbi-1002700-t002" target="_blank">Table 2</a>. The point “H” designates a Hopf bifurcation, and the inset shows the time course of ΔΨ (mV) in the neighborhood of this point.</p