Cloud Microorganisms, an Interesting Source of Biosurfactants

A new scientific hypothesis states that biosurfactants from cloud microorganism origin could change the surface tension of aerosols and thus the mode of precipitations. In order to check this hypothesis, our team has screened a collection of 480 microbial strains isolated from cloud waters for the production of biosurfactants and showed that 42% of these strains were producing such molecules. In the present work, we isolated and identified by LC-MS-MS lipopeptides produced from three strains issued from this screening. Viscosin and massetolide E (cyclic lipopeptides) were produced by Pseudomonas sp. PDD-14b-2, and syringafactins (linear lipopeptides) were produced by Xanthomonas campestris PDD-32b-52 and Pseudomonas syringae PDD-32b-74. The critical micelle concentration (CMC) of these biosurfactants was determined using the pendant drop method. Finally, two approaches of molecular dynamics were used to model the conformation of viscosin and syringafactin A at the water-air interface: one is based on all-atoms simulation (CHARMM force field), while the other one on coarse-grain (CG) simulation (MARTINI force field). To conclude, this work shows how the biodiversity of the cloud microbiota can be explored to search and produce biosurfactants of interest both for atmospheric sciences and also for biotechnological applications

QM/MM Study of Human Transketolase: Thiamine Diphosphate Activation Mechanism and Complete Catalytic Cycle

International audienceA computational model for human transketolase was proposed, showing that thiamine diphosphate activation was based on His110 in place of His481 reported in yeast transketolase. In addition, a complete catalytic reaction pathway was investigated using d-xylulose-5-phosphate and d-ribose-5-phosphate as substrates, showing at every step a perfect superimposition of our model with high-resolution crystallographic structures 3MOS, 4KXV, and 4KXX. This study shows that H2N4′ of the active thiamine diphosphate “V form” no longer has a self-activating role but allows self-stabilization of the cofactor and of the Breslow intermediate. These advances in our knowledge of the human transketolase mechanism offer interesting prospects for the design of new drugs, this enzyme being involved in several diseases, and for a better understanding of the reactions catalyzed by transketolases from other sources

Synthesis and molecular modelling study of new trimeric quinoline derivatives

International audienceDi- and trimeric quinoline derivatives have been recently described as potential modulators of Bcl-2 family protein interactions. However, only a few trimeric compounds have been described so far and an enlargement of the number of analogs of this class is needed to expand the structure-activity relationship study. Therefore, the synthesis of six new trimeric quinoline derivatives is reported. Moreover molecular modeling experiments were performed to study the conformational arrangement of compound 36 in Bak binding site of Bcl-xL, showing that these compounds could be potential ligands for Bcl-xL

Insights into the Thiamine Diphosphate Enzyme Activation Mechanism: Computational Model for Transketolase Using a Quantum Mechanical/Molecular Mechanical Method.

International audienceWe propose the first computational model for transketolase (TK), a thiamine diphosphate (ThDP)-dependent enzyme, using a quantum mechanical/molecular mechanical method on the basis of crystallographic TK structures from yeast and Escherichia coli, together with experimental kinetic data reported in the literature with wild-type and mutant TK. This model allowed us to define a new route for ThDP activation in the enzyme environment. We evidenced a strong interaction between ThDP and Glu418B of the TK active site, itself stabilized by Glu162A. The crucial point highlighted here is that deprotonation of ThDP C2 is not performed by ThDP N4′ as reported in the literature, but by His481B, involving a HOH688A molecule bridge. Thus, ThDP N4′ is converted from an amino form to an iminium form, ensuring the stabilization of the C2 carbanion or carbene. Finally, ThDP activation proceeds via an intermolecular process and not by an intramolecular one as reported in the literature. More generally, this proposed ThDP activation mechanism can be applied to some other ThDP-dependent enzymes and used to define the entire TK mechanism with donor and acceptor substrates more accurately

Edifices glycoconjugués multivalents. Antigènes Tn – béta-Peptides

Communication oral

Cage-like structures based on constrained cyclic arylopeptoids

The access to cupola-like or tube-like structures from ortho- and meta-arylopeptoid macrocycles was explored through CuAAC reaction using a partially flexible bis(azide) and CuI-N-heterocyclic carbene as catalyst. NMR studies showed that a bis-triazolium bicylic compound in the ortho-series adopts well-defined structure in polar aprotic and protic solvents. Besides, preliminary study revealed its potential for oxoanion recognition

A catalytic intramolecular nitrene insertion into a copper(I)–N-heterocyclic carbene bond yielding fused nitrogen heterocycles.

International audienceN-(2-Azidophenyl)azolium salts were easily prepared and reacted with copper(I) under conditions allowing the formation of NHC complexes. Under these conditions, the formation of benzimidazo-fused heterocycles occurred under catalytic, efficient and very mild conditions. This reaction is proposed to proceed via dinitrogen elimination and imido/nitrene–NHC cyclization

Are Cu(I)-mesoionic NHC carbenes associated with nitrogen additives the best Cu-carbene catalysts for the azide-alkyne click reaction in solution? A case study.

International audienceCopper(I)-catalyzed azide alkyne cycloaddition is now a widely used tool for the synthesis of elaborated compounds. Until now, few stable and efficient copper(I) catalysts are available despite the limitations inherent to approaches employing the in situ reduction of a CuII species to deliver the catalytic system. We report that the combination of a copper(I)-mesoionic N-heterocyclic carbene (MIC) with a phenanthroline derivative generates a highly active catalyst, functioning in aqueous alcoholic solvent, without the intervention of a reducing agent. This catalytic system surpasses related 'normal' N-heterocyclic carbene-based systems in their efficiency

Structural insights into the design of inhbitors for the L1 metallo-ß-lactamase from Stenotrophomonas maltophilia

International audienceOne mechanism by which bacteria can escape the action of beta-lactam antibiotics is the production of metallo-beta-lactamases. Inhibition of these enzymes should restore the action of these widely used antibiotics. The tetrameric enzyme L1 from Stenotrophomonas maltophilia was used as a model system to determine a series of high-resolution crystal structures of apo, mono and bi-metal substituted proteins as well as protein-inhibitor complexes. Unexpectedly, although the apo structure revealed only few significant structural differences from the holo structure, some inhibitors were shown to induce amino acid side-chain rotations in the tightly packed active site. Moreover, one inhibitor employs a new binding mode in order to interact with the di-zinc center. This structural information could prove essential in the process of elucidation of the mode of interaction between a putative lead compound and metallo-beta-lactamases, one of the main steps in structure-based drug design

Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors.

International audienceThe synthesis and Pim kinase inhibition potency of a new series of pyrrolo[2,3-g]indazole derivatives is described. The results obtained in this preliminary structure–activity relationship study pointed out that sub-micromolar Pim-1 and Pim-3 inhibitory potencies could be obtained in this series, more particularly for compounds 10 and 20, showing that pyrrolo[2,3-g]indazole scaffold could be used for the development of new potent Pim kinase inhibitors. Molecular modeling experiments were also performed to study the binding mode of these compounds in Pim-3 ATP-binding pocket