Extracellular 4'-phosphopantetheine is a source for intracellular coenzyme A synthesis.

The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA. Here CoA was hydrolyzed extracellularly by ectonucleotide pyrophosphatases to 4'-phosphopantetheine, a biologically stable molecule able to translocate through membranes via passive diffusion. Inside the cell, 4'-phosphopantetheine was enzymatically converted back to CoA by the bifunctional enzyme CoA synthase. Phenotypes induced by intracellular CoA deprivation were reversed when exogenous CoA was provided. Our findings answer long-standing questions in fundamental cell biology and have major implications for the understanding of CoA-related diseases and therapies.

Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering.

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.

Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics.

Tetracyclines (TCs) are medically important antibiotics from the polyketide family of natural products. Chelocardin (CHD), produced by Amycolatopsis sulphurea, is a broad-spectrum tetracyclic antibiotic with potent bacteriolytic activity against a number of Gram-positive and Gram-negative multi-resistant pathogens. CHD has an unknown mode of action that is different from TCs. It has some structural features that define it as 'atypical' and, notably, is active against tetracycline-resistant pathogens. Identification and characterization of the chelocardin biosynthetic gene cluster from A. sulphurea revealed 18 putative open reading frames including a type II polyketide synthase. Compared to typical TCs, the chd cluster contains a number of features that relate to its classification as 'atypical': an additional gene for a putative two-component cyclase/aromatase that may be responsible for the different aromatization pattern, a gene for a putative aminotransferase for C-4 with the opposite stereochemistry to TCs and a gene for a putative C-9 methylase that is a unique feature of this biosynthetic cluster within the TCs. Collectively, these enzymes deliver a molecule with different aromatization of ring C that results in an unusual planar structure of the TC backbone. This is a likely contributor to its different mode of action. In addition CHD biosynthesis is primed with acetate, unlike the TCs, which are primed with malonamate, and offers a biosynthetic engineering platform that represents a unique opportunity for efficient generation of novel tetracyclic backbones using combinatorial biosynthesis.

Glycine in 1-butyl-3-methylimidazolium acetate and trifluoroacetate ionic liquids: effect of fluorination and hydrogen bonding.

The solvation of glycine in two ionic liquids (ILs), namely, 1-butyl-3-methylimidazolium acetate, [C(1)C(4)Im][OAc], and 1-butyl-3-methylimidazolium trifluoroacetate, [C(1)C(4)Im][TFA], was studied by a combination of experimental and theoretical methods. The solubility of glycine in both ILs was determined at 333.15 K to be (8.1±0.5) and (1.0±0.5) wt % in [C(1)C(4)Im][OAc] and [C(1)C(4)Im][TFA], respectively. By IR spectroscopy it was found that, when dissolved in the ILs, glycine was mainly present in its zwitterionic form. Structural and energetic aspects of the solvation of glycine in the ILs and in mixtures of ILs and water were investigated by ab initio calculations and molecular dynamic simulations. It was observed that the firstly solvation shell around glycine consisted predominantly of acetate or trifluoroacetate anions, which formed hydrogen bonds either with the carboxylic group of neutral glycine or with the protonated ammonium group of the zwitterionic form. When water is present in the solutions, hydrogen bonds between water and the anion prevail. The overall energy of the system was decomposed into its components between pairs of species. It was established that the dominant contribution to the interaction energy between glycine and the IL was due to hydrogen bonds with the anions and the statistics of hydrogen bonds were analysed.

Ruthenium nanoparticles in ionic liquids: structural and stability effects of polar solutes.

Ionic liquids are a stabilizing medium for the in situ synthesis of ruthenium nanoparticles. Herein we show that the addition of molecular polar solutes to the ionic liquid, even in low concentrations, eliminates the role of the ionic liquid 3D structure in controlling the size of ruthenium nanoparticles, and can induce their aggregation. We have performed the synthesis of ruthenium nanoparticles by decomposition of [Ru(COD)(COT)] in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], under H(2) in the presence of varying amounts of water or 1-octylamine. For water added during the synthesis of metallic nanoparticles, a decrease of the solubility in the ionic liquid was observed, showed by nanoparticles located at the interface between aqueous and ionic phases. When 1-octylamine is present during the synthesis, stable nanoparticles of a constant size are obtained. When 1-octylamine is added after the synthesis, aggregation of the ruthenium nanoparticles is observed. In order to explain these phenomena, we have explored the molecular interactions between the different species using (13)C-NMR and DOSY (Diffusional Order Spectroscopy) experiments, mixing calorimetry, surface tension measurements and molecular simulations. We conclude that the behaviour of the ruthenium nanoparticles in [C(1)C(4)Im][NTf(2)] in the presence of 1-octylamine depends on the interaction between the ligand and the nanoparticles in terms of the energetics but also of the structural arrangement of the amine at the nanoparticle's surface.

Conversion of aryl iodides into aryliodine(III) dichlorides by an oxidative halogenation strategy using 30% aqueous hydrogen peroxide in fluorinated alcohol.

Oxidative chlorination with HCl/H2O2 in 1,1,1-trifluoroethanol was used to transform aryl iodides into aryliodine(III) dihalides. In this instance 1,1,1-trifluoroethanol is not only the reaction medium, but is also an activator of hydrogen peroxide for the oxidation of hydrochloric acid to molecular chlorine. Aryliodine(III) dichlorides were formed in 72-91% isolated yields in the reaction of aryl iodides with 30% aqueous hydrogen peroxide and hydrochloric acid at ambient temperature. A study of the effect that substituents on the aromatic ring have on the formation and stability of aryliodine(III) dichlorides shows that the transformation is easier to achieve in the presence of the electron-donating groups (i.e. methoxy), but in this case the products rapidly decompose under the reported reaction conditions to form chlorinated arenes. The results suggest that oxidation of hydrogen chloride with hydrogen peroxide is the initial reaction step, while direct oxidation of aryl iodide with hydrogen peroxide is less likely to occur.

Synthesis and reactivity of fluorous and nonfluorous aryl and alkyl iodine(III) dichlorides: new chlorinating reagents that are easily recycled using biphasic protocols.

Fluorous aryl and alkyl iodine(III) dichlorides of the formulas (R(fn)(CH(2))(3))(2)C(6)H(3)ICl(2) (R(fn) = CF(3)(CF(2))(n-1); n = 8 for 3,5-disubstituted and n = 6, 8, 10 for 2,4-disubstituted) and R(fn)CH(2)ICl(2) (n = 8, 10) are prepared in 71-98% yields by reactions of Cl(2) and the corresponding fluorous iodides. These are effective reagents for the conversions of cyclooctene to trans-1,2-dichlorocyclooctene, anisole to 4-chloro- and 2-chloroanisole, 4-tert-butylphenol to 2-chloro-4-tert-butylphenol, PhCOCH(2)COPh to PhCOCHClCOPh, and PhCOCH(3) to PhCOCH(2)Cl and PhCOCHCl(2) (CH(3)CN, rt to 40 degrees C, 100-64% conversions). The chlorinated products and fluorous iodide coproducts are easily separated by organic/fluorous liquid/liquid biphase workups. The latter are obtained in 97-90% yields and reoxidized with Cl(2). Analogous chlorinations are conducted with 3-Cl(2)IC(6)H(4)COOH (16) and 4,4'-Cl(2)IC(6)H(4)C(6)H(4)ICl(2). With the former, the products and coproduct 3-IC(6)H(4)COOH (91-85% recoveries) are easily separated by organic/aqueous NaHCO(3) liquid/liquid biphase workups. The coproduct from the latter, 4,4'-IC(6)H(4)C(6)H(4)I, is insoluble in common organic solvents, allowing separation by liquid/solid phase workups (91-89% recoveries). The effect of the structure of the iodine(III) dichloride upon reactivity is analyzed in detail. The fluorous systems with R(f8) substituents are generally superior, but 16 is more reactive and gives higher selectivities.

Oxidative halogenation with "green" oxidants: oxygen and hydrogen peroxide.

It is difficult to imagine organic chemistry without organo-halogen compounds and the molecular halogens needed for their preparation. The halogens have very different reactivity, with iodine usually requiring some form of activation, while others are reactive and hazardous chemicals. To avoid their use, various modified reagents have been discovered (N-bromo- and N-chlorosuccinimide, Selectfluor..), but halogens are used to prepare these reagents and when they are used the atom economy is poor. A better approach, which is based on biomimetric research on oxidative halogenation in nature, consists of generating the halogenating reagent in situ under acidic conditions from a halide salt. The result of such a reaction has been halogenation with 100 % halogen atom economy. Suitable oxidants for the oxidation of halides are hydrogen peroxide and oxygen.

Effect of water on the carbon dioxide absorption by 1-alkyl-3-methylimidazolium acetate ionic liquids.

The absorption of carbon dioxide by the pure ionic liquids 1-ethyl-3-methylimidazolium acetate ([C(1)C(2)Im][OAc]) and 1-butyl-3-methylimidazolium acetate ([C(1)C(4)Im][OAc]) was studied experimentally from 303 to 343 K. As expected, the mole fraction of absorbed carbon dioxide is high (0.16 at 303 K and 5.5 kPa and 0.19 at 303 and 9.6 KPa for [C(1)C(2)Im][OAc] and [C(1)C(4)Im][OAc], respectively), does not obey Henry's law, and is compatible with the chemisorption of the gas by the liquid. Evidence of a chemical reaction between the gas and the liquid was found both by NMR and by molecular simulation. In the presence of water, the properties of the liquid absorber significantly change, especially the viscosity that decreases by as much as 25% (to 78 mPa s) and 30% (to 262 mPa s) in the presence of 0.2 mol fraction of water for [C(1)C(2)Im][OAc] and [C(1)C(2)Im][OAc] at 303 K, respectively. The absorption of carbon dioxide decreases when the water concentration increases: a decrease of 83% in CO(2) absorption is found for [C(1)C(4)Im][OAc] with 0.6 mol fraction of water at 303 K. It is proved in this work, by combining experimental data with molecular simulation, that the presence of water not only renders the chemical reaction between the gas and the ionic liquid less favorable but also lowers the (physical) solubility of the gas as it competes by the same solvation sites of the ionic liquid. The lowering of the viscosity of the liquid absorbent largely compensates these apparent drawbacks and the mixtures of [C(1)C(2)Im][OAc] and [C(1)C(2)Im][OAc] with water seem promising to be used for carbon dioxide capture.

Influence of ionic association, transport properties, and solvation on the catalytic hydrogenation of 1,3-cyclohexadiene in ionic liquids.

The influence of the nature of two different ionic liquids, namely 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], and 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(1)C(4)Im][NTf(2)], on the catalytic hydrogenation of 1,3-cyclohexadiene with [Rh(COD)(PPh(3))(2)][NTf(2)] (COD = 1,5-cyclooctadiene) was studied. Initially, the effect of different concentrations of 1,3-cyclohexadiene on the molecular interactions and on the structure in two ionic liquids was investigated by NMR and by molecular dynamic simulations. It was found that in both ionic liquids 1,3-cyclohexadiene is solvated preferentially in the lipophilic regions. Furthermore, the higher solubility of 1,3-cyclohexadiene in [C(1)C(4)Im][NTf(2)] and the smaller positive values of the excess molar enthalpy of mixing for the 1,3-cyclohexadiene + [C(1)C(4)Im][NTf(2)] system in comparison with 1,3-cyclohexadiene + [C(1)C(1)C(4)Im][NTf(2)] indicate more favorable interactions between 1,3-cyclohexadiene and the C(1)C(4)Im(+) cation than with the C(1)C(1)C(4)Im(+) cation. Subsequently, diffusivity and conductivity measurements of the 1,3-cyclohexadiene + ionic liquid mixtures at different compositions allowed a characterization of mass and charge transport in the media and access to the ionicity of ionic liquids in the mixture. From the dependence of the ratio between molar conductivity and the conductivity inferred from NMR diffusion measurements, Λ(imp)/Λ(NMR), on concentration of 1,3-cyclohexadiene in the ionic liquid mixture, it was found that increasing the amount of 1,3-cyclohexadiene leads to a decrease in the ionicity of the medium. Finally, the reactivity of the catalytic hydrogenation of 1,3-cyclohexadiene using [Rh(COD)(PPh(3))(2)][NTf(2)] performed in [C(1)C(4)Im][NTf(2)] at different compositions of 1,3-cyclohexadiene and in [C(1)C(1)C(4)Im][NTf(2)] at one composition was related linearly to the viscosity, hence the reaction rate is determined by the mass transport properties of the media.

How do physical-chemical parameters influence the catalytic hydrogenation of 1,3-cyclohexadiene in ionic liquids?

The catalytic hydrogenation of 1,3-cyclohexadiene using [Rh(COD)(PPh(3))(2)]NTf(2) (COD = 1,5-cyclooctadiene) was performed in two ionic liquids: 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], and 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(1)C(4)Im][NTf(2)]. It is observed that the reaction is twice as fast in [C(1)C(4)Im][NTf(2)] than in [C(1)C(1)C(4)Im][NTf(2)]. To explain the difference in reactivity, molecular interactions and the microscopic structure of ionic liquid +1,3-cyclohexadiene mixtures were studied by NMR and titration calorimetry experiments, and by molecular simulation in the liquid phase. Diffusivity and viscosity measurements allowed the characterization of mass transport in the reaction media. We could conclude that the diffusivity of 1,3-cyclohexadiene is 1.9 times higher in [C(1)C(4)Im][NTf(2)] than in [C(1)C(1)C(4)Im][NTf(2)] and that this difference could explain the lower reactivity observed in [C(1)C(1)C(4)Im][NTf(2)].