Ligand-Promoted Surface Solubilization of TiO Nanoparticles by the Enterobactin Siderophore in Biological Medium.

Titanium dioxide nanoparticles (TiO-NPs) are increasingly used in consumer products for their particular properties. Even though TiO is considered chemically stable and insoluble, studying their behavior in biological environments is of great importance to figure their potential dissolution and transformation. The interaction between TiO-NPs with different sizes and crystallographic forms (anatase and rutile) and the strong chelating enterobactin () siderophore was investigated to look at a possible dissolution.

A fragment-based drug discovery strategy applied to the identification of NDM-1 β-lactamase inhibitors.

Hydrolysis of β-lactam drugs, a major class of antibiotics, by serine or metallo-β-lactamases (SBL or MBL) is one of the main mechanisms for antibiotic resistance. New Delhi Metallo-β-lactamase-1 (NDM-1), an acquired metallo-carbapenemase first reported in 2009, is currently considered one of the most clinically relevant targets for the development of β-lactam-β-lactamase inhibitor combinations active on NDM-producing clinical isolates. Identification of scaffolds that could be further rationally pharmacomodulated to design new and efficient NDM-1 inhibitors is thus urgently needed.

Study of a phosphorescent cationic iridium(III) complex displaying a blue-shift in crystals.

We report the synthesis and the characterization of a new cationic iridium(III) complex featuring two 1-(-methoxyphenyl)-5-methoxybenzimidazole cyclometallating ligands and a dimethylbipyridine ancillary ligand. The complex has been fully characterized by 1D and 2D NMR (H, C, F and P), elemental analysis and high-resolution mass spectrometry (HRMS). The photoluminescence studies performed in a solution, on amorphous powder and on crystals revealed an unexpected behavior.

Conformational H-bonding modulation of the iron active site cysteine ligand of superoxide reductase: absorption and resonance Raman studies.

Superoxide reductases (SORs) are mononuclear non-heme iron enzymes involved in superoxide radical detoxification in some microorganisms. Their atypical active site is made of an iron atom pentacoordinated by four equatorial nitrogen atoms from histidine residues and one axial sulfur atom from a cysteinate residue, which plays a central role in catalysis. In most SORs, the residue immediately following the cysteinate ligand is an asparagine, which belongs to the second coordination sphere and is expected to have a critical influence on the properties of the active site.

New Acridine-Based Tridentate Ligand for Ruthenium(II): Coordination with a Twist.

A new tridentate ligand based on acridine has been synthetized. The central acridine heterocycle bears two pyridine coordinating units at positions 4 and 5. The terdentate 2,7-di- tert-butyl-4,5-di(pyridin-2-yl)acridine (dtdpa) was then coordinated to a ruthenium(II) cation.

Iron Hydroperoxide Intermediate in Superoxide Reductase: Protonation or Dissociation First? MM Dynamics and QM/MM Metadynamics Study.

Superoxide reductase is a mononuclear iron enzyme involved in superoxide radical detoxification in some bacteria. Its catalytic mechanism is associated with the remarkable formation of a ferric hydroperoxide Fe-OOH intermediate, which is specifically protonated on its proximal oxygen to generate the reaction product HO. Here, we present a computational study of the protonation mechanism of the Fe-OOH intermediate, at different levels of theory.

Redox Behavior of the S-Adenosylmethionine (SAM)-Binding Fe-S Cluster in Methylthiotransferase RimO, toward Understanding Dual SAM Activity.

RimO, a radical-S-adenosylmethionine (SAM) enzyme, catalyzes the specific C methylthiolation of the D89 residue in the ribosomal S protein. Two intact iron-sulfur clusters and two SAM cofactors both are required for catalysis. By using electron paramagnetic resonance, Mössbauer spectroscopies, and site-directed mutagenesis, we show how two SAM molecules sequentially bind to the unique iron site of the radical-SAM cluster for two distinct chemical reactions in RimO.

Probing the reactivity of singlet oxygen with purines.

The reaction of singlet molecular oxygen with purine DNA bases is investigated by computational means. We support the formation of a transient endoperoxide for guanine and by classical molecular dynamics simulations we demonstrate that the formation of this adduct does not affect the B-helicity. We thus identify the guanine endoperoxide as a key intermediate, confirming a low-temperature nuclear magnetic resonance proof of its existence, and we delineate its degradation pathway, tracing back the preferential formation of 8-oxoguanine versus spiro-derivates in B-DNA.

Hydrogen bonding to the cysteine ligand of superoxide reductase: acid-base control of the reaction intermediates.

Superoxide reductase (SOR) is a non-heme iron metalloenzyme that detoxifies superoxide radical in microorganisms. Its active site consists of an unusual non-heme Fe(2+) center in a [His4Cys1] square pyramidal pentacoordination, with the axial cysteine ligand proposed to be an essential feature in catalysis. Two NH peptide groups from isoleucine 118 and histidine 119 establish hydrogen bonds involving the sulfur ligand (Desulfoarculus baarsii SOR numbering).

Unsymmetrical binding modes of the HOPNO inhibitor of tyrosinase: from model complexes to the enzyme.

The deciphering of the binding mode of tyrosinase (Ty) inhibitors is essential to understand how to regulate the tyrosinase activity. In this paper, by combining experimental and theoretical methods, we studied an unsymmetrical tyrosinase functional model and its interaction with 2-hydroxypyridine-N-oxide (HOPNO), a new and efficient competitive inhibitor for bacterial Ty. The tyrosinase model was a dinuclear copper complex bridged by a chelated ring with two different complexing arms (namely (bis(2-ethylpyridyl)amino)methyl and (bis(2-methylpyridyl)amino)methyl).

Control of the evolution of iron peroxide intermediate in superoxide reductase from Desulfoarculus baarsii. Involvement of lysine 48 in protonation.

Superoxide reductase is a nonheme iron metalloenzyme that detoxifies superoxide anion radicals O(2)(•-) in some microorganisms. Its catalytic mechanism was previously proposed to involve a single ferric iron (hydro)peroxo intermediate, which is protonated to form the reaction product H(2)O(2). Here, we show by pulse radiolysis that the mutation of the well-conserved lysine 48 into isoleucine in the SOR from Desulfoarculus baarsii dramatically affects its reaction with O(2)(•-).

4-hydroxyphenylpyruvate dioxygenase catalysis: identification of catalytic residues and production of a hydroxylated intermediate shared with a structurally unrelated enzyme.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) into homogentisate. HPPD is the molecular target of very effective synthetic herbicides. HPPD inhibitors may also be useful in treating life-threatening tyrosinemia type I and are currently in trials for treatment of Parkinson disease.

Quantum mechanical/molecular mechanical study of mechanisms of heme degradation by the enzyme heme oxygenase: the strategic function of the water cluster.

Heme degradation by heme oxygenase (HO) enzymes is important in maintaining iron homeostasis and prevention of oxidative stress, etc. In response to mechanistic uncertainties, we performed quantum mechanical/molecular mechanical investigations of the heme hydroxylation by HO, in the native route and with the oxygen surrogate donor H2O2. It is demonstrated that H2O2 cannot be deprotonated to yield Fe(III)OOH, and hence the surrogate reaction starts from the FeHOOH complex.

NR transfer reactivity of azo-compound I of P450. How does the nitrogen substituent tune the reactivity of the species toward C-H and C=C activation?

We studied electronic structures and reactivity patterns of azo-compound I species (RN-Cpd I) by comparison to O-Cpd I of, e.g., cytochrome P450.

Formation of the active species of cytochrome p450 by using iodosylbenzene: a case for spin-selective reactivity.

The generation of the active species for the enzyme cytochrome P450 by using the highly versatile oxygen surrogate iodosylbenzene (PhIO) often produces different results compared with the native route, in which the active species is generated through O(2) uptake and reduction by NADPH. One of these differences that is addressed here is the deuterium kinetic isotope effect (KIE) jump observed during N-dealkylation of N,N-dimethylaniline (DMA) by P450, when the reaction conditions change from the native to the PhIO route. The paper presents a theoretical analysis targeted to elucidate the mechanism of the reaction of PhIO with heme, to form the high-valent iron-oxo species Compound I (Cpd I), and define the origins of the KIE jump in the reaction of Cpd I with DMA.

On the suitability of strictly localized orbitals for hybrid QM/MM calculations.

In the QM/MM method we have developed (LSCF/MM), the QM and the MM parts are held together by means of strictly localized bonding orbitals (SLBOs). Generally these SLBOs are derived from localized bond orbitals (LBOs) that undergo tails deletion, resulting in a nonpredictable change of their properties. An alternative set of SLBOs is provided by the extremely localized molecular orbitals (ELMOs) approach, where the orbitals are rigorously localized on some prefixed atoms without tails on the other atoms of the molecule.