Dynamics of human acetylcholinesterase bound to non-covalent and covalent inhibitors shedding light on changes to the water network structure.

We investigated the effects of non-covalent reversible and covalent irreversible inhibitors on human acetylcholinesterase and human butyrylcholinesterase. Remarkably a non-covalent inhibitor, Huperzine A, has almost no effect on the molecular dynamics of the protein, whereas the covalently binding nerve agent soman renders the molecular structure stiffer in its aged form. The modified movements were studied by incoherent neutron scattering on different time scales and they indicate a stabilization and stiffening of aged human acetylcholinesterase.

Interaction of prion protein with acetylcholinesterase: potential pathobiological implications in prion diseases.

Introduction: The prion protein (PrP) binds to various molecular partners, but little is known about their potential impact on the pathogenesis of prion diseases

Results: Here, we show that PrP can interact in vitro with acetylcholinesterase (AChE), a key protein of the cholinergic system in neural and non-neural tissues. This heterologous association induced aggregation of monomeric PrP and modified the structural properties of PrP amyloid fibrils. Following its recruitment into PrP fibrils, AChE loses its enzymatic activity and enhances PrP-mediated cytotoxicity.

Reduction of lectin valency drastically changes glycolipid dynamics in membranes but not surface avidity.

Multivalency is proposed to play a role in the strong avidity of lectins for glycosylated cell surfaces and also in their ability to affect membrane dynamics by clustering glycosphingolipids. Lectins with modified valency were designed from the β-propeller fold of Ralstonia solanacearum lectin (RSL) that presents six fucose binding sites. After identification of key amino acids by molecular dynamics calculations, two mutants with reduced valency were produced.

Progress in the development of enzyme-based nerve agent bioscavengers.

Acetylcholinesterase is the physiological target for acute toxicity of nerve agents. Attempts to protect acetylcholinesterase from phosphylation by nerve agents, is currently achieved by reversible inhibitors that transiently mask the enzyme active site. This approach either protects only peripheral acetylcholinesterase or may cause side effects.

Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase.

The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g.

Energy landscapes of human acetylcholinesterase and its Huperzine A-inhibited counterpart.

Enzymes are animated by a hierarchy of motions occurring on time scales that span more than 15 orders of magnitude from femtoseconds (10(-15) s) to several minutes. As a consequence, an enzyme is characterized by a large number of conformations, so-called conformational substates that interconvert via molecular motions. The energy landscapes of these macromolecules are very complex, and many conformations are separated by only small energy barriers.

Relation between dynamics, activity and thermal stability within the cholinesterase family.

Incoherent neutron scattering is one of the most powerful tools for studying dynamics in biological matter. Using the cold neutron backscattering spectrometer IN16 at the Institut Laue Langevin (ILL, Grenoble, France), temperature dependence of cholinesterases' dynamics (human butyrylcholinesterase from plasma: hBChE; recombinant human acetylcholinesterase: hAChE and recombinant mouse acetylcholinesterase: mAChE) was examined using elastic incoherent neutron scattering (EINS). The dynamics was characterized by the averaged atomic mean square displacement (MSD), associated with the sample flexibility at a given temperature.

Human butyrylcholinesterase produced in insect cells: huprine-based affinity purification and crystal structure.

Butyrylcholinesterase (BChE) is a serine hydrolase that is present in all mammalian tissues. It can accommodate larger substrates or inhibitors than acetylcholinesterase (AChE), the enzyme responsible for hydrolysis of the neurotransmitter acetylcholine in the central nervous system and neuromuscular junctions. AChE is the specific target of organophosphorous pesticides and warfare nerve agents, and BChE is a stoichiometric bioscavenger.

Activity and molecular dynamics relationship within the family of human cholinesterases.

The temperature dependence of the dynamics of recombinant human acetylcholinesterase (hAChE) and plasma human butyrylcholinesterase (hBChE) is examined using elastic incoherent neutron scattering. These two enzymes belong to the same family and present 50% amino acid sequence identity. However, significantly higher flexibility and catalytic activity of hAChE when compared to the ones of hBChE are measured.

Laccase chloride inhibition reduction by an anthraquinonic substrate.

Due to their low substrate specificity, fungal laccases have a great potential in industrial applications, including the bioremediation of colored wastewaters from textile industry. However, the presence of halides in these effluents (up to 1M NaCl) which inhibit laccases is a drawback for bioremediation processes. In order to develop an efficient enzymatic remediation process for textile dye effluent, the possibility to reduce this halide inhibition is conditioned by a better understanding of the phenomenon.

Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation.

Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct.

Decolorization, cytotoxicity, and genotoxicity reduction during a combined ozonation/fungal treatment of dye-contaminated wastewater.

In view of compliance with increasingly stringent environmental legislation imposed by regional, national, and supranational (e.g., European Union) authorities, innovative environmental technologies for the treatment of dye-contaminated effluents are necessary in the color industry.

Coupling occurs before breakdown during biotransformation of Acid Blue 62 by white rot fungi.

Only few data exist on the metabolites produced during the biotransformation of anthraquinonic dyes by white rot fungi (WRF). During the biotransformation of an anthraquinonic dye Acid Blue 62 (ABu62) using Pycnoporus sanguineus MUCL 41582 strain, it was previously demonstrated that the blue colour of the medium turned to red before complete dye decolourisation. To better understand the phenomenon, this study carried out ABu62 biotransformation with five different WRF strains (Coriolopsis polyzona MUCL 38443, Perenniporia ochroleuca MUCL 41114, Perenniporia tephropora MUCL 41562, P.

Fluorescence and FTIR study of pressure-induced structural modifications of horse liver alcohol dehydrogenase (HLADH).

The process of pressure-induced modification of horse liver alcohol dehydrogenase (HLADH) was followed by measuring in situ catalytic activity (up to 250 MPa), intrinsic fluorescence (0.1-600 MPa) and modifications of FTIR spectra (up to 1000 MPa). The tryptophan fluorescence measurements and the kinetic data indicated that the pressure-induced denaturation of HLADH was a process involving several transitions and that the observed transient states have characteristic properties of molten globules.