The Molecular Basis of the Interaction of Cyclophilin A with α-Synuclein

Peptidylprolyl isomerases (PPIases) catalyze cis/trans isomerization of prolines. The PPIase CypA colocalizes with the Parkinson's disease (PD)-associated protein α-synuclein in cells and interacts with α-synuclein oligomers. Herein, we describe atomic insights into the molecular details of the α-synuclein/CypA interaction. NMR spectroscopy shows that CypA catalyzes isomerization of proline 128 in the C-terminal domain of α-synuclein. Strikingly, we reveal a second CypA-binding site formed by the hydrophobic sequence ⁴⁷GVVHGVATVA⁵⁶, termed PreNAC. The 1.38 Å crystal structure of the CypA/PreNAC complex displays a contact between alanine 53 of α-synuclein and glutamine 111 in the catalytic pocket of CypA. Mutation of alanine 53 to glutamate, as found in patients with early-onset PD, weakens the interaction of α-synuclein with CypA. Our study provides high-resolution insights into the structure of the PD-associated protein α-synuclein in complex with the most abundant cellular cyclophilin.     

Synthesis of Potential Cytotoxic α-Methylene γ-Lactams

α-Methylene γ-lactones are known to have physiological activity, especially as cytotoxic agents, and are widely found in nature (1). However they are often toxic which makes them inappropriate for cancer treatment.     

The Effect of Silver Perchlorate of the Reaction of Trialkyl Phosphite with α-Halogenoketones

Abstract

Trialkyl phosphites are known to react with α-halogenoketones to yield β-ketophosphonates (Arbuzov product) or vinyl phosphates (Perkow product) according to coniiitions.¹ α-Hydroxyphosphonate may be formed in addition, in prcltic media.² We have now shown that none of these products is formed in the presence of silver perchlorate (in benzene sclutim); nor could we detect the ketophosphonium perchlorate reported previously. Phosphorus-31 nmr showed the formation of trimethyl phosphate and tetramethyl pyrophosphate as the exclusive phosphorus-containing products. The sequence of possible reaction is complex and the overall stoichiometry may vary somewhat according to the rate and order of rixing. Trialkyl phosphate could be formed by elimination of alkyne from vinyloxyphosphonium intermediate produced together with silver iodine in first stage of the interaction. Pyrophosphate formation would then result from nucleophilic attack of trimethyl phosphate on the trimethoxy(1-nethylvinyloxy)phosphoniun ion, which may be formed as a reactive intermediate. Evidence for formation of methyl perchlorate in the final dealkylation of the quasiphosphonium intermediate is provided by proton nmr spectroscopy and by the formation of the N-methylquino-linium salt on addition of quinoline. No change in the ³¹P nmr spectrum occurs at this stage. Other by-products of the main reactions include the dehalogenated ketone (acetone from iodoacetone or acetnphenone from α-iodoacetophenone).     

Site-Specific Differences in Proteasome-Dependent Degradation of Monoubiquitinated α-Synuclein

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Acrolein and Copper as Competitive Effectors of α-Synuclein

Mounting evidence supports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by α-synuclein (αSyn) accumulation and aggregation in brain regions, also promoted by Cu²⁺. αSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper, and αSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on αSyn using an approach based on LC-MS/MS analysis. We also evaluated the influence of Cu²⁺ on the protein carbonylation and how the ACR modification impacts the Cu²⁺ binding and the production of Reactive Oxygen Species (ROS). Finally, we investigated the effects of ACR and Cu²⁺ ions on the αSyn aggregation by dynamic light scattering and fluorescence assays. Cu²⁺ regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu²⁺ and ACR inhibits αSyn aggregation both in the presence and in the absence of Cu²⁺.     

Effect of Temperature on The Solubility of α-Amino Acids and α,ω-Amino Acids in Water

The aqueous solubilities of glycine, dl-α-alanine (2-aminopropanoic acid), dl-α-aminobutyric acid (2-aminobutanoic acid), dl-α-norvaline (2-aminopentanoic acid), dl-α-norleucine (2-aminohexanoic acid), β-alanine (3-aminopropanoic acid), γ-aminobutyric acid (4-aminobutanoic acid), 5-aminovaleric acid (5-aminopentanoic acid), and 6-aminocaproic acid (6-aminohexanoic acid) were determined from 293.15 to 323.15 K at intervals of 5.00 K using the gravimetric method. The temperature dependence of the solubility of α-amino acids and α,ω-amino acids in water is well described by the van’t Hoff equation. Linear van’t Hoff plots were used to determine the differential enthalpy of solution. The results obtained are compared with reported values in literature and are discussed in terms of the position of the ionic groups in the hydrocarbon chain.     

The Enhanced MR Effect of Dense Magnetic Particles Suspensions Consisting of Superfine α-Fe Particles

It is reported that magnetorheological (MR) effect was enhanced when superfineα-Fe particles and other nanosize particles were added to suspensions of dense micron magnetic particles. The effect of adding superfine particles on dynamics shear stress, sedimentation stability and structure of solidified MR of magnetic suspensions were studied. The experiment showed considerable increase of shear stress and much stability of sedimentation when the suspension consisting of superfine particles. The enhanced MR effect by superfine particles dealt with the properties, weight ratio and scale of superfine particles.     

The Concentration of Hydrogen Peroxide Generated during Aggregation of α-Synuclein in vitro Is Lower than 5 nmol／L

Using a fluorometric method with a detection limit of 5 nmol/L, here it is reported that albeit positive results were got from bovine serum albumin (BSA) and chicken ovalbumin (OVA) as published in literature, no detectable amount of hydrogen peroxide (H2O2) was generated during α-synuclein (α-Syn) aggregation in vitro even in the presence of transition metal ions Cu(Ⅱ) or Fe(Ⅲ). The results suggest that the concentration of H2O2 generated during aggregation of α-Syn in vitro be lower than 5 nmol/L beyond the detection limit of the adopted method and it is far too poor to be responsible for the cytotoxicity of α-Syn aggregates, thus allowing people to extensively elucidate the mechanism underlying neurotoxicifies of the aggregates formed by some amyloidogenic proteins.     

The gas-phase ozonolysis of α-humulene

α-Humulene contains three double bonds (DB), and after ozonolysis of the first DB the first-generation products are still reactive towards O(3) and produce second- and third-generation products. The primary aim of this study consisted of identifying the products of the three generations, focusing on the carboxylic acids, which are known to have a high aerosol formation potential. The experiments were performed in a 570 litre spherical glass reactor at 295 K and 730 Torr. Initial mixing ratios were 260-2090 ppb for O(3) and 250-600 ppb for α-humulene in synthetic air. Reactants and gas-phase products were measured by in situ FTIR spectroscopy. Particulate products were sampled on Teflon filters, extracted with methanol and analyzed by LC-MS/MS-TOF. Using cyclohexane (10-100 ppm) as an OH-radical scavenger and by monitoring the yield of cyclohexanone by PTR-MS, an OH-yield of (10.5 ± 0.7)% was determined for the ozonolysis of the first DB, and (12.9 ± 0.7)% of the first-generation products. The rate constant of the reaction of O(3) with α-humulene is known as k(0) = 1.17 × 10(-14) cm(3) molecule(-1) s(-1) [Y. Shu and R. Atkinson, Int. J. Chem. Kinet., 1994, 26, 1193-1205]. The reaction rate constants of O(3) with the first-generation products and the second-generation products were, respectively, determined as k(1) = (3.6 ± 0.9) × 10(-16) and k(2) = (3.0 ± 0.7) × 10(-17) cm(3) molecule(-1) s(-1) by Facsimile-simulation of the observed ozone decay by FTIR. A total of 37 compounds in the aerosol phase and 5 products in the gas phase were tentatively identified: 25 compounds of the first-generation products contained C13-C15 species, 9 compounds of the second-generation products contained C8-C11 species, whereas 8 compounds of the third-generation products contained C4-C6 species. The products of all three generations consisted of a variety of dicarboxylic-, hydroxy-oxocarboxylic- and oxo-carboxylic acids. The formation mechanisms of some of the products are discussed. The residual FTIR spectra indicate the formation of secondary ozonides (SOZ) in the gas phase, which are formed by the intramolecular reaction of the Criegee moiety with the carbonyl endgroup. These SOZ revealed to be stable over several hours and its formation was shown not to be affected by the addition of Criegee-radical scavengers such as HCOOH or H(2)O. This suggests that in the ozonolysis of α-humulene at atmospheric pressures the POZ will decompose rapidly, and that a large fraction of the formed exited Criegee Intermediate will be stabilized to form stable SOZ, while the formation of OH-radicals via the hydroperoxide channel will be a minor process.     

The Fascinating Chemistry of α-Haloamides

The aim of this review is to highlight the rich chemistry of α-haloamides originally mainly used to discover new C−N, C−O and C−S bond forming reactions, and later widely employed in C−C cross-coupling reactions with C(sp³), C(sp²) and C(sp) coupling partners. Radical-mediated transformations of α-haloamides bearing a suitable located unsaturated bond has proven to be a straightforward alternative to access diverse cyclic compounds by means of either radical initiators, transition metal redox catalysis or visible light photoredox catalysis. On the other hand, cycloadditions with α-halohydroxamate-based azaoxyallyl cations have garnered significant attention. Moreover, in view of the important role in life and materials science of difluoroalkylated compounds, a wide range of catalysts has been developed for the efficient incorporation of difluoroacetamido moieties into activated as well as unactivated substrates.     

Molecular Composition of Sub-stoichiometrically Labeled α-Synuclein Oligomers Determined by Single-Molecule Photobleaching

Bleaching proteins: Single-molecule photobleaching approaches and sub-stoichiometric labeling with fluorophores give insight into the number of monomers that form a specific α-synuclein oligomer. The results show that this α-synuclein oligomer is present as a single, well-defined species consisting of 31 monomers.     

Remodeling of the Fibrillation Pathway of α-Synuclein by Interaction with Antimicrobial Peptide LL-III

Liquid-liquid phase separation (LLPS) has emerged as a key mechanism for intracellular organization, and many recent studies have provided important insights into the role of LLPS in cell biology. There is also evidence that LLPS is associated with a variety of medical conditions, including neurodegenerative disorders. Pathological aggregation of α-synuclein, which is causally linked to Parkinson's disease, can proceed via droplet condensation, which then gradually transitions to the amyloid state. We show that the antimicrobial peptide LL-III is able to interact with both monomers and condensates of α-synuclein, leading to stabilization of the droplet and preventing conversion to the fibrillar state. The anti-aggregation activity of LL-III was also confirmed in a cellular model. We anticipate that studying the interaction of antimicrobial-type peptides with liquid condensates such as α-synuclein will contribute to the understanding of disease mechanisms (that arise in such condensates) and may also open up exciting new avenues for intervention.     

Effect of Acridine Derivatives on the Dissolution of α-Brass

Acridine derivatives as inhibitors of diffusion- and diffusion–kinetic-controlled dissolution of -brass are studied. Inhibition coefficients of the dissolution and its steps correlate with parameters of a standard reaction series and wavelengths of the longest-wave absorption band of the electronic spectrum.     

The Cleavage Effect of Histidyl-Lysine on RNA

Recentlytherehasbeenconsiderableinterestindevel0pingcatalyststhathydrolyticallycleavethePhosPhodiesterbackbone0fRNAsite-specificallyforthepotentialaPplicati0nstomolecularbi0l0gyandgenetheraPy"2SmallmoleculeswithRNAcleavageactivityareusedasresearchtoolsfortheinVestigationofnucleicacidstrUctUres.3'4SeveralexamPlesofoxidativecleavagecatalystshavebeenrePortCd.'MuchefforthasbeendevotedtoRNAhydIolysiscatalystSduet0theadvatgesover0xidativecleavageones.'MetaLbasedhydrolysisofRNAhasbeenreport…     

The Effect of α-Branched Side Chains on the Structural and Opto-Electronic Properties of Poly(Diketopyrrolopyrrole-alt-Terthiophene)

Introducing solubilizing α-branched alkyl chains on a poly(diketopyrrolopyrrole-alt-terthiophene) results in a dramatic change of the structural, optical, and electronic properties compared to the isomeric polymer carrying β-branched alkyl side chains. When branched at the α-position the alkyl substituent creates a steric hindrance that reduces the tendency of the polymer to π–π stack and endows the material with a much higher solubility in common organic solvents. The wider π–π stacking and reduced tendency to crystallize, evidenced from grazing-incidence wide-angle X-ray scattering, result in a wider optical band gap in the solid state. In solar cells with a fullerene acceptor, the α-branched isomer affords a higher open-circuit voltage, but an overall lower power conversion efficiency as a result of a too well-mixed nanomorphology. Due its reduced π–π stacking, the α-branched isomer fluoresces and affords near-infrared light-emitting diodes emitting at 820 nm.     

The reaction of α-stannylmethyllithium with esters

Ketonic compounds were prepared from esters using α-stannylmethyllithium as the reagent.     

The synthesis of enantioenriched α-hydroxy esters

α-Hydroxy esters are key structural units of valuable synthetic intermediates as well as natural products. In this review, enantioenriched α-hydroxy esters with moderate to excellent yield were prepared via various organocatalytic synthesis reactions.     

Dynamical Spin Chirality and Magnetoelectric Effect of α-Glycine

Dynamical spin chirality of α-glycine crystal at 301−302 K was investigated by DC (direct current)-magnetic susceptibility measurement at temperatures ranging from 2 to 315 K under the external magnetic fields (H=±1 T) parallel to the b axis. The α-glycine crystallizes in space group P2₁/n with four molecules in a cell, which has centrosymmetric charge distribution. The bifurcated hydrogen bonds N⁺(3)−H(8)···O(1) and N⁺(3)−H(8)···O(2) are stacked along the b axis with different bond intensities and angles, which form anti-parallel double layers. Atomic force spectroscopy result at 303 K indicated that the surface molecular structures of α-glycine formed a regular flexuous framework in the b axis direction. The strong temperature dependence is related to the reorientation of NH³⁺ group and the electron spin flip-flop of (N⁺H) mode. Under the opposite external magnetic field of 1 T and −1 T, the electron spins of N⁺(3)−H(8)···O(1) and N⁺(3)−H(8)···O(2) flip-flop at 301−302 K. These results suggested a mechanism of the magnetoelectric effect based on the dynamical spin chirality of (N⁺H), which induced the electric polarization to produce the onset of pyroelectricity of α-glycine around 304 K.