Charge-Pairing Mechanism of Phosphorylation Effect upon Amyloid Fibrillation of Human Tau Core Peptide

Phosphorylation of a fibrillogenic protein, human tau, is believed to play crucial roles in the pathogenesis of Alzheimer’s disease. For elucidating molecular mechanisms of the phosphorylation effect on tau fibrillation, we synthesized a peptide, VQIVY310K (PHF6) and its phosphorylated derivative (PHF6pY). PHF6 is a partial peptide surrounding a plausible in vivo phosphorylation site Tyr310 and forms amyloid-type fibrils similar to those generated by full-length tau. Fibrillation of PHF6 and PHF6pY were studied by spectroscopic and microscopic methods, and the critical concentration of the fibrillation was determined for comparing the fibril stability. The results showed that the phosphorylation strongly influenced the fibrillation propensity of PHF6 by changing its dependency on pH and ionic strength. On the basis of the observations, we suggested that charged sites on the phosphate group and its electrostatic pairing with the neighboring charged residues were physical origins of the phosphorylation effect. To verify this charge-pairing mechanism, we conducted experiments using a series of PHF6 derivatives with non-native charge distributions. The electrostatic interaction in an intermolecular mode was also demonstrated by the system composed of two different peptide species, which found that fibrillation of nonphosphorylated PHF6 was drastically enhanced when a trace amount of phosphorylated PHF6 molecules coexisted. A simulation analysis utilizing crystal coordinates of the PHF6 fibril was also performed for interpreting the experimental results in a molecular level. The present study using the model peptide system gave us a microscopically insightful view on the roles of tau phosphorylation in amyloid-related diseases

Silver/ThioClickFerrophos-Catalyzed Enantioselective Conjugate Addition and Cycloaddition of Glycine Imino Ester with Nitroalkenes

We applied the combination of AgOAc with ThioClickFerrophos, the chiral ferrocenyl triazole-based P,S-ligand, to the reaction of glycine imino ester with nitroalkenes. The conjugate addition of the imino methyl ester preferentially produced anti-α-imino-γ-nitrobutyrates in good yields with high enantioselectivities (ee) of up to 99% at −25 °C in THF in the presence of triethylamine. Meanwhile, the pyrrolidine cycloadducts were obtained as major products in good yields with high enantioselectivities (up to 96% ee) using tert-butyl imino ester in the absence of triethylamine at room temperature

Silver/ThioClickFerrophos-Catalyzed Enantioselective Conjugate Addition and Cycloaddition of Glycine Imino Ester with Nitroalkenes

We applied the combination of AgOAc with ThioClickFerrophos, the chiral ferrocenyl triazole-based <i>P,S</i>-ligand, to the reaction of glycine imino ester with nitroalkenes. The conjugate addition of the imino methyl ester preferentially produced <i>anti-</i>α-imino-γ-nitrobutyrates in good yields with high enantioselectivities (ee) of up to 99% at −25 °C in THF in the presence of triethylamine. Meanwhile, the pyrrolidine cycloadducts were obtained as major products in good yields with high enantioselectivities (up to 96% ee) using <i>tert</i>-butyl imino ester in the absence of triethylamine at room temperature

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an o-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an o-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an o-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an o-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration

Silver/ThioClickFerrophos-Catalyzed Enantioselective Conjugate Addition and Cycloaddition of Glycine Imino Ester with Nitroalkenes

We applied the combination of AgOAc with ThioClickFerrophos, the chiral ferrocenyl triazole-based P,S-ligand, to the reaction of glycine imino ester with nitroalkenes. The conjugate addition of the imino methyl ester preferentially produced anti-α-imino-γ-nitrobutyrates in good yields with high enantioselectivities (ee) of up to 99% at −25 °C in THF in the presence of triethylamine. Meanwhile, the pyrrolidine cycloadducts were obtained as major products in good yields with high enantioselectivities (up to 96% ee) using tert-butyl imino ester in the absence of triethylamine at room temperature

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration

Stereochemistry of Substitution of the α‑Dimethylamino Group by Dialkylzinc in Chiral Benzylferrocene

The stereochemistry of the substitution of the α-dimethylamino group by dimethylzinc in the presence of acetyl chloride in the chiral benzylferrocene backbone was examined. The reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at both ferrocene and the phenyl ring proceeded with inversion of configuration, while the reaction with the benzylferrocene bearing an <i>o</i>-bromo substituent at either ferrocene or the phenyl ring proceeded with retention of configuration