Kazuhiro Irie

The aggregation of the 42-residue amyloid β-protein (Aβ42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aβ42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Aβ42 aggreg

Amyloid fibrils in Alzheimer's disease mainly consist of 40- and 42-mer beta-amyloid peptides (Abeta40 and Abeta42) that exhibit aggregative ability and neurotoxicity. Although the aggregates of Abeta peptides are rich in intermolecular beta-sheet, the precise secondary structure of Abeta in the aggregates remains unclear. To identify the amino acid residues involved in the beta-sheet formation, 34 proline-substituted mutants of Abeta42 were synthesized and their aggregative ability and neurotox

The protein kinase C (PKC) family of enzymes plays a crucial role in cellular signal transduction and tumor promotion. Conventional and novel PKC isozymes consist of a catalytic domain for protein phosphorylation and a regulatory domain which binds the endogenous messenger diacyl glycerol or exogenous agents such as phorbol esters. The N-terminal regulatory region of these isozymes contains two cysteine-rich domains (C1A and C1B, also known as CRD1 and CRD2), both of which are candidates for the

Aggregation of the 42-residue amyloid beta-protein (Abeta42) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Despite numerous structural studies on Abeta aggregates, the relationship between tertiary structure and toxicity remains unclear. Our proline scanning and solid-state NMR studies suggested that aggregates both of wild-type Abeta42 and of E22K-Abeta42 (one of the mutants related to cerebral amyloid angiopathy) contain two conformers: a major one with a turn at positi

Diacylglycerol kinase (DGK) and protein kinase C (PKC) are two distinct enzyme families associated with diacylglycerol. Both enzymes have cysteine-rich C1 domains (C1A, C1B, and C1C) in the regulatory region. Although most PKC C1 domains strongly bind phorbol esters, there has been no direct evidence that DGK C1 domains bind phorbol esters. We synthesized 11 cysteine-rich sequences of DGK C1 domains with good sequence homology to those of the PKC C1 domains. Among them, only DGKgamma-C1A and DGK

New water-soluble fullerene carboxylic acids (1 and 2) derived from C60 and C70 fullerenes, respectively, were examined for photocytotoxicity toward Raji cells (B lymphocyte). These compounds did not show any photocytotoxic effect even at 50 microM, while pheophorbide a showed significant photocytotoxicity at 0.5 microM. Therefore, fullerene derivatives derived from C60 and C70 would not be practical agents for photodynamic therapy.

The tumor-promoting teleocidins and their core structure (−)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (−)-N13-desmethyl-N13-allylindolactam-V (3) and a sofa-restricted analogue, (−)-5-methylind

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is

Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (alpha, betaI, betaII, and gamma) and novel PKC isozymes (delta, epsilon, eta, and theta). As these C1 domains play differential roles in PKC activation and their transl

Recent investigations suggest that soluble oligomeric amyloid β (Aβ) species may be involved in early onset of Alzheimer's disease (AD). Using systematic proline replacement, solid-state NMR, and ESR, we identified a toxic turn at position 22 and 23 of Aβ42, the most potent neurotoxic Aβ species. Through radicalization, the toxic turn can induce formation of the C-terminal hydrophobic core to obtain putative Aβ42 dimers and trimers. Synthesized dimer and trimer models showed that the C-terminal