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91.
92.
Motoshima K Sugita K Hashimoto Y Ishikawa M 《Bioorganic & medicinal chemistry letters》2011,21(10):3041-3045
Novel dipeptidyl peptidase IV (DPP-IV) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on α-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Representative compounds showed non-competitive inhibition of DPP-IV and 28a exhibited 10-fold selectivity for DPP-IV over DPP-8. Compound 28a is the first non-competitive, selective DPP-IV inhibitor. 相似文献
93.
Aoyama H Sugita K Nakamura M Aoyama A Salim MT Okamoto M Baba M Hashimoto Y 《Bioorganic & medicinal chemistry》2011,19(8):2675-2687
We identified a fused heteroaromatic amido structure based on the phenanthridine skeleton as a superior scaffold for candidate drugs with potent anti-HCV activity. Among the compounds synthesized, a phenanthridine analogue with a 1,3-dioxolyl group (24) possessed the most potent anti-HCV activity (EC(50) value: 50 nM), with acceptable cytotoxicity. The structural development and structure-activity relationships of these compounds are described. 相似文献
94.
Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure-activity relationship analysis and docking studies led us to the potent PPAR agonists 13c-e. The absolute configuration of 13c-e affects the PPAR subtype selectivity. 相似文献
95.
The small ubiquitin-related modifier (SUMO) is a ubiquitin-like post-translational modifier that alters the localization,
activity, or stability of many proteins. In the sumoylation process, an activated SUMO is transferred from SUMO-activating
enzyme E1 complex (SAE1/SAE2) to SUMO-conjugating enzyme E2 (Ubc9). Among the multiple domains in E1, a C-terminal ubiquitin
fold domain (UFD) of SAE2 shows high affinity for Ubc9, implying that UFD will be functionally important. We report NMR chemical
shift assignments of UFD in SAE2 from rice. Almost all the resonances of UFD were assigned uniquely, representing a single
conformation of UFD in solution. This is a contrast to the previous report for the corresponding UFD of human SAE2 which shows
two conformational states. The secondary structure prediction of UFD in rice SAE2 shows the similar overall structure to the
crystal structures of UFD in other E1 proteins such as SAE2 of human and yeast, ubiquitin-activating enzyme of yeast, and
NEDD8-activating enzyme E1 catalytic subunit of human. Concomitantly, differences in the length of helices, strands, and loops
are observed, particularly in the binding region to E2, supposing the variation in the UFD-E2 binding mode which may play
a critical role in determining E1-E2 specificity. 相似文献
96.
Mirhendi H Makimura K Zomorodian K Yamada T Sugita T Yamaguchi H 《Journal of microbiological methods》2005,61(2):281-284
A PCR-RFLP method targeted toward 26S rDNA and with 2 restriction enzymes, CfoI and BstF51, was developed to identify 11 Malassezia species. Not only type and standard strains but also 13 clinical isolates were identified successfully in this study. The results of identifications were confirmed by DNA sequencing. 相似文献
97.
Fibroblast cells derived from nevoid basal carcinoma syndrome (NBCCS) patients show increased levels of DNA synthesis after X-ray irradiation. Genes, whose expression is modulated in association with the DNA synthesis induction, were searched by using PCR-based mRNA differential display analysis in one of the NBCCS cell lines, NBCCS1 cells. Decreased levels of SMT3A gene expression were found in X-ray-irradiated NBCCS1 cells. This decrease was also shown by RT-PCR analysis in another cell line, NBCCS3 cells. In addition to NBCCS cells, normal fibroblast cells showed the DNA synthesis induction after X-ray irradiation when they were treated with antisense oligonucleotides (AO) for SMT3A. However, treatment of normal fibroblasts with the random oligonucleotides (RO) resulted in decreased levels of DNA synthesis after X-ray irradiation. Thus, down-regulation of SMT3A gene expression may be involved in the DNA synthesis induction after X-ray irradiation in the NBCCS cells at least tested. 相似文献
98.
99.
S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance 总被引:3,自引:0,他引:3
Yasukawa T Tokunaga E Ota H Sugita H Martyn JA Kaneki M 《The Journal of biological chemistry》2005,280(9):7511-7518
Inducible nitric-oxide synthase (iNOS) has been implicated in many human diseases including insulin resistance. However, how iNOS causes or exacerbates insulin resistance remains largely unknown. Protein S-nitrosylation is now recognized as a prototype of a redox-dependent, cGMP-independent signaling component that mediates a variety of actions of nitric oxide (NO). Here we describe the mechanism of inactivation of Akt/protein kinase B (PKB) in NO donor-treated cells and diabetic (db/db) mice. NO donors induced S-nitrosylation and inactivation of Akt/PKB in vitro and in intact cells. The inhibitory effects of NO donor were independent of phosphatidylinositol 3-kinase and cGMP. In contrast, the concomitant presence of oxidative stress accelerated S-nitrosylation and inactivation of Akt/PKB. In vitro denitrosylation with reducing agent reactivated recombinant and cellular Akt/PKB from NO donor-treated cells. Mutated Akt1/PKBalpha (C224S), in which cysteine 224 was substituted by serine, was resistant to NO donor-induced S-nitrosylation and inactivation, indicating that cysteine 224 is a major S-nitrosylation acceptor site. In addition, S-nitrosylation of Akt/PKB was increased in skeletal muscle of diabetic (db/db) mice compared with wild-type mice. These data suggest that S-nitrosylation-mediated inactivation may contribute to the pathogenesis of iNOS- and/or oxidative stress-involved insulin resistance. 相似文献
100.
Exocytosis, a critical process for neuronal communication and hormonal regulation, involves several distinct steps including MgATP-dependent priming (which involves the synthesis of phosphatidylinositol 4,5-bisphosphate). Type I phosphatidylinositol phosphate kinases (PIPKIs) were purified biochemically as a priming factor. PIPKI consists of three domains: the N-terminal region, the central kinase domain, and the C-terminal region. Three isoforms (alpha, beta, and gamma) of PIPKI have been identified, and each is alternatively spliced at the C-terminal region. In the present study, we conducted a structure/function analysis of PIPKIs in the priming of exocytosis, and we found that recombinant PIPKIalpha and PIPKIgamma had priming activity. However, an unexpected finding of these results was that PIPKIbeta did not prime exocytosis. The N- or C-terminal region of PIPKIalpha and PIPKIgamma was not required for priming, which indicates that the central kinase domain is sufficient for this process. Alternative splicing in each isoform did not affect the isoform specificity in priming. Priming activity by isoforms is strongly correlated with their phosphatidylinositol phosphate kinase activity because PIPKIalpha and PIPKIgamma had higher kinase activity than PIPKIbeta. These results suggest that PIPKIalpha and PIPKIgamma are the critical priming factors for exocytosis; it also suggests that the levels of phosphatidylinositol phosphate kinase activity in producing phosphatidylinositol 4,5-bisphosphate specify the function of PIPKI isoforms in priming. 相似文献