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51.
Kadono S Sakamoto A Kikuchi Y Oh-Eda M Yabuta N Yoshihashi K Kitazawa T Suzuki T Koga T Hattori K Shiraishi T Haramura M Kodama H Ono Y Esaki T Sato H Watanabe Y Itoh S Ohta M Kozono T 《Biochemical and biophysical research communications》2005,326(4):859-865
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. A novel peptide mimetic factor VIIa inhibitor, ethylsulfonamide-d-biphenylalanine-Gln-p-aminobenzamidine, shows 100-fold selectivity against thrombin in spite of its large P3 moiety, unlike previously reported FVIIa/TF selective inhibitors. X-ray crystal structure analysis reveals that the large P3 moiety, d-biphenylalanine, and the small P4 moiety, ethylsulfonamide, make novel interactions with the 170-loop and Lys192 of FVIIa/TF, respectively, accompanying ligand-induced conformational changes of the 170-loop, Gln217, and Lys192. Structural comparisons of FVIIa with thrombin and amino acid sequence comparisons among coagulation serine proteases suggest that these interactions play an important role in achieving selective inhibition for FVIIa/TF. 相似文献
52.
Dehydroepiandrosterone decreases elevated hepatic glucose production in C57BL/KsJ-db/db mice 总被引:1,自引:0,他引:1
Aoki K Taniguchi H Ito Y Satoh S Nakamura S Muramatsu K Yamashita R Ito S Mori Y Sekihara H 《Life sciences》2004,74(25):3075-3084
Dehydroepiandrosterone (DHEA) is known to improve hyperglycemia in diabetic db/db mice that are obese and insulin resistant. In a previous study, we reported that DHEA suppresses the elevated hepatic gluconeogenic glucose-6-phosphatase (G6Pase) activity and gene expression in C57BL/KsJ-db/db mice. In the present study, we evaluated the total amount of gluconeogenesis using NaH[(14)C]CO(3) and hepatic glucose production using fructose as a substrate in primary cultured hepatocytes. Despite hyperinsulinemia, the glucose production of db/db mice in the total body and hepatocytes was elevated as compared to their heterozygote littermate C57BL/KsJ-db/+m mice. Administration of DHEA significantly decreased the blood glucose level and increased the plasma insulin level in db/db mice. Administration of DHEA decreased the elevated total body and hepatic glucose production in db/db mice. In addition, the glucose production in the primary cultured hepatocytes of db/db mice was decreased significantly by the direct addition of DHEA or DHEA-S to the medium. These results suggest that administration of DHEA suppresses the elevated total body and hepatic glucose production in db/db mice, and this effect on the liver is considered to result from increased plasma insulin and DHEA or DHEA-S itself. 相似文献
53.
Yoshino H Sato H Shiraishi T Tachibana K Emura T Honma A Ishikura N Tsunenari T Watanabe M Nishimoto A Nakamura R Nakagawa T Ohta M Takata N Furumoto K Kimura K Kawata H 《Bioorganic & medicinal chemistry》2010,18(23):8150-8157
A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model. 相似文献
54.
Nakayama S Murata T Yasui Y Murayama K Isomura H Kanda T Tsurumi T 《Journal of virology》2010,84(24):12589-12598
The Epstein-Barr virus BMRF1 DNA polymerase processivity factor, which is essential for viral genome replication, exists mainly as a C-shaped head-to-head homodimer but partly forms a ring-shaped tetramer through tail-to-tail association. Based on its molecular structure, several BMRF1 mutant viruses were constructed to examine their influence on viral replication. The R256E virus, which has a severely impaired capacity for DNA binding and polymerase processivity, failed to form replication compartments, resulting in interference of viral replication, while the C95E mutation, which impairs head-to-head contact in vitro, unexpectedly hardly affected the viral replication. Also, surprisingly, replication of the C206E virus, which is expected to have impairment of tail-to-tail contact, was severely restricted, although the mutant protein possesses the same in vitro biochemical activities as the wild type. Since the tail-to-tail contact surface is smaller than that of the head-to-head contact area, its contribution to ring formation might be essential for viral replication. 相似文献
55.
Emiko Yoda Keiko Hachisu Yoshitaka Taketomi Kotomi Yoshida Masanori Nakamura Kazutaka Ikeda Ryo Taguchi Yoshihito Nakatani Hiroshi Kuwata Makoto Murakami Ichiro Kudo Shuntaro Hara 《Journal of lipid research》2010,51(10):3003-3015
Group VIB Ca2+-independent phospholipase A2γ (iPLA2γ) is a membrane-bound iPLA2 enzyme with unique features, such as the utilization of distinct translation initiation sites and the presence of mitochondrial and peroxisomal localization signals. Here we investigated the physiological functions of iPLA2γ by disrupting its gene in mice. iPLA2γ-knockout (KO) mice were born with an expected Mendelian ratio and appeared normal and healthy at the age of one month but began to show growth retardation from the age of two months as well as kyphosis and significant muscle weakness at the age of four months. Electron microscopy revealed swelling and reduced numbers of mitochondria and atrophy of myofilaments in iPLA2γ-KO skeletal muscles. Increased lipid peroxidation and the induction of several oxidative stress-related genes were also found in the iPLA2γ-KO muscles. These results provide evidence that impairment of iPLA2γ causes mitochondrial dysfunction and increased oxidative stress, leading to the loss of skeletal muscle structure and function. We further found that the compositions of cardiolipin and other phospholipid subclasses were altered and that the levels of myoprotective prostanoids were reduced in iPLA2γ-KO skeletal muscle. Thus, in addition to maintenance of homeostasis of the mitochondrial membrane, iPLA2γ may contribute to modulation of lipid mediator production in vivo. 相似文献
56.
Yoshimi Sugiura Kazutaka Araki Shun-ichiro Iemura Tohru Natsume Jun Hoseki Kazuhiro Nagata 《The Journal of biological chemistry》2010,285(10):7135-7142
In the endoplasmic reticulum (ER), a number of thioredoxin (Trx) superfamily proteins are present to enable correct disulfide bond formation of secretory and membrane proteins via Trx-like domains. Here, we identified a novel transmembrane Trx-like protein 4 (TMX4), in the ER of mammalian cells. TMX4, a type I transmembrane protein, was localized to the ER and possessed a Trx-like domain that faced the ER lumen. A maleimide alkylation assay showed that a catalytic CXXC motif in the TMX4 Trx-like domain underwent changes in its redox state depending on cellular redox conditions, and, in the normal state, most of the endogenous TMX4 existed in the oxidized form. Using a purified recombinant protein containing the Trx-like domain of TMX4 (TMX4-Trx), we confirmed that this domain had reductase activity in vitro. The redox potential of this domain (−171.5 mV; 30 °C at pH 7.0) indicated that TMX4 could work as a reductase in the environment of the ER. TMX4 had no effect on the acceleration of ER-associated degradation. Because TMX4 interacted with calnexin and ERp57 by co-immunoprecipitation assay, the role of TMX4 may be to enable protein folding in cooperation with these proteins consisting of folding complex in the ER. 相似文献
57.
58.
Mizuho Kusuda Mitsuhiro Ueda Yasuhito Konishi Yoshihito Araki Katsuji Yamanaka Masami Nakazawa Kazutaka Miyatake Takao Terashita 《Mycoscience》2006,47(4):184-189
We investigated extracellular carbohydrase production in the medium of an ectomycorrhizal fungus, Tricholoma matsutake, to reveal its ability to utilize carbohydrates such as starch as a growth substrate and to survey the saprotrophic aspects.
We found β-glucosidase activity in the static culture filtrate of this fungus. The β-glucosidase was purified and characterized.
The purified enzyme was obtained from about 2.1 l static culture filtrate, with 9.0% recovery, and showed a single protein
band on SDS-PAGE. Molecular mass was about 160 kDa. The enzyme was most active around 60°C and pH 5.0, and stable over a pH
of 4.0–8.0 for 30 min at 37°C. The purified enzyme was activated by the presence of Ca2+ and Mn2+ ions (about 2–3 times that of the control). The enzyme readily hydrolyzed oligosaccharides having a β-1,4-glucosidic linkage
such as cellobiose and cellotriose. However, it did not hydrolyze polysaccharides such as avicel and CM-cellulose or oligosaccharides
having an α-glucosidic linkage. Moreover, cellotriose was hydrolyzed by the enzyme for various durations, and the resultant
products were analyzed by TLC. We concluded that the enzyme from T. matsutake seems to be a β-glucosidase because cellotriose with a β-1,4-glucosidic linkage decomposed to glucose during the enzyme reaction. 相似文献
59.
Description of alternative male reproductive tactics in a shell-brooding cichlid, Telmatochromis vittatus, in Lake Tanganyika 总被引:1,自引:0,他引:1
Telmatochromis vittatus (Cichlidae) is a Tanganyikan substrate brooder which spawns in the gastropod-shell nests of a cichlid, Lamprologus callipterus. We describe male reproductive tactics of T. vittatus in and around the shell nests, where males of various sizes were found. Based on utilization patterns of the shell nests, interactions among males, and spawning behaviors, males could be categorized into four types based on reproductive tactics and in order of body size: sneaker males, satellite males, territorial males and piracy males. Size range of males in tactic groups rarely overlapped. Territorial males defended shell nests harboring multiple females, but during pair-spawning they were occasionally taken over by large piracy males that visited several nests repeatedly. Small sneaker males darted to pair-spawning territorial males and might ejaculate sperm. Satellite males did not perform parasitic spawning but pair-spawned in a single shell outside the nests. Spawning of satellite males was infrequently parasitized. The largest gonado-somatic index (GSI) was found in sneaker males followed by piracy males, territorial males and satellite males, suggesting that gonadal investment of males using the four tactics may be consistent with intensity or risk of sperm competition. 相似文献
60.
Kukimoto-Niino M Takagi T Akasaka R Murayama K Uchikubo-Kamo T Terada T Inoue M Watanabe S Tanaka A Hayashizaki Y Kigawa T Shirouzu M Yokoyama S 《The Journal of biological chemistry》2006,281(42):31843-31853
Rap2-interacting protein x (RPIPx) is a homolog of RPIP8, a specific effector of Rap2 GTPase. The N-terminal region of RPIP8, which contains the RUN domain, interacts with Rap2. Using cell-free synthesis and NMR, we determined that the region encompassing residues 83-255 of mouse RPIPx, which is 40-residues larger than the predicted RUN domain (residues 113-245), is the minimum fragment that forms a correctly folded protein. This fragment, the RPIPx RUN domain, interacted specifically with Rap2B in vitro in a nucleotide-dependent manner. The crystal structure of the RPIPx RUN domain was determined at 2.0 A of resolution by the multiwavelength anomalous dispersion (MAD) method. The RPIPx RUN domain comprises eight anti-parallel alpha-helices, which form an extensive hydrophobic core, followed by an extended segment. The residues in the core region are highly conserved, suggesting the conservation of the RUN domain-fold among the RUN domain-containing proteins. The residues forming a positively charged surface are conserved between RPIP8 and its homologs, suggesting that this surface is important for Rap2 binding. In the crystal the putative Rap2 binding site of the RPIPx RUN domain interacts with the extended segment in a segment-swapping manner. 相似文献