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121.
Gamma-glutamyl transpeptidase (GGT, EC 2.3.2.2) catalyzes the transfer of the gamma-glutamyl group of glutathione and related gamma-glutamyl amides to water (hydrolysis) or to amino acids and peptides (transpeptidation) and plays a central role in glutathione metabolism. GGT is involved in a number of biological events, such as drug resistance and metastasis of cancer cells by detoxification of xenobiotics and reactive oxygen species through glutathione metabolism, and is also implicated in physiological disorders, such as Parkinson's disease, neurodegerative disease, diabetes, and cardiovascular diseases. In this study, we designed, synthesized, and evaluated a series of gamma-phosphono diester analogues of glutamate as transition-state mimic inhibitors of GGT. The electrophilic phosphonate diesters served as highly potent mechanism-based inhibitors that caused the time-dependent and irreversible inhibition of both the E. coli and human enzymes, probably by phosphonylating the catalytic Thr residue of the enzyme. In particular, one of the inhibitors exhibited more than 6000 times higher activity toward human GGT than acivicin, a classical but nonselective inhibitor of GGT. The dependence of the inactivation rate on the leaving group ability of the phosphonates (Br?nsted plot) revealed that the phosphonylation of the catalytic Thr residue proceeded via a dissociative transition-state with substantial bond cleavage between the phosphorus and the leaving group for both E. coli and human GGTs. The binding site of GGT for the Cys-Gly moiety of glutathione or for the acceptor molecules was probed by the phosphonate diesters to reveal a significant difference in the mechanism of substrate recognition between E. coli and human GGT. Thus, in the human enzyme, a specific residue in the Cys-Gly binding site played a critical role in recognizing the Cys-Gly moiety or the acceptor molecules by interacting with the C-terminal carboxy group, whereas the Cys side chain and the Cys-Gly amide bond were not recognized significantly. In contrast, the E. coli enzyme was a nonselective enzyme that accommodated substrates without specifically recognizing the C-terminal carboxy group of the Cys-Gly moiety of gamma-glutamyl compounds or the acceptor molecules. The phosphonate diester-based GGT inhibitors shown here should serve as a blue print for the future design of highly selective GGT inhibitors for use as drug leads and biological probes that gain insight into the hitherto undefined physiological roles of GGT and the relationships between GGT and a variety of diseases. 相似文献
122.
Bäck M Sakata K Qiu H Haeggström JZ Dahlén SE 《Prostaglandins & other lipid mediators》2007,83(3):209-212
Leukotriene B(4) (LTB(4)) is an inflammatory mediator derived from the 5-lipoxygenase pathway of arachidonic acid metabolism and has recently implicated in the pathogenesis of atherosclerosis. There are two membrane bound receptors for LTB(4): BLT(1) and BLT(2), which represent the high and low affinity receptors, respectively. BLT receptors are expressed on leukocytes, and LTB(4) is a potent chemoattractant for neutrophils, eosinophils, and T lymphocytes. Recent studies have in addition shown that LTB(4) is an indirectly acting vasoconstrictor of isolated vascular preparations. In the guinea pig aorta, the LTB(4)-induced contractions were inhibited by endothelium-denudation. In addition, pre-treatment with the NO synthase inhibitor, L-NOARG, significantly enhanced the contractions induced by LTB(4). The contractile response induced by LTB(4) in the guinea pig aorta was abolished by the selective BLT(1) receptor antagonist U75302 and the expression of BLT(1) receptor mRNA in the guinea pig aorta was established by RT-PCR. Taken together, these results suggest that LTB(4) activates BLT(1) receptors on the endothelium of the guinea pig aorta, associated with the release of both contractile factors and NO. 相似文献
123.
124.
Li JB Hashimoto F Shimizu K Sakata Y 《Bioscience, biotechnology, and biochemistry》2007,71(11):2833-2836
Ten anthocyanins, cyanidin 3-sambubioside, 3-glucoside and their acylated derivatives, cyanidin 3-lathyroside and cyanidin 3-galactoside, were isolated from red flowers of Camellia reticulata. Their structures were determined on the basis of spectroscopic analyses, and the chemotaxonomic distribution of the accumulated anthocyanins in the petals of wild Camellia reticulata and C. pitardii var. yunnanica is discussed. 相似文献
125.
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127.
Nodake Y Fukumoto S Fukasawa M Yamasaki N Sakakibara R 《Bioscience, biotechnology, and biochemistry》2011,75(1):165-167
β-Lactoglobulin (BLG), a major allergen of cow's milk, was conjugated with the N-hydroxysuccinimide ester of the amylose-glycylglycine adduct (AG-ONSu) to reduce its immunogenicity, and the biochemical and immunological properties of the resulting conjugate (AG-BLG) were studied. The conjugate was prepared by modifying BLG with AG-ONSu, and was purified in a Sephadex G-100 column. The analytical data for AG-BLG indicated that 10.5 moles of AG-ONSu, with a mean molecular weight of 2,800, was covalently attached to the amino groups of the BLG molecule. Conjugation with AG-ONSu greatly decreased the reactivity of BLG with anti-BLG polyclonal antibodies owing to its shielding action for epitopes on the protein's surface. These findings suggest that AG-ONSu can be used advantageously to suppress the hypersensitivity mediated by IgG antibodies in milk allergy. 相似文献
128.
Abscisic acid (ABA) is not a plant-specific compound but one found in organisms across kingdoms from bacteria to animals,
suggesting that it is a ubiquitous and versatile substance that can modulate physiological functions of various organisms.
Recent studies have shown that plants developed an elegant system for ABA sensing and early signal transduction mechanisms
to modulate responses to environmental stresses for survival in terrestrial conditions. ABA-induced increase in stress tolerance
has been reported not only in vascular plants but also in non-vascular bryophytes. Since bryophytes are the key group of organisms
in the context of plant evolution, clarification of their ABA-dependent processes is important for understanding evolutionary
adaptation of land plants. Molecular approaches using Physcomitrella patens have revealed that ABA plays a role in dehydration stress tolerance in mosses, which comprise a major group of bryophytes.
Furthermore, we recently reported that signaling machinery for ABA responses is also conserved in liverworts, representing
the most basal members of extant land plant lineage. Conservation of the mechanism for ABA sensing and responses in angiosperms
and basal land plants suggests that acquisition of this mechanism for stress tolerance in vegetative tissues was one of the
critical evolutionary events for adaptation to the land. This review describes the role of ABA in basal land plants as well
as non-land plant organisms and further elaborates on recent progress in molecular studies of model bryophytes by comparative
and functional genomic approaches. 相似文献
129.
Uchiyama Makoto Inoue Yuichi Uchimura Naohisa Kawamori Ryuzo Kurabayashi Masahiko Kario Kazuomi Watada Hirotaka 《Sleep and biological rhythms》2011,9(2):63-72
Sleep and Biological Rhythms - Several epidemiological studies have shown that more than 20% of the general adult population has symptoms of insomnia, but only about 5% of them are receiving... 相似文献
130.
Mishina M Ishiwata K Naganawa M Kimura Y Kitamura S Suzuki M Hashimoto M Ishibashi K Oda K Sakata M Hamamoto M Kobayashi S Katayama Y Ishii K 《PloS one》2011,6(2):e17338
Adenosine A(2A) receptors (A2ARs) are thought to interact negatively with the dopamine D(2) receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-na?ve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([(11)C]TMSX) in nine drug-na?ve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-na?ve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-na?ve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-na?ve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-na?ve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD. 相似文献