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991.
Influence of the acetylcholinesterase active site protonation on omega loop and active site dynamics
Wiesner J Kříž Z Kuča K Jun D Koča J 《Journal of biomolecular structure & dynamics》2010,28(3):393-403
Existence of alternative entrances in acetylcholinesterase (AChE) could explain the contrast between the very high AChE catalytic efficiency and the narrow and long access path to the active site revealed by X-ray crystallography. Alternative entrances could facilitate diffusion of the reaction products or at least water and ions from the active site. Previous molecular dynamics simulations identified side door and back door as the most probable alternative entrances. The simulations of non-inhibited AChE suggested that the back door opening events occur only rarely (0.8% of the time in the 10ns trajectory). Here we present a molecular dynamics simulation of non-inhibited AChE, where the back door opening appears much more often (14% of the time in the 12ns trajectory) and where the side door opening was observed quite frequently (78% of trajectory time). We also present molecular dynamics, where the back door does not open at all, or where large conformational changes of the AChE omega loop occur together with alternative passage opening events. All these differences in AChE dynamical behavior are caused by different protonation states of two glutamate residues located on bottom of the active site gorge (Glu202 and G450 in Mus musculus AChE). Our results confirm the results of previous molecular dynamics simulations, expand the view and suggest the probable reasons for the overall conformational behavior of AChE omega loop. 相似文献
992.
Background
The intake of soy isoflavones among women with breast cancer has become a public health concern, because these compounds have weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy.Methods
For patients who underwent surgery for breast cancer between August 2002 and July 2003 and who were receiving adjuvant endocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by means of multivariable Cox proportional hazards regression models. We further stratified the analyses by hormonal receptor status and endocrine therapy.Results
The median follow-up period for the 524 patients in this study was 5.1 years. Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones (HR = 1.05, 95% CI 0.78–1.71 for the highest quartile [> 42.3 mg/day] v. the lowest quartile [< 15.2 mg/day], p for trend = 0.87). Relative to post-menopausal patients in the lowest quartile of soy isoflavone intake, the risk of recurrence for post-menopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54–0.85, p for trend = 0.02). Inverse associations were observed in patients with estrogen and progesterone receptor positive disease and those receiving anastrozole therapy.Interpretation
High dietary intake of soy isoflavones was associated with lower risk of recurrence among post-menopausal patients with breast cancer positive for estrogen and progesterone receptor and those who were receiving anastrozole as endocrine therapy.A variety of health benefits in terms of cancer and cardiovascular disease have been attributed to the consumption of soy foods, primarily because of soy isoflavones.1 Three primary isoflavones account for virtually all of the isoflavones in soy beans: genistein (about 50%), daidzein (about 40%) and glycitein (about 10%). The chemical structure of soy isoflavones is similar to that of estrogens. The isoflavones are therefore considered to be possible selective estrogen receptor modulators, which may bind to estrogen receptors and selectively stimulate or inhibit estrogen-like action in various tissues.2 Given that soy-based foods are now more frequently consumed than was previously the case, both as an alternative approach to treating the symptoms of menopause and for promoting cardiovascular health,3,4 concerns have arisen about the intake of these compounds by patients with hormone-sensitive breast cancer, in whom tumour growth depends largely on estrogen. Tamoxifen and anastrozole are commonly used as adjuvant endocrine therapy for hormone-sensitive breast cancer, and these drugs are effective in preventing recurrence and prolonging survival.5,6 In some experimental studies the inhibitory effects of tamoxifen on growth of implanted mammary tumours were negated by dietary administration of soy isoflavones,7,8 but in other rodent cancer models, soy food appeared to enhance the beneficial effects of tamoxifen.9 Little is known about the potential effects of consuming soy isoflavones for patients with breast cancer who are receiving adjuvant endocrine therapy. We used data for a cohort of postoperative patients with breast cancer who were receiving adjuvant endocrine therapy to examine the relation between intake of soy isoflavones and recurrence of breast cancer and death. 相似文献993.
Zhengfeng Fang Kang Yao Xiaoling Zhang Shengjun Zhao Zhihong Sun Gang Tian Bing Yu Yan Lin Biquan Zhu Gang Jia Keying Zhang Daiwen Chen De Wu 《Amino acids》2010,39(3):633-640
Sulfur amino acids (SAA), particularly methionine and cysteine, are critical for the gut to maintain its functions including the digestion, absorption and metabolism of nutrients, the immune surveillance of the intestinal epithelial layer and regulation of the mucosal response to foreign antigens. However, the metabolism of SAA in the gut, specifically the transmethylation of methionine, will result in a net release of homocysteine, which is shown to be associated with cardiovascular disease and stroke. Furthermore, the extensive catabolism of dietary methionine by the intestine or by luminal microbes may result in a decrease in nutritional efficiency. Therefore, the regulation of SAA metabolism in the gut is not only nutritionally relevant, but also relevant to the overall health and well-being. The superiority of dl-2-hydroxy-4-methylthiobutyrate to dl-methionine in decreasing homocysteine production, alleviating stress responses, and reducing the first-pass intestinal metabolism of dietary methionine may provide a promising implication for nutritional strategies to manipulate SAA metabolism and thus to improve the nutrition and health status of animals and perhaps humans. 相似文献
994.
Viivi Majava Chaozhan Wang Matti Myllykoski Salla M. Kangas Sung Ung Kang Nobuhiro Hayashi Peter Baumgärtel Anthony M. Heape Gert Lubec Petri Kursula 《Amino acids》2010,39(1):59-71
Myelin basic protein (MBP) is present between the cytoplasmic leaflets of the compact myelin membrane in both the peripheral and central nervous systems, and characterized to be intrinsically disordered in solution. One of the best-characterized protein ligands for MBP is calmodulin (CaM), a highly acidic calcium sensor. We pulled down MBP from human brain white matter as the major calcium-dependent CaM-binding protein. We then used full-length brain MBP, and a peptide from rodent MBP, to structurally characterize the MBP–CaM complex in solution by small-angle X-ray scattering, NMR spectroscopy, synchrotron radiation circular dichroism spectroscopy, and size exclusion chromatography. We determined 3D structures for the full-length protein–protein complex at different stoichiometries and detect ligand-induced folding of MBP. We also obtained thermodynamic data for the two CaM-binding sites of MBP, indicating that CaM does not collapse upon binding to MBP, and show that CaM and MBP colocalize in myelin sheaths. In addition, we analyzed the post-translational modifications of rat brain MBP, identifying a novel MBP modification, glucosylation. Our results provide a detailed picture of the MBP–CaM interaction, including a 3D model of the complex between full-length proteins. 相似文献
995.
Hong-In Lee Jin-Won Lee Tran-Chin Yang Sa-Ouk Kang Brian M. Hoffman 《Journal of biological inorganic chemistry》2010,15(2):175-182
Superoxide dismutases (SODs) protect cells against oxidative stress by disproportionating O2
− to H2O2 and O2. The recent finding of a nickel-containing SOD (Ni-SOD) has widened the diversity of SODs in terms of metal contents and
SOD catalytic mechanisms. The coordination and geometrical structure of the metal site and the related electronic structure
are the keys to understanding the dismutase mechanism of the enzyme. We performed Q-band 14N,1/2H continuous wave (CW) and pulsed electron–nuclear double resonance (ENDOR) and X-band 14N electron spin echo envelope modulation (ESEEM) on the resting-state Ni-SOD extracted from Streptomyces seoulensis. In-depth analysis of the data obtained from the multifrequency advanced electron paramagnetic resonance techniques detailed
the electronic structure of the active site of Ni-SOD. The analysis of the field-dependent Q-band 14N CW ENDOR yielded the nuclear hyperfine and quadrupole coupling tensors of the axial Nδ of the His-1 imidazole ligand. The tensors are coaxial with the g-tensor frame, implying the g-tensor direction is modulated by the imidazole plane. X-band 14N ESEEM characterized the hyperfine coupling of Nε of His-1 imidazole. The nuclear quadrupole coupling constant of the nitrogen suggests that the hydrogen-bonding between Nε–H and OGlu-17 present for the reduced-state Ni-SOD is weakened or broken upon oxidizing the enzyme. Q-band 1H CW ENDOR and pulsed 2H Mims ENDOR showed a strong hyperfine coupling to the protons(s) of the equatorially coordinated His-1 amine and a weak hyperfine
coupling to either the proton(s) of a water in the pocket at the side opposite the axial Nδ or the proton of a water hydrogen-bonded to the equatorial thiolate ligand. 相似文献
996.
997.
Kang Hee-Kwon Jang Jun-Hyuck Shim Jae-Hoon Park Jong-Tae Kim Young-Wan Park Kwan-Hwa 《World journal of microbiology & biotechnology》2010,26(10):1915-1918
4-α-Glucanotransferases possess strong transglycosylation activity which has been used in various carbohydrate chemistry fields.
Due to safety issues of the recombinant enzymes we chose Bacillus subtilis as an expression host to produce a thermostable 4-α-glucanotransferase from Thermus scotoductus (TSαGT). The HpaII promoter in the Gram-positive bacterial vector pUB110 was used first to express TSαGT gene in B. subtilis. However, the activity of TSαGT in B. subtilis was only 4% of that in our previous Escherichia coli system. Two expression systems constructed by sequential alignment of another constitutive promoter for either α-amylase
from B. subtilis NA64 or maltogenic amylase from Bacillus licheniformis downstream of the HpaII promoter elevated the TSαGT productivity by 11- and 12-fold, respectively, compared to the single HpaII promoter system. In conclusion, the dual promoter systems in this study were much better than the single promoter system
to express the TSαGT gene in B. subtilis. 相似文献
998.
999.
1000.
Nguyen Huu Tung Gyu Yong Song Jeong-Ah Kim Jae-Hee Hyun Hee-Kyoung Kang Young Ho Kim 《Bioorganic & medicinal chemistry letters》2010,20(1):309-314
Six dammarane-type saponins, including three new compounds, floralginsenosides Ta–Tc (1–3), and three known, floralginsenoside Td (4), ginsenoside F1 (5), and ginsenoside F5 (6), were isolated from the flower buds of Panax ginseng. Floralginsenoside Td (4) was first isolated from natural plant sources. Their structures were elucidated on the basis of extensive chemical and spectroscopic methods. Compounds 1, 5, and 6 showed cytotoxic activities towards the HL-60 human leukemia cell line with respective IC50 values of 36.3, 23.2, and 62.4 μM. In addition, after the HL-60 cells were treated with these compounds, several apoptosis events, including chromatin condensation and increase in the population of sub-G1 hypodiploid cells, were observed. 相似文献