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451.
Jiao Chen Hui Chen Yun Shi Feng Hu Xingzhen Lao Xiangdong Gao Heng Zheng Wenbing Yao 《PloS one》2013,8(12)
New Delhi metallo-β-lactmase-1 (NDM-1) has attracted extensive attention for its high catalytic activities of hydrolyzing almost all β-lactam antibiotics. NDM-1 shows relatively higher similarity to subclass B1 metallo-β-lactmases (MβLs), but its residue at position 229 is identical to that of B2/B3 MβLs, which is a Tyr instead of a B1-MβL-conserved Trp. To elucidate the possible role of Y229 in the bioactivity of NDM-1, we performed mutagenesis study and molecular dynamics (MD) simulations. Although residue Y229 is spatially distant from the active site and not contacting directly with the substrate or zinc ions, the Y229W mutant was found to have higher kcat and Km values than those of wild-type NDM-1, resulting in 1∼7 fold increases in kcat/Km values against tested antibiotics. In addition, our MD simulations illustrated the enhanced flexibility of Loop 2 upon Y229W mutation, which could increase the kinetics of both substrate entrance (kon) and product egress (koff). The enhanced flexibility of Loop 2 might allow the enzyme to adjust the geometry of its active site to accommodate substrates with different structures, broadening its substrate spectrum. This study indicated the possible role of the residue at position 229 in the evolution of NDM-1. 相似文献
452.
BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules 总被引:9,自引:0,他引:9
Bloom's helicase (BLM) is thought to prevent crossing-over during DNA double-strand-break repair (DSBR) by disassembling double-Holliday junctions (dHJs) or by preventing their formation. We show that the Saccharomyces cerevisiae BLM ortholog, Sgs1, prevents aberrant crossing-over during meiosis by suppressing formation of joint molecules (JMs) comprising three and four interconnected duplexes. Sgs1 and procrossover factors, Msh5 and Mlh3, are antagonistic since Sgs1 prevents dHJ formation in msh5 cells and sgs1 mutation alleviates crossover defects of both msh5 and mlh3 mutants. We propose that differential activity of Sgs1 and procrossover factors at the two DSB ends effects productive formation of dHJs and crossovers and prevents multichromatid JMs and counterproductive crossing-over. Strand invasion of different templates by both DSB ends may be a common feature of DSBR that increases repair efficiency but also the likelihood of associated crossing-over. Thus, by disrupting aberrant JMs, BLM-related helicases maximize repair efficiency while minimizing the risk of deleterious crossing-over. 相似文献
453.
454.
Marsilje TH Alper PB Lu W Mutnick D Michellys PY He Y Karanewsky DS Chow D Gerken A Lao J Kim MJ Seidel HM Tian SS 《Bioorganic & medicinal chemistry letters》2008,18(19):5259-5262
The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag. 相似文献
455.
Debenham JS Madsen-Duggan CB Walsh TF Wang J Tong X Doss GA Lao J Fong TM Schaeffer MT Xiao JC Huang CR Shen CP Feng Y Marsh DJ Stribling DS Shearman LP Strack AM MacIntyre DE Van der Ploeg LH Goulet MT 《Bioorganic & medicinal chemistry letters》2006,16(3):681-685
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1. 相似文献
456.
ABSTRACT
The roles of SUMOylation and the related enzymes in autophagic regulation are unclear. Based on our previous studies that identified the SUMO2/3-specific peptidase SENP3 as an oxidative stress-responsive molecule, we investigated the correlation between SUMOylation and macroautophagy/autophagy. We found that Senp3± mice showed increased autophagy in the liver under basal and fasting conditions, compared to Senp3+/+ mice. We constructed a liver-specific senp3 knockout mouse; these Senp3-deficient liver tissues showed increased autophagy as well. Autophagic flux was accelerated in hepatic and other cell lines following knockdown of SENP3, both before and after the cells underwent starvation in the form of the serum and amino acid deprivation. We demonstrated that BECN1/beclin 1, the core molecule of the BECN1-PIK3C3 complex, could be SUMO3-conjugated by PIAS3 predominantly at K380 and deSUMOylated by SENP3. The basal SUMOylation of BECN1 was increased upon cellular starvation, which enhanced autophagosome formation by facilitating BECN1 interaction with other complex components UVRAG, PIK3C3 and ATG14, thus promoting PIK3C3 activity. In contrast, SENP3 deSUMOylated BECN1, which impaired BECN1-PIK3C3 complex formation or stability to suppress the PIK3C3 activity. DeSUMOylation of BECN1 restrained autophagy induction under basal conditions and especially upon starvation when SENP3 had accumulated in response to the increased generation of reactive oxygen species. Thus, while reversible SUMOylation regulated the degree of autophagy, SENP3 provided an intrinsic overflow valve for fine-tuning autophagy induction. 相似文献
457.
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459.
Two new phytotoxic γ‐lactones, pestalotines A and B ( 1 and 2 , resp.), along with 4‐oxo‐4H‐pyran‐3‐acetic acid ( 3 ) and 6‐hydroxyramulosin (=3,4,4a,5,6,7‐hexahydro‐6,8‐dihydroxy‐3‐methyl‐1H‐2‐benzopyran‐1‐one; 4 ), were isolateded from the culture of Pestalotiopsis sp. HC02, a fungus residing in the Chondracris rosee gut. Structures of the new metabolites were elucidated on the basis of their IR, NMR, and MS data. Pestalotines A and B ( 1 and 2 , resp.) significantly inhibited the radical growth of Echinochloa crusgalli with IC50 values of 1.85×10?4 and 2.50×10?4 M , respectively, comparable to that of 2‐(2,4‐dichlorophenoxy)acetic acid (0.94×10?4 M ) used as a positive control. 相似文献
460.