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991.
Guo-Xin Hu Guang Liang Yanhui Chu Xiaokun Li Qing-Quang Lian Han Lin Yi He Yadong Huang Dianne O. Hardy Ren-Shan Ge 《Bioorganic & medicinal chemistry letters》2010,20(8):2549-2551
Non-steroidal compounds that inhibit 17β-hydroxysteroid dehydrogenase isoform 3 (17β-HSD3), an enzyme catalyzing the final step in testosterone biosynthesis in Leydig cells, are under development for male contraceptive or treatment of androgen dependent diseases including prostate cancer. A series of curcumin analogues with more stable chemical structures were compared to curcumin as inhibitors of 17β-HSD3 in rat intact Leydig cells as well as rat and human testis microsomes. 相似文献
992.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
993.
994.
Kuei-Min Chung Jai-Hong Cheng Ching-Shu Suen Chih-Hsiang Huang Cheng-Han Tsai Li-Hao Huang Yi-Rong Chen Andrew H-J Wang Weir-Torn Jiaang Ming-Jing Hwang Xin Chen 《Protein science : a publication of the Protein Society》2010,19(9):1627-1638
Dipeptidyl peptidase IV (DPP‐IV) is a drug target in the treatment of human type II diabetes. It is a type II membrane protein with a single transmembrane domain (TMD) anchoring the extracellular catalytic domain to the membrane. DPP‐IV is active as a dimer, with two dimer interacting surfaces located extracellularly. In this study, we demonstrate that the TM of DPP‐IV promotes DPP‐IV dimerization and rescues monomeric DPP‐IV mutants into partial dimers, which is specific and irreplaceable by TMs of other type II membrane proteins. By bioluminescence resonance energy transfer (BRET) and peptide electrophoresis, we found that the TM domain of DPP‐IV is dimerized in mammalian cells and in vitro. The TM dimer interaction is very stable, based on our results with TM site‐directed mutagenesis. None of the mutations, including the introduction of two prolines, resulted in their complete disruption to monomers. However, these TM proline mutations result in a significant reduction of DPP‐IV enzymatic activity, comparable to what is found with mutations near the active site. A systematic analysis of TM structures deposited in the Protein Data Bank showed that prolines in the TM generally produce much bigger kinking angles than occur in nonproline‐containing TMs. Thus, the proline‐dependent reduction in enzyme activity may result from propagated conformational changes from the TM to the extracellular active site. Our results demonstrate that TM dimerization and conformation contribute significantly to the structure and activity of DPP‐IV. Optimal enzymatic activity of DPP‐IV requires an optimal interaction of all three dimer interfaces, including its TM. 相似文献
995.
Song Song Bo Zhang Hui Sun Xia Li Yanhui Xiang Zhonghua Liu Xun Huang Mei Ding 《PLoS genetics》2010,6(8)
One of the challenges to understand the organization of the nervous system has been to determine how axon guidance molecules govern axon outgrowth. Through an unbiased genetic screen, we identified a conserved Wnt pathway which is crucial for anterior-posterior (A/P) outgrowth of neurites from RME head motor neurons in Caenorhabditis elegans. The pathway is composed of the Wnt ligand CWN-2, the Frizzled receptors CFZ-2 and MIG-1, the co-receptor CAM-1/Ror, and the downstream component Dishevelled/DSH-1. Among these, CWN-2 acts as a local attractive cue for neurite outgrowth, and its activity can be partially substituted with other Wnts, suggesting that spatial distribution plays a role in the functional specificity of Wnts. As a co-receptor, CAM-1 functions cell-autonomously in neurons and, together with CFZ-2 and MIG-1, transmits the Wnt signal to downstream effectors. Yeast two-hybrid screening identified DSH-1 as a binding partner for CAM-1, indicating that CAM-1 could facilitate CWN-2/Wnt signaling by its physical association with DSH-1. Our study reveals an important role of a Wnt-Frz/Ror-Dsh pathway in regulating neurite A/P outgrowth. 相似文献
996.
997.
Dihydroorotase (DHO; EC 3.5.2.3) is an essential metalloenzyme in the biosynthesis of pyrimidine nucleotides. Here, we identified
and characterized DHO from the pathogenic bacterium Klebsiella pneumoniae (Kp). The activity of KpDHO toward l-dihydroorotate was observed with K
m = 0.04 mM and V
max = 8.87 μmol/(mg min). Supplementing the standard growth medium with Co2+, Mn2+, Mg2+, or Ni2+ increased enzyme activity. The catalytic activity of KpDHO was inhibited with Co2+, Zn2+, Mn2+, Cd2+, Ni2+, and phosphate ions. Substituting the putative metal binding residues His17, His19, Lys103, His140, His178, and Asp251 with
Ala completely abolished KpDHO activity. However, the activity of the mutant D251E was fourfold higher than that of the wild-type protein. On the basis
of these biochemical and mutational analyses, KpDHO (KPN01074) was identified as type II DHO. 相似文献
998.
999.
Steven S.-S. Wang Jinn-Tsyy Lai Ming-Shan Huang Clifford Y. Tai Hwai-Shen Liu 《Bioprocess and biosystems engineering》2010,33(8):1007-1015
The current research examines the impact of agitation on deactivation of isoamylase and β-amylase under supercritical carbon
dioxide (SC-CO2). Our experimental results showed that the activity of either enzyme decreased with increasing pressure or speed of agitation.
The degree of enzymatic deactivation caused by pressure became more prominent in the presence of agitation, suggesting that
the agitation plays an important role in enzymatic deactivation in SC-CO2 environment. Moreover, the enzymatic deactivation behavior associated with agitation and pressure was further quantitatively
analyzed using a proposed inactivation kinetic model. Our analysis indicated that isoamylase and β-amylase exhibited significantly
different relationships between the inverse of percentage residual activity and the product of number of revolution per time
and time elapsed under pressurized carbon dioxide. We believe that the outcome from this work may provide a better understanding
of the effects of agitation and pressure in enzyme deactivation behavior under SC-CO2. 相似文献
1000.
The overlapping ranges of closely related species provide a natural setting for the investigation of reticulate hybridization
and other evolutionary processes. In the present study, we examined the pattern of genetic variation and interspecific gene
flow in seven Actinidia species across ten localities in which sympatry among at least two species occurs. Our results showed that 48.7% of the alleles
across the nine nuclear microsatellite loci examined were shared among the seven Actinidia species. Moreover, at the species level, Actinidia chinensis and Actinidia deliciosa exhibited the highest genetic similarity, with a large percentage of shared alleles (P
s = 81.3%) and a significant consistency between the distribution frequency of their allele sizes (r = 0.859, P = 0.045). Yet, the genetic distinctions between species are obvious except for the species pair A. chinensis and A. deliciosa. Interspecific introgression was detected among the two main species pairs (Actinidia latifolia–Actinidia eriantha and A. chinensis–A. deliciosa), but more apparent in the latter in which 30% of the A. chinensis individuals and 49% of the A. deliciosa individuals showed genetic admixture in the STRUCTURE analysis. Possibly active hybrid zones relating to the two main species
pairs were discussed at last, which are expected to pave the way for the introgression breeding of kiwifruit from natural
sympatric populations. 相似文献