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21.
Anderka O Loenze P Klabunde T Dreyer MK Defossa E Wendt KU Schmoll D 《Biochemistry》2008,47(16):4683-4691
Glycogen phosphorylase (GP) is a validated target for the treatment of type 2 diabetes. Here we describe highly potent GP inhibitors, AVE5688, AVE2865, and AVE9423. The first two compounds are optimized members of the acyl urea series. The latter represents a novel quinolone class of GP inhibitors, which is introduced in this study. In the enzyme assay, both inhibitor types compete with the physiological activator AMP and act synergistically with glucose. Isothermal titration calorimetry (ITC) shows that the compounds strongly bind to nonphosphorylated, inactive GP (GPb). Binding to phosphorylated, active GP (GPa) is substantially weaker, and the thermodynamic profile reflects a coupled transition to the inactive (tense) conformation. Crystal structures confirm that the three inhibitors bind to the AMP site of tense state GP. These data provide the first direct evidence that acyl urea and quinolone compounds are allosteric inhibitors that selectively bind to and stabilize the inactive conformation of the enzyme. Furthermore, ITC reveals markedly different thermodynamic contributions to inhibitor potency that can be related to the binding modes observed in the cocrystal structures. For AVE5688, which occupies only the lower part of the bifurcated AMP site, binding to GPb (Kd = 170 nM) is exclusively enthalpic (Delta H = -9.0 kcal/mol, TDelta S = 0.3 kcal/mol). The inhibitors AVE2865 (Kd = 9 nM, Delta H = -6.8 kcal/mol, TDelta S = 4.2 kcal/mol) and AVE9423 (Kd = 24 nM, Delta H = -5.9 kcal/mol, TDelta S = 4.6 kcal/mol) fully exploit the volume of the binding pocket. Their pronounced binding entropy can be attributed to the extensive displacement of solvent molecules as well as to ionic interactions with the phosphate recognition site. 相似文献
22.
Summary In 214 healthy young Germans the activity of Pyruvatekinase from red blood cells has been determined. Three persons had values in the heterozygote range between 10.0 and 20.0 U. Suggesting a 2-allele-model the frequency of the three phenotypes in the German population can be calculated as followed: PK(A)=98.6%, PK(AB)=1.4%, PK(B)=0.005%.No correlation could be found between the distribution of blood-and serum-groups and the enzyme-activity.
Direktor: Prof. Dr. med. G. W. Löhr
Direktor: Prof. Dr. med. G. G. Wendt
Mit dankenswerter Unterstützung durch die Deutsche Volkswagen-Stiftung.
Herrn Professor Dr.H. E. Bock, Tübingen, zum 65. Geburtstag gewidmet. Wesentliche Teile dieser Arbeit werden von Olaf Praetsch der Medizinischen Fakultät als Dissertation vorgelegt. 相似文献
Direktor: Prof. Dr. med. G. W. Löhr
Direktor: Prof. Dr. med. G. G. Wendt
Mit dankenswerter Unterstützung durch die Deutsche Volkswagen-Stiftung.
Herrn Professor Dr.H. E. Bock, Tübingen, zum 65. Geburtstag gewidmet. Wesentliche Teile dieser Arbeit werden von Olaf Praetsch der Medizinischen Fakultät als Dissertation vorgelegt. 相似文献
23.
The fate of glycerol trinitrate when exposed to microbial attack has been investigated. Contrary to some earlier reports, this compound was readily biodegraded by employing batch or continuous techniques under a variety of cultural conditions. Breakdown of glycerol trinitrate took place stepwise via the dinitrate and mononitrate isomers, with each succeeding step proceeding at a slower rate. After a residence time of 8 to 15 h, none of the glycerol nitrates could be detected in the effluent from a continuous-culture apparatus (chemostat) supplied with an influent containing 30 mg of glycerol trinitrate per liter. 相似文献
24.
Douétts-Peres Jackellinne Caetano Aragão Victor Paulo Mesquita Cruz Marco Antônio Lopes Reis Ricardo Souza Elbl Paula dos Santos André Luis Wendt Floh Eny Iochevet Segal Silveira Vanildo Santa-Catarina Claudete 《Plant Cell, Tissue and Organ Culture》2019,138(2):273-286
Plant Cell, Tissue and Organ Culture (PCTOC) - The Monopolar Spindle 1 (Mps1) protein is a dual-specificity kinase that plays a critical role in the progression of the cell cycle. Studies on... 相似文献
25.
Wang Y Pitet LM Finlay JA Brewer LH Cone G Betts DE Callow ME Callow JA Wendt DE Hillmyer MA DeSimonea JM 《Biofouling》2011,27(10):1139-1150
The facile preparation of amphiphilic network coatings having a hydrophobic dimethacryloxy-functionalized perfluoropolyether (PFPE-DMA; M(w) = 1500 g mol(-1)) crosslinked with hydrophilic monomethacryloxy functionalized poly(ethylene glycol) macromonomers (PEG-MA; M(w) = 300, 475, 1100 g mol(-1)), intended as non-toxic high-performance marine coatings exhibiting antifouling characteristics is demonstrated. The PFPE-DMA was found to be miscible with the PEG-MA. Photo-cured blends of these materials containing 10 wt% of PEG-MA oligomers did not swell significantly in water. PFPE-DMA crosslinked with the highest molecular weight PEG oligomer (ie PEG1100) deterred settlement (attachment) of algal cells and cypris larvae of barnacles compared to a PFPE control coating. Dynamic mechanical analysis of these networks revealed a flexible material. Preferential segregation of the PEG segments at the polymer/air interface resulted in enhanced antifouling performance. The cured amphiphilic PFPE/PEG films showed decreased advancing and receding contact angles with increasing PEG chain length. In particular, the PFPE/PEG1100 network had a much lower advancing contact angle than static contact angle, suggesting that the PEG1100 segments diffuse to the polymer/water interface quickly. The preferential interfacial aggregation of the larger PEG segments enables the coating surface to have a substantially enhanced resistance to settlement of spores of the green seaweed Ulva, cells of the diatom Navicula and cypris larvae of the barnacle Balanus amphitrite as well as low adhesion of sporelings (young plants) of Ulva, adhesion being lower than to a polydimethyl elastomer, Silastic T2. 相似文献
26.
27.
Yields of groundnut, the traditional grain legume grown in central and southern Cameroon and in much of the humid zone of Central Africa, are generally low. Other food legumes may provide alternatives to groundnut. On-farm experiments examined the relative yields of up to 15 pigeonpea, 10 groundnut, 7 soybean, and 4 cowpea varieties over three growing seasons in four to six rural communities. Soil analytical values and rainfall data from all seasons were used as covariates in the analysis of variance. In the first two trials, variety-within-species interactions were significant (P<0.0001 and 0.04). Groundnut var. JL-24 yielded 60% more than local groundnuts in the first season of 2000, while soybean var. TGx1838-5E, local cowpea var. `Mefak' and pigeonpea var. ICEAP 00436 outyielded several other varieties of their respective species. Comparing these selected varieties over three seasons, significant species×community and species×season effects (P<0.0001) were observed. Covariate analysis showed that soybean yields increased with increasing soil Mg saturation and P levels. Groundnut yielded more in the first season of 2000 compared to the second seasons of 1999 and 2000 (average yields of 927 kg ha–1 vs. 422 and 522 kg ha–1, respectively). Improved yields were related to soil exchangeable Ca levels greater than 5 cmol(+) kg–1 in both second seasons, but not during the first season. Cowpea yields were superior in both second seasons. Pigeonpea yields were unrelated to soil factors, showing its wide adaptability to soil conditions. Pigeonpea, which matured in February during the dry season, was severely affected by the early cessation of rains in 2000. In 1999 yields averaged 820 kg ha–1 across communities. The results show that good food legume alternatives to groundnut exist, particularly for second season production. Species can be targeted to communities based on soil properties and season of production. 相似文献
28.
Cornélissen G Masalov A Halberg F Richardson JD Katinas GS Sothern RB Watanabe Y Syutkina EV Wendt HW Bakken EE Romanov Y 《Fiziologiia cheloveka》2004,30(2):86-92
AIMS: Velocity changes in the solar wind, recorded by satellite (IMP8 and Wind) are characterized by a solar cycle dependent approximately 1.3-year component. The presence of any approximately 1.3-year component in human blood pressure (BP) and heart rate (HR) and in mortality from myocardial infarction (MI) is tested and its relative prominence compared to the 1.0-year variation. MATERIALS AND METHODS: Around the clock manual or automatic BP and HR measurements from four subjects recorded over 5 to 35 years and a 29-year record of mortality from MI in Minnesota were analyzed by linear-nonlinear rhythmometry. Point and 95% confidence interval (CI) estimates were obtained for the approximately 1.3-year period and amplitude. The latter is compared with the 1.0-year amplitude for BP and HR records concurrent to the solar data provided by one of us (JDR). RESULTS: An approximately 1.3-year component is resolved nonlinearly for MI, with a period of 1.23 (95% CI: 1.21; 1.26) year. This component was invariably validated with statistical significance for BP and HR by linear rhythmometry. Nonlinearly, the 95% CI for the 1.3-year amplitude did not overlap zero in 11 of the 12 BP and HR series. Given the usually strong synchronizing role of light and temperature, it is surprising that 5 of the 12 cardiovascular series had a numerically larger amplitude of the 1.3-year versus the precise 1.0-year component. The beating of the approximately 1.3-year and 1.0-year components was shown by gliding spectra on actual and simulated data. DISCUSSION AND CONCLUSION: The shortest 5-year record (1998-2003) revealed an approximately 1.3-year component closer to the solar wind speed period characterizing the entire available record (1994-2003) than that for the concurrent 5-year span. Physiological variables may resonate with non-photic environmental cycles that may have entered the genetic code during evolution. 相似文献
29.
Yeong FM Hombauer H Wendt KS Hirota T Mudrak I Mechtler K Loregger T Marchler-Bauer A Tanaka K Peters JM Ogris E 《Current biology : CB》2003,13(23):2058-2064
Protein phosphatase 2A (PP2A) holoenzymes consist of a catalytic C subunit, a scaffolding A subunit, and one of several regulatory B subunits that recruit the AC dimer to substrates. PP2A is required for chromosome segregation, but PP2A's substrates in this process remain unknown. To identify PP2A substrates, we carried out a two-hybrid screen with the regulatory B/PR55 subunit. We isolated a human homolog of C. elegans HCP6, a protein distantly related to the condensin subunit hCAP-D2, and we named this homolog hHCP-6. Both C. elegans HCP-6 and condensin are required for chromosome organization and segregation. HCP-6 binding partners are unknown, whereas condensin is composed of the structural maintenance of chromosomes proteins SMC2 and SMC4 and of three non-SMC subunits. Here we show that hHCP-6 becomes phosphorylated during mitosis and that its dephosphorylation by PP2A in vitro depends on B/PR55, suggesting that hHCP-6 is a B/PR55-specific substrate of PP2A. Unlike condensin, hHCP-6 is localized in the nucleus in interphase, but similar to condensin, hHCP-6 associates with chromosomes during mitosis. hHCP-6 is part of a complex that contains SMC2, SMC4, kleisin-beta, and the previously uncharacterized HEAT repeat protein FLJ20311. hHCP-6 is therefore part of a condensin-related complex that associates with chromosomes in mitosis and may be regulated by PP2A. 相似文献
30.