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991.
The structure of Rauvolfia serpentina strictosidine synthase is a novel six-bladed beta-propeller fold in plant proteins
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The enzyme strictosidine synthase (STR1) from the Indian medicinal plant Rauvolfia serpentina is of primary importance for the biosynthetic pathway of the indole alkaloid ajmaline. Moreover, STR1 initiates all biosynthetic pathways leading to the entire monoterpenoid indole alkaloid family representing an enormous structural variety of approximately 2000 compounds in higher plants. The crystal structures of STR1 in complex with its natural substrates tryptamine and secologanin provide structural understanding of the observed substrate preference and identify residues lining the active site surface that contact the substrates. STR1 catalyzes a Pictet-Spengler-type reaction and represents a novel six-bladed beta-propeller fold in plant proteins. Structure-based sequence alignment revealed a common repetitive sequence motif (three hydrophobic residues are followed by a small residue and a hydrophilic residue), indicating a possible evolutionary relationship between STR1 and several sequence-unrelated six-bladed beta-propeller structures. Structural analysis and site-directed mutagenesis experiments demonstrate the essential role of Glu-309 in catalysis. The data will aid in deciphering the details of the reaction mechanism of STR1 as well as other members of this enzyme family. 相似文献
992.
993.
Stadlmann S Renner K Pollheimer J Moser PL Zeimet AG Offner FA Gnaiger E 《Cell biochemistry and biophysics》2006,44(2):179-186
The peritoneal mesothelium acts as a regulator of serosal responses to injury, infection, and neoplastic diseases. After inflammation
of the serosal surfaces, proinflammatory cytokines induce an “activated” mesothelial cell phenotype, the mitochondrial aspect
of which has not previously been studied. After incubation of cultured human peritoneal mesothelial cells with interleukin
(IL)-1β for 48 h, respiratory activity of suspended cells was analyzed by high-resolution respirometry. Citrate synthase (CS)
and lactate dehydrogenase (LDH) activities were determined by spectrophotometry. Treatment with IL-1β resulted in a significant
decline of respiratory capacity (p<0.05). Respiratory control ratios (i.e., uncoupled respiration at optimum carbonyl cyanide p-trifluoromethoxyphenylhydrazone concentration divided by oligomycin inhibited respiration measured in unpermeabilized cells)
remained as high as 11, indicating well-coupled mitochondria and functional integrity of the inner mitochondrial membrane.
Whereas respiratory capacities of the cells declined in proportion with decreased CS activity (p<0.05), LDH activity increased (p<0.05). Taken together, these results indicate that IL-1β exposure of peritoneal mesothelial cells does not lead to irreversible
defects or inhibition of specific components of the respiratory chain, but is associated with a decrease of mitochondrial
content of the cells that is correlated with an increase in LDH (and thus glycolytic) capacity.
Contributed equally to this work.
For papers with multiple authorship, the asterisk identifies the author to whom correspondence and reprint requests should
be addressed. 相似文献
994.
Background
Today, data evaluation has become a bottleneck in chromatographic science. Analytical instruments equipped with automated samplers yield large amounts of measurement data, which needs to be verified and analyzed. Since nearly every GC/MS instrument vendor offers its own data format and software tools, the consequences are problems with data exchange and a lack of comparability between the analytical results. To challenge this situation a number of either commercial or non-profit software applications have been developed. These applications provide functionalities to import and analyze several data formats but have shortcomings in terms of the transparency of the implemented analytical algorithms and/or are restricted to a specific computer platform. 相似文献995.
Drosophila sensory organ precursor (SOP) cells undergo several rounds of asymmetric cell division to generate the four different cell types that make up external sensory organs. Establishment of different fates among daughter cells of the SOP relies on differential regulation of the Notch pathway. Here, we identify the protein Lethal (2) giant discs (Lgd) as a critical regulator of Notch signaling in the SOP lineage. We show that lgd encodes a conserved C2 domain protein that binds to phospholipids present on early endosomes. When Lgd function is compromised, Notch and other transmembrane proteins accumulate in enlarged early endosomal compartments. These enlarged endosomes are positive for Rab5 and Hrs, a protein involved in trafficking into the degradative pathway. Our experiments suggest that Lgd is a critical regulator of endocytosis that is not present in yeast and acts in the degradative pathway after Hrs. 相似文献
996.
997.
Robert T. Hendricks Jay B. Fell James F. Blake John P. Fischer John E. Robinson Stacey R. Spencer Peter J. Stengel April L. Bernacki Vincent J.P. Leveque Sophie Le Pogam Sonal Rajyaguru Isabel Najera John A. Josey Jason R. Harris Steven Swallow 《Bioorganic & medicinal chemistry letters》2009,19(13):3637-3641
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure–activity relationships for a variety of new analogs are also discussed. 相似文献
998.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee George Adjabeng Todd R. Elworthy Jim Li Beihan Wang Joe T. Bamberg Seth F. Harris April Wong Vincent J.P. Leveque Robert Farrell 《Bioorganic & medicinal chemistry letters》2009,19(19):5652-5656
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure–activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue. 相似文献
999.
Robert T. Hendricks Stacey R. Spencer James F. Blake Jay B. Fell John P. Fischer Peter J. Stengel Vincent J.P. Leveque Sophie LePogam Sonal Rajyaguru Isabel Najera John A. Josey Steven Swallow 《Bioorganic & medicinal chemistry letters》2009,19(2):410-414
Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure–activity relationships are detailed, along with enzyme and cellular activity. 相似文献
1000.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee Junping Zhao Todd R. Elworthy Jahari Tracy Elbert Chin Jim Li Al Lui Beihan Wang Connie Oshiro Tatyana Voronin 《Bioorganic & medicinal chemistry letters》2009,19(19):5648-5651
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core. 相似文献