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971.
Takeshi Fujii Masataka G. Suzuki Susumu Katsuma Katsuhiko Ito Yu Rong Shogo Matsumoto Tetsu Ando Yukio Ishikawa 《Biochemical and biophysical research communications》2013
Female Ascotis selenaria (Geometridae) moths use 3,4-epoxy-(Z,Z)-6,9-nonadecadiene, which is synthesized from linolenic acid, as the main component of their sex pheromone. While the use of dietary linolenic or linoleic fatty acid derivatives as sex pheromone components has been observed in moth species belonging to a few families including Geometridae, the majority of moths use derivatives of a common saturated fatty acid, palmitic acid, as their sex pheromone components. We attempted to gain insight into the differentiation of pheromone biosynthetic pathways in geometrids by analyzing the desaturase genes expressed in the pheromone gland of A. selenaria. We demonstrated that a Δ11-desaturase-like gene (Asdesat1) was specifically expressed in the pheromone gland of A. selenaria in spite of the absence of a desaturation step in the pheromone biosynthetic pathway in this species. Further analysis revealed that the presumed transmembrane domains were degenerated in Asdesat1. Phylogenetic analysis demonstrated that Asdesat1 anciently diverged from the lineage of Δ11-desaturases, which are currently widely used in the biosynthesis of sex pheromones by moths. These results suggest that an ancestral Δ11-desaturase became dysfunctional in A. selenaria after a shift in pheromone biosynthetic pathways. 相似文献
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978.
Peter W. Glunz Xiaojun Zhang Yan Zou Indawati Delucca Alexandra H. Nirschl Xuhong Cheng Carolyn A. Weigelt Daniel L. Cheney Anzhi Wei Rushith Anumula Joseph M. Luettgen Alan R. Rendina Mark Harpel Gang Luo Robert Knabb Pancras C. Wong Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(18):5244-5248
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype. 相似文献
979.
Carl R. Illig Carl L. Manthey Sanath K. Meegalla Mark J. Wall Jinsheng Chen Kenneth J. Wilson Renee L. DesJarlais Shelley K. Ballentine Carsten Schubert Carl S. Crysler Yanmin Chen Christopher J. Molloy Margery A. Chaikin Robert R. Donatelli Edward Yurkow Zhao Zhou Mark R. Player Bruce E. Tomczuk 《Bioorganic & medicinal chemistry letters》2013,23(23):6363-6369
Structure–activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats. 相似文献
980.
L. Szerszen S. Mukherjee L. Chollet‐Hinton H. Katayama B. L. Pentelute R. J. Collier M. T. Fisher 《Protein science : a publication of the Protein Society》2013,22(5):586-594
We have visualized by cryo‐electron microscopy (cryo‐EM) the complex of the anthrax protective antigen (PA) translocon and the N‐terminal domain of anthrax lethal factor (LFN) inserted into a nanodisc model lipid bilayer. We have determined the structure of this complex at a nominal resolution of 16 Å by single‐particle analysis and three‐dimensional reconstruction. Consistent with our previous analysis of negatively stained unliganded PA, the translocon comprises a globular structure (cap) separated from the nanodisc bilayer by a narrow stalk that terminates in a transmembrane channel (incompletely distinguished in this reconstruction). The globular cap is larger than the unliganded PA pore, probably due to distortions introduced in the previous negatively stained structures. The cap exhibits larger, more distinct radial protrusions, previously identified with PA domain three, fitted by elements of the NMFF PA prepore crystal structure. The presence of LFN, though not distinguished due to the seven‐fold averaging used in the reconstruction, contributes to the distinct protrusions on the cap rim volume distal to the membrane. Furthermore, the lumen of the cap region is less resolved than the unliganded negatively stained PA, due to the low contrast obtained in our images of this specimen. Presence of the LFN extended helix and N terminal unstructured regions may also contribute to this additional internal density within the interior of the cap. Initial NMFF fitting of the cryoEM‐defined PA pore cap region positions the Phe clamp region of the PA pore translocon directly above an internal vestibule, consistent with its role in toxin translocation. 相似文献