9 research outputs found
ヘム タンパクシツ ノ カッセイ サンソ ニ ヨル セイギョ キコウ ニ カンスル ケンキュウ
No full text京都大学0048新制・課程博士博士(工学)甲第14640号工博第3108号新制||工||1462(附属図書館)UT51-2009-D352京都大学大学院工学研究科分子工学専攻(主査)教授 白川 昌宏, 教授 田中 庸裕, 教授 青山 安宏学位規則第4条第1項該当Doctor of EngineeringKyoto UniversityDA
Deposition Dosages of Three Cromolyn Forms by Cascade Impactor
No full textAmong inhaled asthma therapies, the present study aimed to identify factors for selecting the type of inhalation therapy for asthma. Three methods are used to deliver inhaled cromoglycate, and the airway deposition rate was evaluated using a cascade impactor with 3 dosage forms: dry powder (DP), pressurized metered dose inhaler (pMDI), and solution (jet- and mesh-types). The percentage of particles with diameters of 2–6 μm was 17.0% for the capsule, 51.8% for pMDI, 49.0% for jet-type NE-C28, and 40.4% for mesh-type NE-U22. The amounts of drug deposited in the bronchi were based on the particle distribution of the various dosage forms: 3.4 mg for the capsule, 1.0 mg for pMDI, 9.8 mg for one solution (jet-type NE-C28), and 8.1 mg for the other solution (mesh-type NE-U22). Jet-type or mesh-type electric nebulizers delivered 2-3 times more of the drug than capsules, and, compared with pMDI, 8-9 times more of the drug was deposited in the bronchi/bronchioles. Electric nebulizers are considered the best method. This study suggests that the size of particles deposited at sites of obstruction is larger than previously reported, and no obstruction of small airways occurs (<2 mm).</jats:p
Regio‐ and Chemoselective Transfer Hydrogenation of Quinolines Catalyzed by a Cp*Ir Complex.
No full textStructural Characterization of Heme Environmental Mutants of CgHmuT that Shuttles Heme Molecules to Heme Transporters
No full textCorynebacteria contain a heme uptake system encoded in hmuTUV genes, in which HmuT protein acts as a heme binding protein to transport heme to the cognate transporter HmuUV. The crystal structure of HmuT from Corynebacterium glutamicum (CgHmuT) reveals that heme is accommodated in the central cleft with His141 and Tyr240 as the axial ligands and that Tyr240 forms a hydrogen bond with Arg242. In this work, the crystal structures of H141A, Y240A, and R242A mutants were determined to understand the role of these residues for the heme binding of CgHmuT. Overall and heme environmental structures of these mutants were similar to those of the wild type, suggesting that there is little conformational change in the heme-binding cleft during heme transport reaction with binding and the dissociation of heme. A loss of one axial ligand or the hydrogen bonding interaction with Tyr240 resulted in an increase in the redox potential of the heme for CgHmuT to be reduced by dithionite, though the wild type was not reduced under physiological conditions. These results suggest that the heme environmental structure stabilizes the ferric heme binding in CgHmuT, which will be responsible for efficient heme uptake under aerobic conditions where Corynebacteria grow
ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses
No full textThe poly(ADP-ribose) polymerases (PARPs) participate in various processes. Here, we report that the PARP-13/ZAP shorter isoform (hereafter called ZAPS), rather than the full length protein, is selectively induced by 3pRNA, and functions as a potent stimulator of retinoic acid-inducible gene-I (RIG-I)-mediated interferon (IFN) responses in human cells. ZAPS associates with RIG-I to promote the oligomerization and ATPase activity of RIG-I, leading to robust activation of IRF3 and NF-κB pathways. Disruption of the PARP-13/ZAP gene, ZC3HAV1, severely abrogated the induction of IFN-α, IFN-β and other cytokines upon viral infection. These results indicate that ZAPS is a key regulator of RIG-I signaling during the innate antiviral immune response, suggesting its possible use as a therapeutic target for viral control
Protein oxidation mediated by heme-induced active site conversion specific for heme-regulated transcription factor, iron response regulator
No full textThe Bradyrhizobium japonicum transcriptional regulator Irr (iron response regulator) is a key regulator of the iron homeostasis, which is degraded in response to heme binding via a mechanism that involves oxidative modification of the protein. Here, we show that heme-bound Irr activates O-2 to form highly reactive oxygen species (ROS) with the "active site conversion" from heme iron to non-heme iron to degrade itself. In the presence of heme and reductant, the ROS scavenging experiments show that Irr generates H2O2 from O-2 as found for other hemoproteins, but H2O2 is less effective in oxidizing the peptide, and further activation of H2O2 is suggested. Interestingly, we find a time-dependent decrease of the intensity of the Soret band and appearance of the characteristic EPR signal at g = 4.3 during the oxidation, showing the heme degradation and the successive formation of a non-heme iron site. Together with the mutational studies, we here propose a novel "two-step self-oxidative modification" mechanism, during which O-2 is activated to form H2O2 at the heme regulatory motif (HRM) site and the generated H2O2 is further converted into more reactive species such as OH at the non-heme iron site in the His-cluster region formed by the active site conversion
