451 results on '"Fuyuhiko Inagaki"'
Search Results
2. Structural Basis for Receptor-Mediated Selective Autophagy of Aminopeptidase I Aggregates
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Akinori Yamasaki, Yasunori Watanabe, Wakana Adachi, Kuninori Suzuki, Kazuaki Matoba, Hiromi Kirisako, Hiroyuki Kumeta, Hitoshi Nakatogawa, Yoshinori Ohsumi, Fuyuhiko Inagaki, and Nobuo N. Noda
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Biology (General) ,QH301-705.5 - Abstract
Selective autophagy mediates the degradation of various cargoes, including protein aggregates and organelles, thereby contributing to cellular homeostasis. Cargo receptors ensure selectivity by tethering specific cargo to lipidated Atg8 at the isolation membrane. However, little is known about the structural requirements underlying receptor-mediated cargo recognition. Here, we report structural, biochemical, and cell biological analysis of the major selective cargo protein in budding yeast, aminopeptidase I (Ape1), and its complex with the receptor Atg19. The Ape1 propeptide has a trimeric coiled-coil structure, which tethers dodecameric Ape1 bodies together to form large aggregates. Atg19 disassembles the propeptide trimer and forms a 2:1 heterotrimer, which not only blankets the Ape1 aggregates but also regulates their size. These receptor activities may promote elongation of the isolation membrane along the aggregate surface, enabling sequestration of the cargo with high specificity.
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- 2016
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3. Rh(I)-catalyzed intramolecular [2 + 2 + 1] cycloaddition of allenenes: Construction of bicyclo[4.3.0]nonenones with an angular methyl group and tricyclo[6.4.0.01,5]dodecenone
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Fuyuhiko Inagaki, Naoya Itoh, Yujiro Hayashi, Yumi Matsui, and Chisato Mukai
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allene ,bicyclo[4.3.0] derivatives ,carbonylative [2 + 2 + 1] cycloaddition ,quaternary center construction ,rhodium ,Science ,Organic chemistry ,QD241-441 - Abstract
The [RhCl(CO)dppp]2-catalyzed intramolecular carbonylative [2 + 2 + 1] cycloaddition of allenenes was developed to prepare bicyclo[4.3.0]nonenones possessing a methyl group at the ring junction, which is difficult to achieve by the Pauson–Khand reaction of the corresponding enynes. This method also provided a new procedure for the construction of the tricyclo[6.4.0.01,5]dodecenone framework in a satisfactory yield.
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- 2011
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4. Proteomic profiling of autophagosome cargo in Saccharomyces cerevisiae.
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Kuninori Suzuki, Shingo Nakamura, Mayumi Morimoto, Kiyonaga Fujii, Nobuo N Noda, Fuyuhiko Inagaki, and Yoshinori Ohsumi
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Medicine ,Science - Abstract
Macroautophagy (autophagy) is a bulk protein-degradation system ubiquitously conserved in eukaryotic cells. During autophagy, cytoplasmic components are enclosed in a membrane compartment, called an autophagosome. The autophagosome fuses with the vacuole/lysosome and is degraded together with its cargo. Because autophagy is important for the maintenance of cellular homeostasis by degrading unwanted proteins and organelles, identification of autophagosome cargo proteins (i.e., the targets of autophagy) will aid in understanding the physiological roles of autophagy. In this study, we developed a method for monitoring intact autophagosomes ex vivo by detecting the fluorescence of GFP-fused aminopeptidase I, the best-characterized selective cargo of autophagosomes in Saccharomyces cerevisiae. This method facilitated optimization of a biochemical procedure to fractionate autophagosomes. A combination of LC-MS/MS with subsequent statistical analyses revealed a list of autophagosome cargo proteins; some of these are selectively enclosed in autophagosomes and delivered to the vacuole in an Atg11-independent manner. The methods we describe will be useful for analyzing the mechanisms and physiological significance of Atg11-independent selective autophagy.
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- 2014
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5. Characterization and Functionality of Immidazolium Ionic Liquids Modified Magnetic Nanoparticles
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Ying Li, Ning Tang, Fuyuhiko Inagaki, Chisato Mukai, and Kazuichi Hayakawa
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Chemistry ,QD1-999 - Abstract
1,3-Dialkylimidazolium-based ionic liquids were chemically synthesized and bonded on the surface of magnetic nanoparticles (MNPs) with easy one-step reaction. The obtained six kinds of ionic liquid modified MNPs were characterized with transmission electron microscopy, thermogravimetric analysis, magnetization, and FTIR, which owned the high adsorption capacity due to the nanometer size and high-density modification with ionic liquids. Functionality of MNPs with ionic liquids greatly influenced the solubility of the MNPs with organic solvents depending on the alkyl chain length and the anions of the ionic liquids. Moreover, the obtained MNPs showed the specific extraction efficiency to organic pollutant, polycyclic aromatic hydrocarbons, while superparamagnetic property of the MNPs facilitated the convenient separation of MNPs from the bulks water samples.
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- 2013
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6. Construction of 2,2-Dimethyloxepane Frameworks from Ene-Diols Catalyzed by Metal Catalyst or Brønsted Acid via 7-Endo-Trig Cyclization
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Ryo Murakami, Fuyuhiko Inagaki, and Kakeru Maeda
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chemistry.chemical_classification ,chemistry ,Alkene ,Drug Discovery ,Organic chemistry ,General Chemistry ,General Medicine ,Metal catalyst ,Brønsted–Lowry acid–base theory ,Ene reaction ,Catalysis - Abstract
The synthesis of 2,2-dimethyloxepane frameworks based on the 7-endo-trig cyclization of ene-diol using a catalytic amount of metal catalysts (Au, Ag) or Bronsted acid (TfOH) has been developed. Also, the spiro-type dioxabicyclic products were also derived from the diene-diols. For the condition using metal catalysts, the cyclization selectively reacted between the 1,1,3-trisubstituted alkenes and alcohols to form the 2,2-dimethyloxepane frameworks. On the other hand, the TfOH reacted with not only the 1,1,2-trisubstituted alkene, but also the 1-substituted and 1,2-disubstituted alkenes providing the corresponding cyclic ethers, which is quite different from the conditions of the metal catalysts.
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- 2021
7. Synthesis of Gold Catalyst Featuring Z-Type Ligand and Its Catalyic Reaction
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Ryo Murakami and Fuyuhiko Inagaki
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chemistry.chemical_compound ,chemistry ,Ligand ,Organic Chemistry ,Borane ,Combinatorial chemistry ,Catalysis - Published
- 2020
8. Spectroscopic Characterization of Halorhodopsin Reconstituted into Nanodisks Using Native Lipids
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Takashi Tsukamoto, Eri Hashimoto, Kenshiro Suzuki, Takeshi Uchida, Ayumi Yamamoto, Koichiro Ishimori, Kousuke Shibasaki, Makoto Demura, Fuyuhiko Inagaki, and Yoshihiro Kobashigawa
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0303 health sciences ,Circular dichroism ,Chemistry ,Spectrum Analysis ,Lipid Bilayers ,Kinetics ,Biophysics ,Articles ,Chromophore ,Lipids ,Halorhodopsin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Membrane ,lipids (amino acids, peptides, and proteins) ,Sodium dodecyl sulfate ,Halorhodopsins ,Polyacrylamide gel electrophoresis ,POPC ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
We successfully reconstituted single Natronomonas pharaonis halorhodopsin (NpHR) trimers into a nanodisk (ND) using the native archaeal lipid (NL) and an artificial lipid having a zwitterionic headgroup, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Incorporation of single trimeric NpHR into NDs was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, size-exclusion chromatography, and visible circular dichroism spectroscopy. The Cl- binding affinity of NpHR in NDs using NL (NL-ND NpHR) or POPC (POPC-ND NpHR) was examined by absorption spectroscopy, showing that the Cl--releasing affinities (K-d,K-N O) of these ND-reconstituted NpHRs are more than 10 times higher than that obtained from native NpHR membrane fragments (MFs) harvested from a NpHR-overexpressing archaeal strain (MF NpHR). The photoreaction kinetics of these ND-reconstituted NpHRs revealed that the Cl- uptake was faster than that of MF NpHR. These differences in the Cl--releasing and uptake properties of ND-reconstituted NpHRs and MF NpHR may arise from suppression of protein conformational changes associated with Cl- release from the trimeric NpHR caused by ND reconstitution, conformational perturbation in the trimeric state, and loss of the trimer-trimer interactions. On the other hand, POPC-ND NpHR demonstrated accelerated Cl- uptake compared to NL-ND NpHR, suggesting that the negative charge on the archaeal membrane surface regulates the photocycle of NpHR. Although NL-ND NpHR and MF NpHR are embedded in the same lipid, the lower Cl--binding affinity at the initial state (K-d,K-initial) and faster recovering from the NpHR' state to the original state of the photoreaction cycle were observed for NL-ND NpHR, probably because of insufficient interactions with a chromophore in the native membrane, bacterioruberin in reconstituted NDs. Our results indicate that specific interactions of NpHR with surrounding lipids and bacterioruberin, structural flexibility of the membrane, and interactions between trimeric NpHRs may be necessary for efficient Cl- pumping. SIGNIFICANCE Natronomonas pharaonis halorhodopsin (NpHR), a cytoplasmic membrane Cl- pump, was reconstituted into nanodisks (NDs) using endogenous and exogenous membranes. The photoreaction cycle was examined by absorption, circular dichroism spectra, and flash photolysis. Based on the thermodynamic and kinetic parameters of the photoreaction in detergent-solubilized NpHRs, NpHRs reconstituted into artificial lipid NDs, and NpHR reconstituted into native membrane NDs, we propose that the functional differences in these NpHRs are due to 1) the low content of bacterioruberin in the membrane, 2) the different charge on the membrane surface, 3) the suppression of the conformational changes associated with the Cl- release, 4) the conformational perturbation in the NpHR trimers, and 5) the lack of the intertrimer interactions of NpHR.
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- 2020
9. Aliphatic Oxaboroles Enabling Remarkable Recognition of Diols
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Fuyuhiko Inagaki, Yuto Sumida, Kazunori Nagao, Hiroshi Arakawa, Nozomi Arakawa, Ryo Murakami, and Hirohisa Ohmiya
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Chemistry ,ALIZARIN RED ,Reactivity (chemistry) ,sense organs ,General Chemistry ,Ring (chemistry) ,Medicinal chemistry - Abstract
5-Membered ring aliphatic oxaboroles revealed unique characteristics in their reactivity with diols. The aliphatic oxaborole derivatives exhibited a higher complexation activity for Alizarin Red S ...
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- 2020
10. Fluorescent-Oxaboroles: Synthesis and Optical Property by Sugar Recognition
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Yuto Sumida, Fuyuhiko Inagaki, Misaki Nakano, Hirohisa Ohmiya, Taniyuki Furuyama, Rikako Nakamura, and Kazunori Nagao
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Boron Compounds ,Molecular Structure ,Optical Phenomena ,chemistry.chemical_element ,General Chemistry ,General Medicine ,Nicotinamide adenine dinucleotide ,Photochemistry ,NAD ,Fluorescence ,chemistry.chemical_compound ,Molecular recognition ,chemistry ,Drug Discovery ,Nucleic acid ,Molecule ,NAD+ kinase ,Boron ,Sugars ,Quantum ,Fluorescent Dyes - Abstract
The optical property of fluorescent unit-conjugated aliphatic oxaboroles has been investigated. The oxaboroles provide good fluorescence quantum yields and selective recognition toward D-ribose and D-ribose containing molecules. The molecular recognition induced significant fluorescence quenching. The property of the boroles showed the possibility of the boron-based nicotinamide adenine dinucleotide (NAD) sensor probe.
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- 2021
11. Copper complex featuring Cation-Excess alternation counterion catalyzing Mukaiyama-Aldol reaction of ketene silyl acetals and ketones
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Hiroto Tanishima, Ryo Murakami, and Fuyuhiko Inagaki
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Organic Chemistry ,Drug Discovery ,Biochemistry - Published
- 2022
12. [Development of Gold-catalyzed Reaction Utilizing Electron Acceptability of Z-type Ligand]
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Fuyuhiko Inagaki and Ryo Murakami
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Pharmacology ,chemistry.chemical_classification ,Molecular Structure ,Chemistry ,Hydride ,Ligand ,Pharmaceutical Science ,Alkyne ,Electrons ,Ligands ,Catalysis ,Gold Compounds ,Metal ,Transition metal ,Cyclization ,visual_art ,Alkynes ,Polymer chemistry ,visual_art.visual_art_medium ,Reactivity (chemistry) ,Gold ,Alkyl - Abstract
The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and halogen) and/or dative L-type ligands (e.g., P, N, CO, olefin, etc.). Therefore, the interaction of the Z-type ligands (B, Al and Si, etc.) with transition metals is emerging as a new concept for the reactivity of the metal center. Recently, we developed the synthesis of the gold complex Au(DPB)X (DPB=diphosphine-borane) featuring the Z-type ligand, and their catalytic reaction. The gold catalysts showed a high activity compared to the general catalysts (without Z-ligand) for the various cyclization reactions due to the electron-withdrawing effect of the Z-ligand on the coordinating gold center. In this review, first the structure analysis of the synthesized Au→Z complex is introduced in detail, and second, the catalytic reactions based on the alkyne activation are described.
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- 2021
13. Protein NMR Resonance Assignment
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Takahisa Ikegami and Fuyuhiko Inagaki
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- 2021
14. Construction of the Oxazolidinone Framework from Propargylamine and CO2 in Air at Ambient Temperature: Catalytic Effect of a Gold Complex Featuring an L2 /Z-Type Ligand
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Fuyuhiko Inagaki, Kakeru Maeda, Chisato Mukai, and Kenta Nakazawa
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Carboxylation ,010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,Carbon fixation ,Physical and Theoretical Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Catalytic effect - Published
- 2018
15. Activation of disulfide bond cleavage triggered by hydrophobization and lipophilization of functionalized dihydroasparagusic acid
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Kenkyo Matsuura, Fuyuhiko Inagaki, Miyuki Momose, Tsukasa Matsunaga, Chisato Mukai, and Naoya Maruyama
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010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Disulfide bond ,Dithiol ,Oxidation Activity ,010402 general chemistry ,Cleavage (embryo) ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Functional group ,Physical and Theoretical Chemistry ,Dihydroasparagusic acid ,Reaction site - Abstract
Concisely synthesized and functionalized dihydroasparagusic acid (DHAA) derivatives were used to show that the introduction of a hydrophobic functional group dramatically reduced air oxidation activity at the dithiol moieties and dominantly activated the cleavage of S-S bonds in proteins, presumably due to the hydrophobization and lipophilization. Notably, the reaction sites of water-reactive dithiol moieties behaved similarly to hydrophobic and lipophilic functional groups, which suggests impersonation of the reaction site.
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- 2018
16. Diastereoselective tricyclization/dimerization of yne-indoles catalyzed by a Au(III) complex featuring an L2/Z-type ligand
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Ryoya Kamo, Kazuki Kawasaki, Motoki Matsuo, Hikari Kawamitsu, Hiroto Tanishima, Ayaka Uchida, Chihiro Kiyohara, Ryo Murakami, Fuyuhiko Inagaki, Daisuke Naito, and Kakeru Maeda
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Ligand ,Chemistry ,Organic Chemistry ,Drug Discovery ,Cationic polymerization ,Z-Ligand ,Biochemistry ,Medicinal chemistry ,Catalysis - Abstract
In order to investigate catalyst activation via a (Au → B)8 interaction, Au(DPB)X3 (DPB = diphosphine-borane) featuring an L2/Z ligand was synthesized. The resulting cationic catalyst was utilized for the unprecedented diastereoselective tricyclization/dimerization of yne-indoles.
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- 2021
17. Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed Intermolecular [5 + 2] Cycloaddition Reactions
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Fuyuhiko Inagaki, Paul A. Wender, Brandon D Fennell, Birte Schröder, and Christian Ebner
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chemistry.chemical_element ,Ketene ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Article ,Rhodium ,chemistry.chemical_compound ,Molecule ,Organic chemistry ,Physical and Theoretical Chemistry ,Cycloaddition Reaction ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Regioselectivity ,Ethylenes ,Ketones ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,Alkynes ,Yield (chemistry) ,Ynol ,Ethers - Abstract
The previously unexplored metal-catalyzed [5 + 2] cycloadditions of vinylcyclopropanes (VCPs) and electron-rich alkynes (ynol ethers) have been found to provide a highly efficient, direct route to dioxygenated seven-membered rings, a common feature of numerous natural and non-natural targets and building blocks for synthesis. The reactions proceed in high yield at room temperature and tolerate a broad range of functionalities. Substituted VCPs were found to react with high regioselectivity.
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- 2017
18. Substituent Effects in the Cyclization of Yne-Diols Catalyzed by Gold Complexes Featuring L2/Z-Type Diphosphinoborane Ligands
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Tomoya Koseki, Kenta Nakazawa, Fuyuhiko Inagaki, Chisato Mukai, and Kakeru Maeda
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010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Cationic polymerization ,Substituent ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Physical and Theoretical Chemistry ,Boron - Abstract
Gold(I) complexes featuring Z-type ligands introducing electron-withdrawing groups (EWG), Au(DPBF)Cl (4a) and Au(DPBCl)Cl (4b) (DPB = diphosphine-boron), have been synthesized and structurally characterized. These studies suggest that increasing the electron-withdrawing properties of the boron phenyl substituent only results in minor structural changes of the gold complexes. These complexes can be converted into Au(DPBF)SbF6 and Au(DPBCl)SbF6 by treatment of 4a,b with AgSbF6. The cationic complexes show interesting catalytic properties and readily promote the cyclization of yne-diols into unprecedented dioxabicyclo[3.2.2] derivatives.
- Published
- 2017
19. Silver(I)-Catalyzed Deprenylation of Allylsulfonamide Derivatives
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Fuyuhiko Inagaki, Shisen Hira, and Chisato Mukai
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chemistry.chemical_classification ,Double bond ,010405 organic chemistry ,Organic Chemistry ,010402 general chemistry ,Cleavage (embryo) ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Catalysis ,Sulfonamide ,Elimination reaction ,chemistry ,Prenylation ,Moiety ,Organic chemistry ,Reactivity (chemistry) - Abstract
The silver(I)-catalyzed deprenylation of sulfonamide bearing prenyl functional groups on the nitrogen atom has been developed. In this reaction, the prenyl moiety was selectively eliminated without allyl or benzyl cleavage on the nitrogen atom. In addition, geranyl was also applicable for this elimination reaction. Furthermore, sulfonamide possessing two prenyl groups underwent a double deprenylation to form the corresponding deprenylated sulfonamide. Thus, a novel reactivity between the silver cation and double bond was observed.
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- 2017
20. Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling
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Hiroyuki Oshiumi, Kenji Funami, Tsukasa Seya, Misako Matsumoto, and Fuyuhiko Inagaki
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0301 basic medicine ,Scaffold protein ,Endosome ,Acylation ,Amino Acid Motifs ,Endosomes ,Biology ,Models, Biological ,Myristic Acid ,Biochemistry ,03 medical and health sciences ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Binding site ,Receptor ,Adaptor Proteins, Signal Transducing ,Myristoylation ,Type I interferon production ,Cell biology ,Toll-Like Receptor 4 ,Adaptor Proteins, Vesicular Transport ,Protein Transport ,030104 developmental biology ,TRIF ,Interferon Type I ,TLR4 ,Protein Multimerization ,Dimerization ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS), produces pro-inflammatory cytokines and type I interferons, and associates with a trigger of endotoxin shock. TLR4 is interacted with a TIR domain-containing adaptor molecule-2 (TICAM-2)/TRAM [TRIF (TIR domain-containing adaptor-inducing interferon-β)-related adaptor molecule] via its Toll–interleukin-1 receptor homology (TIR) domain. TICAM-2 acts as a scaffold protein and activates TIR domain-containing adaptor molecule-1 (TICAM-1)/TRIF. According to the structural analysis by NMR, TICAM-2 interacts with TICAM-1 by the acidic amino acids motif, E87/D88/D89. The TIR domain of TICAM-2 couples with the dimer of TIR domain of TLR4 beneath the membrane, and TICAM-2 itself also forms dimer and constitutes a binding site with TICAM-1. Endosomal localization of TICAM-2 is essential for TLR4-mediated type I interferon-inducing signal from the endosome. N-terminal myristoylation allows TICAM-2 to anchor to the endosomal membrane. Additionally, we have identified two acidic amino acids, D91/E92, as a functional motif that cooperatively determines endosomal localization of TICAM-2. This structural information of TICAM-2 suggests that the specific structure is indispensable for the endosomal localization and type I interferon production of TICAM-2. Taken together with the knowledge on cytoplasmic sensors for LPS, TICAM-2/TICAM-1 may conform to a signal network on TLR4 to facilitate induction of cytokine disorders.
- Published
- 2017
21. CO2-Selective Absorbents in Air: Reverse Lipid Bilayer Structure Forming Neutral Carbamic Acid in Water without Hydration
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Chisato Mukai, Chiaki Matsumoto, Takashi Iwata, and Fuyuhiko Inagaki
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Moisture ,Chemistry ,Inorganic chemistry ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Biochemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Carbamic acid ,Carbon dioxide ,Anhydrous ,Phenyl group ,Absorption (chemistry) ,0210 nano-technology ,Lipid bilayer ,Selectivity - Abstract
Emission gas and air contain not only CO2 but also plentiful moisture, making it difficult to achieve selective CO2 absorption without hydration. To generate absorbed CO2 (wet CO2) under heating, the need for external energy to release the absorbed water has been among the most serious problems in the fields of carbon dioxide capture and storage (CCS) and direct air capture (DAC). We found that the introduction of the hydrophobic phenyl group into alkylamines of CO2 absorbents improved the absorption selectivity between CO2 and water. Furthermore, ortho-, meta-, and para-xylylenediamines (OXDA, MXDA, PXDA, respectively) absorbed only CO2 in air without any hydration. Notably, MXDA·CO2 was formed as an anhydrous carbamic acid even in water, presumably because it was covered with hydrophobic phenyl groups, which induces a reverse lipid bilayer structure. Dry CO2 was obtained from heating MXDA·CO2 at 103–120 °C, which was revealed to involve chemically the Grignard reaction to form the resulting carboxylic a...
- Published
- 2017
22. Substrate Specific Silver(I)-Catalyzed Cycloisomerization of Diene Involving Alkyl Rearrangements: Syntheses of 1,2,5,6-Tetrahydrocuminic Acid, p-Menth-3-en-7-ol, and p-Menth-3-en-7-al
- Author
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Fuyuhiko Inagaki, Mizuki Matsumoto, Shisen Hira, and Chisato Mukai
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chemistry.chemical_classification ,Diene ,010405 organic chemistry ,Stereochemistry ,Diol ,Cationic polymerization ,Substrate (chemistry) ,General Chemistry ,General Medicine ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Catalysis ,chemistry.chemical_compound ,Cycloisomerization ,chemistry ,Drug Discovery ,Derivatization ,Alkyl - Abstract
The novel cationic Ag(I)-catalyzed cycloisomerization, which is associated with alkyl rearrangements, from dimethyl 2-allyl-2-prenylmalonate (1) to dimethyl 4-isopropylcyclohex-3-ene-1,1-dicarboxylate (2) has been developed. Derivatization from the diester 2 into the diol 3 and its X-ray crystallographic analysis determined the structure. The mechanisms of the novel reaction were investigated by isotopic experiments, which supported the unusual alkyl shifts. In addition, the product 2 was used for the total syntheses of three natural products, 1,2,5,6-tetrahydrocuminic acid (12), p-menth-3-en-7-ol (13), and p-menth-3-en-7-al (14) in short steps.
- Published
- 2017
23. The Gold-catalyzed Formal Hydration, Decarboxylation, and [4+2] Cycloaddition of Alkyne Derivatives Featuring L2/Z-type Diphosphinoborane Ligands
- Author
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Chiaki Matsumoto, Xun Dong, Masayuki Yamada, Fuyuhiko Inagaki, and Chisato Mukai
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chemistry.chemical_classification ,010405 organic chemistry ,Decarboxylation ,Z-Ligand ,Alkyne ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Cycloaddition ,0104 chemical sciences ,Catalysis ,chemistry ,Intramolecular force - Abstract
The catalytic formal hydration of alkynes and decarboxylation of alkynoic acid were developed using a Au catalyst featuring a Z-ligand. Furthermore, the intramolecular [4+2] cycloaddition of the al...
- Published
- 2018
24. New methodology for preparation of two substituted 5,6,7-azaindoles and their anticancer activity
- Author
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Montaser Sh. A. Shaykoon, Mohamed, Mamdouh F. A., Marzouk, Adel A, Hafez, Mahmoud A., Fuyuhiko Inagaki, and Mukai, Chisato
- Published
- 2019
- Full Text
- View/download PDF
25. Biophysical characterization of drug-resistant mutants of fibroblast growth factor receptor 1
- Author
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Shun Amemiya, Kaito Yoza, Natsuki Fukuda, Rika Himeno, Shinjiro Amano, Hiroyuki Kumeta, Fuyuhiko Inagaki, Yoshihiro Kobashigawa, and Hiroshi Morioka
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Models, Molecular ,0301 basic medicine ,Magnetic Resonance Spectroscopy ,Protein Conformation ,Adenylyl Imidodiphosphate ,Mutant ,Drug Resistance ,Quinolones ,Fibroblast growth factor ,Receptor tyrosine kinase ,03 medical and health sciences ,Genetics ,Humans ,Fluorometry ,Receptor, Fibroblast Growth Factor, Type 1 ,Protein Kinase Inhibitors ,biology ,Fibroblast growth factor receptor 1 ,Imidazoles ,Wild type ,Cell Biology ,Fibroblast growth factor receptor 3 ,Pyridazines ,Pyrimidines ,Spectrometry, Fluorescence ,030104 developmental biology ,Biochemistry ,Fibroblast growth factor receptor ,Mutation ,biology.protein ,Benzimidazoles ,Tyrosine kinase - Abstract
Over-expression and aberrant activation of tyrosine kinases occur frequently in human cancers. Various tyrosine kinase inhibitors (TKIs) are under clinical use, but acquisition of resistance to these drugs is a major problem. Here, we studied the interaction between two drug-resistant mutants of fibroblast growth factor receptor 1 (FGFR1), N546K and V561M, and four ATP-competitive inhibitors, ponatinib, dovitinib, PD173074 and BGJ-398. Among these protein-drug systems, the only marked reduction in affinity was that of PD173074 for the V561M mutant. We also examined the interaction of these FGFR1 variants to AMP-PNP, a nonhydrolyzable analogue of ATP, and showed that N546K showed increased affinity for the ATP analogue as compared with the wild type. These findings will help to clarify the mechanism of drug resistance in mutant tyrosine kinases.
- Published
- 2016
26. Structural Basis for Receptor-Mediated Selective Autophagy of Aminopeptidase I Aggregates
- Author
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Hiromi Kirisako, Kazuaki Matoba, Nobuo N. Noda, Kuninori Suzuki, Fuyuhiko Inagaki, Yoshinori Ohsumi, Hiroyuki Kumeta, Yasunori Watanabe, Hitoshi Nakatogawa, Wakana Adachi, and Akinori Yamasaki
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0301 basic medicine ,Saccharomyces cerevisiae Proteins ,ATG8 ,Vesicular Transport Proteins ,Autophagy-Related Proteins ,Cellular homeostasis ,Receptors, Cell Surface ,Saccharomyces cerevisiae ,Plasma protein binding ,Vacuole ,macromolecular substances ,Biology ,Protein aggregation ,Crystallography, X-Ray ,Aminopeptidases ,General Biochemistry, Genetics and Molecular Biology ,Protein Aggregates ,03 medical and health sciences ,0302 clinical medicine ,Autophagy ,Protein Precursors ,lcsh:QH301-705.5 ,Receptor-mediated endocytosis ,Cell biology ,Transport protein ,Protein Transport ,030104 developmental biology ,lcsh:Biology (General) ,Vacuoles ,Peptides ,030217 neurology & neurosurgery ,Protein Binding - Abstract
SummarySelective autophagy mediates the degradation of various cargoes, including protein aggregates and organelles, thereby contributing to cellular homeostasis. Cargo receptors ensure selectivity by tethering specific cargo to lipidated Atg8 at the isolation membrane. However, little is known about the structural requirements underlying receptor-mediated cargo recognition. Here, we report structural, biochemical, and cell biological analysis of the major selective cargo protein in budding yeast, aminopeptidase I (Ape1), and its complex with the receptor Atg19. The Ape1 propeptide has a trimeric coiled-coil structure, which tethers dodecameric Ape1 bodies together to form large aggregates. Atg19 disassembles the propeptide trimer and forms a 2:1 heterotrimer, which not only blankets the Ape1 aggregates but also regulates their size. These receptor activities may promote elongation of the isolation membrane along the aggregate surface, enabling sequestration of the cargo with high specificity.
- Published
- 2016
27. Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus
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Hajjaj H.M. Abdu-Allah, Mohammed T. A. Salim, Y. A. Mohamed, Chisato Mukai, Bahaa G.M. Youssif, and Fuyuhiko Inagaki
- Subjects
benzimidazole ,triazole ,anilide ,antiviral ,HCV ,HBV ,Benzimidazole ,1,2,3-Triazole ,Time Factors ,Stereochemistry ,Cell Survival ,Hepatitis C virus ,Substituent ,Triazole ,Pharmaceutical Science ,Hepacivirus ,010402 general chemistry ,medicine.disease_cause ,Virus Replication ,01 natural sciences ,Antiviral Agents ,chemistry.chemical_compound ,Structure-Activity Relationship ,medicine ,hcv ,Moiety ,Humans ,Cytotoxicity ,Pharmaceutical industry ,Pharmacology ,Hepatitis B virus ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,General Medicine ,Hep G2 Cells ,Triazoles ,0104 chemical sciences ,chemistry ,Drug Design ,DNA, Viral ,hbv ,Hepatocytes ,Benzimidazoles ,HD9665-9675 - Abstract
New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.
- Published
- 2016
28. Nuclear magnetic resonance analysis of the conformational state of cancer mutant of fibroblast growth factor receptor 1 tyrosine kinase domain
- Author
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Hiroyuki Kumeta, Shinjiro Amano, Fuyuhiko Inagaki, Joseph Schlessinger, Kaito Yoza, Hiroshi Morioka, Mariko Yokogawa, Rika Himeno, Yoshihiro Kobashigawa, and Shun Amemiya
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Protein tyrosine phosphatase ,SH2 domain ,Receptor tyrosine kinase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nuclear magnetic resonance ,Protein Domains ,Neoplasms ,Genetics ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Phosphorylation ,Nuclear Magnetic Resonance, Biomolecular ,biology ,Tyrosine phosphorylation ,Cell Biology ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,ROR1 ,biology.protein ,GRB2 ,Platelet-derived growth factor receptor ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Tyrosine kinases are key enzymes that play critical roles in growth signaling, the abnormal activation of which is associated with various human cancers. Activation of tyrosine kinases is mediated by tyrosine phosphorylation in the activation-loop, which transforms the catalytic domain to the active state conformation. Cancer mutations are supposed to transform the conformation of the catalytic domain into the active-form independent of the phosphorylation state of the activation-loop. Here, we report structural and biophysical analyses of cancer mutations of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1). Based on the nuclear magnetic resonance analyses, phosphorylation of the activation-loop exhibited cooperative structural transition in the activation-loop, C-helix and P-loop regions, whereas cancer mutations induced structural transformation at either one or two of these regions.
- Published
- 2016
29. Energyless CO2 Absorption, Generation, and Fixation Using Atmospheric CO2
- Author
-
Fuyuhiko Inagaki, Chisato Mukai, Masayuki Yamada, Chiaki Matsumoto, Yasuhiko Okada, and Kenta Nakazawa
- Subjects
010405 organic chemistry ,Chemistry ,Carbon fixation ,Carbon respiration ,chemistry.chemical_element ,General Chemistry ,General Medicine ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Environmental chemistry ,Atmospheric chemistry ,Drug Discovery ,Carbon dioxide ,Energy source ,Carbon ,Electrochemical reduction of carbon dioxide ,Negative carbon dioxide emission - Abstract
From an economic and ecological perspective, the efficient utilization of atmospheric CO2 as a carbon resource should be a much more important goal than reducing CO2 emissions. However, no strategy to harvest CO2 using atmospheric CO2 at room temperature currently exists, which is presumably due to the extremely low concentration of CO2 in ambient air (approximately 400 ppm=0.04 vol%). We discovered that monoethanolamine (MEA) and its derivatives efficiently absorbed atmospheric CO2 without requiring an energy source. We also found that the absorbed CO2 could be easily liberated with acid. Furthermore, a novel CO2 generator enabled us to synthesize a high value-added material (i.e., 2-oxazolidinone derivatives based on the metal catalyzed CO2-fixation at room temperature) from atmospheric CO2.
- Published
- 2016
30. Recent topics of gold catalyst featuring Z-type ligands
- Author
-
Ryo Murakami and Fuyuhiko Inagaki
- Subjects
010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Catalysis ,Metal ,Covalent bond ,visual_art ,Drug Discovery ,visual_art.visual_art_medium ,Reactivity (chemistry) - Abstract
In the long history regarding the development of the transition metal-catalyzed reactions, almost all ligands in metals are classified as the covalent X-type and/or dative L-type ligands. Therefore, exploring the reactivity of the metal complexes bearing the σ-acceptor, i.e., the Z-ligand, is required. This digest briefly describes our recent results regarding 1) the syntheses of gold complexes featuring the Z-type ligand, and 2) their catalytic reactions, which would be speculated that the electron-withdrawing effect of the Z-ligand on the neighboring gold activated the catalytic reactivity due to the increase in the Lewis acidity.
- Published
- 2019
31. Structural Study of Proteins by Paramagnetic Lanthanide Probe Methods
- Author
-
Tomohide Saio and Fuyuhiko Inagaki
- Subjects
Lanthanide ,Conformational change ,Materials science ,Paramagnetic effect ,010405 organic chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Ion ,Crystallography ,Paramagnetism ,Nuclear magnetic resonance ,Protein structure ,Residual dipolar coupling - Abstract
Long-range structural information provided by the paramagnetic lanthanide probe methods is invaluable in the structural analysis of proteins, particularly protein complexes and multi-domain proteins. The application of paramagnetic lanthanide probe methods in protein structural analysis is expanding, owing to recent developments in lanthanide-binding tags. Here, we describe paramagnetic effects observed in the presence of paramagnetic lanthanide ions, which can be exploited to obtain structural information about proteins. We also illustrate practical aspects of the experiments and analyses utilizing the paramagnetic lanthanide probe methods. Applications in structure determination of protein–protein complexes and visualization of conformational changes in multi-domain proteins are also described.
- Published
- 2017
32. Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain
- Author
-
Yoshihiro Kobashigawa, Fuyuhiko Inagaki, Shinjiro Amano, Hiroshi Morioka, Mariko Yokogawa, Joseph Schlessinger, Masayori Inouye, and Hiroyuki Kumeta
- Subjects
Protein tyrosine phosphatase ,SH2 domain ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Genetics ,Homeostasis ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Phosphorylation ,biology ,Tyrosine phosphorylation ,Cell Biology ,Protein-Tyrosine Kinases ,Magnetic Resonance Imaging ,Protein Structure, Tertiary ,Cell biology ,Molecular Docking Simulation ,chemistry ,Mutation ,ROR1 ,biology.protein ,Tyrosine ,GRB2 ,Protein Multimerization ,Platelet-derived growth factor receptor ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Receptor and nonreceptor tyrosine kinases are enzymes that play important roles in regulating signal transduction pathways in a variety of normal cellular process and in many pathological conditions. Ordered phosphorylation is required for receptor tyrosine kinase (RTK) activation, a process mediated by transient dimer formation of the kinase domains. This process is triggered by the tyrosine phosphorylation in the activation loop. Here, we report structural and biochemical analyses of the tyrosine kinase domain interaction of fibroblast growth factor receptor 1 (FGFR1) required for the initial phosphorylation step. On the basis of nuclear magnetic resonance (NMR) analysis and covalent cross-linking experiments, we propose a parallel symmetric dimer model where specific contacts are formed between the N-lobes and C-lobes, respectively, in the FGFR1 kinase domains. Moreover, assignment of the contact sites between two FGFR1 kinase domains are supported by a trans-phosphorylation assay and by mutational analyses. The present report shows the molecular mechanism underlying the control of trans-phosphorylation of a critical auto-regulatory site in FGF receptors' catalytic domain.
- Published
- 2015
33. Mechanisms of Autophagy
- Author
-
Fuyuhiko Inagaki and Nobuo N. Noda
- Subjects
Autophagosome ,endocrine system ,Atg1 ,Autophagy ,Vesicular Transport Proteins ,Biophysics ,Bioengineering ,Saccharomyces cerevisiae ,Cell Biology ,Biology ,Autophagosome formation ,Biochemistry ,Atg12-Atg5-Atg16 complex ,Cell biology ,Structural biology ,Structural Biology ,Multiprotein Complexes ,Phagosomes ,Animals ,Humans - Abstract
The formation of the autophagosome, a landmark event in autophagy, is accomplished by the concerted actions of Atg proteins. The initial step of starvation-induced autophagy in yeast is the assembly of the Atg1 complex, which, with the help of other Atg groups, recruits Atg conjugation systems and initiates the formation of the autophagosome. In this review, we describe from a structural-biological point of view the structure, interaction, and molecular roles of Atg proteins, especially those in the Atg1 complex and in the Atg conjugation systems.
- Published
- 2015
34. Concise Construction of Bicyclo[6.4.0] and -[7.4.0] Frameworks by [4+2] Cycloaddition of 3,4-Dimethylene-2,5-bis(phenylsulfonyl)cycloalk-1-enes
- Author
-
Chisato Mukai, Fuyuhiko Inagaki, Yasuhito Takahashi, and Masanobu Ueda
- Subjects
chemistry.chemical_compound ,Cyclononene ,chemistry ,Bicyclic molecule ,Cyclooctene ,Stereochemistry ,Organic Chemistry ,Intermolecular force ,Physical and Theoretical Chemistry ,Vicinal ,Cycloaddition - Abstract
The thermal intermolecular [4+2] cycloadditions of vicinal bis(exo-methylene)cyclooctene with carbon dienophiles efficiently produce the bicyclo[6.4.0] framework. Similar cycloadditions with the one-carbon-homologated cyclononene derivatives result in the formation of the bicyclo[7.4.0] skeleton. Both aza- and oxadieonphiles are suitable for this [4+2] reaction and provide the corresponding hetero-Diels–Alder-type products.
- Published
- 2015
35. Rhodium(I)-Catalyzed Cycloisomerization of Allene-Allenylcyclopropanes
- Author
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Takamasa Kawamura, Katsuya Sugikubo, Chisato Mukai, Fuyuhiko Inagaki, and Yasuaki Kawaguchi
- Subjects
Ethylene ,Stereochemistry ,Allene ,Organic Chemistry ,chemistry.chemical_element ,Ring (chemistry) ,Medicinal chemistry ,Cycloaddition ,Cyclopropane ,Rhodium ,chemistry.chemical_compound ,Cycloisomerization ,chemistry ,Intramolecular force ,Physical and Theoretical Chemistry - Abstract
The RhI-catalyzed intramolecular [5+2–2]-type cycloisomerization of allene–allenylcyclopropanes was developed. In this reaction, ethylene was liberated from the cyclopropane ring to afford the 1,5,6,7-tetrahydroazulene skeletons.
- Published
- 2014
36. Air-Stable Cationic Gold(I) Catalyst Featuring a Z-Type Ligand: Promoting Enyne Cyclizations
- Author
-
Naoya Maruyama, Yasuhiko Okada, Chiaki Matsumoto, Fuyuhiko Inagaki, and Chisato Mukai
- Subjects
inorganic chemicals ,Enyne ,Chemistry ,Ligand ,Cationic polymerization ,General Medicine ,General Chemistry ,Ligands ,Photochemistry ,Boron atom ,Catalysis ,Coordination Complexes ,Cyclization ,Cations ,Polymer chemistry ,Reactivity (chemistry) ,Gold ,Boron - Abstract
An air-stable cationic Au(I) complex featuring a Z-type ligand (boron atom) as a σ-acceptor was developed for elucidating the effect of B on catalytic reactions. An enyne cyclization in the presence of either [Au→B](+) or [Au](+) showed that [Au→B](+) promotes the reactivity, which enabled the effective construction of not only five- and six-membered rings, but also seven-membered rings.
- Published
- 2014
37. Atg7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-Step Recognition
- Author
-
Yoshinori Ohsumi, Fuyuhiko Inagaki, Yuko Fujioka, Kenji Satoo, Nobuo N. Noda, Masaya Yamaguchi, and Hironori Suzuki
- Subjects
0301 basic medicine ,Models, Molecular ,Conformational change ,Saccharomyces cerevisiae Proteins ,Protein Conformation ,ATG8 ,Saccharomyces cerevisiae ,Conjugated system ,Crystallography, X-Ray ,Autophagy-Related Protein 7 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adenosine Triphosphate ,Ubiquitin ,Structural Biology ,Protein Interaction Domains and Motifs ,Molecular Biology ,chemistry.chemical_classification ,Phosphatidylethanolamine ,biology ,Autophagy ,Autophagy-Related Protein 8 Family ,030104 developmental biology ,Enzyme ,chemistry ,030220 oncology & carcinogenesis ,Helix ,biology.protein ,Biophysics ,Protein Binding - Abstract
Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. Atg7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of Atg7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of Atg7, both of which were observed in previously reported Atg7-Atg8 structures. Instead, Atg8 binds to the C-terminal α-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free Atg7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that Atg7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in Atg7 that is optimal for the activation reaction.
- Published
- 2017
38. CO
- Author
-
Fuyuhiko, Inagaki, Chiaki, Matsumoto, Takashi, Iwata, and Chisato, Mukai
- Subjects
Absorption, Physicochemical ,Molecular Structure ,Air ,Lipid Bilayers ,Water ,Carbamates ,Amines ,Carbon Dioxide ,Hydrophobic and Hydrophilic Interactions - Abstract
Emission gas and air contain not only CO
- Published
- 2017
39. Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents
- Author
-
Matthew S. Jeffreys, Dennis N. Fournogerakis, Ryan V. Quiroz, Magnus Pfaffenbach, Paul A. Wender, and Fuyuhiko Inagaki
- Subjects
chemistry.chemical_classification ,Dual purpose ,Molecular Structure ,Diene ,Stereochemistry ,General Chemical Engineering ,Alkyne ,General Chemistry ,Combinatorial chemistry ,Article ,Cycloaddition ,Structural complexity ,chemistry.chemical_compound ,chemistry ,Cyclization ,Alkynes ,Reagent ,Molecule ,Reactivity (chemistry) - Abstract
Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions--the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.
- Published
- 2014
40. Structural basis of starvation-induced assembly of the autophagy initiation complex
- Author
-
Yuko Fujioka, Yayoi Kimura, Nobuo N. Noda, Chika Kondo-Kakuta, Fuyuhiko Inagaki, Yoshinori Ohsumi, Rinji Akada, Hayashi Yamamoto, Sho W. Suzuki, and Hisashi Hirano
- Subjects
Models, Molecular ,Saccharomyces cerevisiae Proteins ,Atg1 ,Molecular Sequence Data ,Autophagy-Related Proteins ,Biology ,Crystallography, X-Ray ,Dephosphorylation ,Sequence Analysis, Protein ,Structural Biology ,Autophagy-initiation complex ,Autophagy ,Serine ,Phosphorylation ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Binding Sites ,Autophagy-related protein 13 ,Yeast ,Protein Structure, Tertiary ,Cell biology ,Transport protein ,Biochemistry ,Carrier Proteins ,Protein Kinases - Abstract
Assembly of the preautophagosomal structure (PAS) is essential for autophagy initiation in yeast. Starvation-induced dephosphorylation of Atg13 is required for the formation of the Atg1-Atg13-Atg17-Atg29-Atg31 complex (Atg1 complex), a prerequisite for PAS assembly. However, molecular details underlying these events have not been established. Here we studied the interactions of yeast Atg13 with Atg1 and Atg17 by X-ray crystallography. Atg13 binds tandem microtubule interacting and transport domains in Atg1, using an elongated helix-loop-helix region. Atg13 also binds Atg17, using a short region, thereby bridging Atg1 and Atg17 and leading to Atg1-complex formation. Dephosphorylation of specific serines in Atg13 enhanced its interaction with not only Atg1 but also Atg17. These observations update the autophagy-initiation model as follows: upon starvation, dephosphorylated Atg13 binds both Atg1 and Atg17, and this promotes PAS assembly and autophagy progression.
- Published
- 2014
41. Rh(I)-Catalyzed Intramolecular Carbonylative [2+2+1] Cycloaddition Reaction: Preparation of Bicyclo[5.3.0]decadienones with Substituted Cyclopentenone Frameworks
- Author
-
Fuyuhiko Inagaki, Yasuhito Takahashi, Yujiro Hayashi, K. Ogawa, and Chisato Mukai
- Subjects
Cyclopentenone ,Cycloaddition Reaction ,Bicyclic molecule ,Stereochemistry ,Allene ,Substituent ,chemistry.chemical_element ,Cyclopentanes ,General Chemistry ,General Medicine ,Catalysis ,Cycloaddition ,Rhodium ,Bridged Bicyclo Compounds ,chemistry.chemical_compound ,chemistry ,Cyclization ,Intramolecular force ,Drug Discovery - Abstract
The [RhCl(CO)2]2-catalyzed [2+2+1] cycloaddition of bis(allene)s, which have a substituent at the allenic terminus, produced the 8-substituted bicyclo[5.3.0]deca-1(10),6-dien-9-one frameworks. The synthesis of 8,10-dimethylbicyclo[5.3.0]deca-1(10),6-dien-9-one could also be achieved from the bis(1,1,3-trisubstituted-allene).
- Published
- 2014
42. Coinage metal catalyzed 7-endo-trig cyclization of ene-diols: Construction of 2,2-dimethyloxepane frameworks
- Author
-
Ryo Murakami, Fuyuhiko Inagaki, and Kakeru Maeda
- Subjects
inorganic chemicals ,integumentary system ,010405 organic chemistry ,Chemistry ,organic chemicals ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Catalysis ,Metal ,visual_art ,Drug Discovery ,polycyclic compounds ,visual_art.visual_art_medium ,Organic chemistry ,heterocyclic compounds ,Ene reaction - Abstract
The silver catalyzed 7-endo-trig cyclization of an ene-diol for the formation of 2,2-dimethyloxepane frameworks has been developed. The spirotype dioxabicyclic products were also produced from the diene-diols. In addition, a gold catalyst featuring the Z-ligand also produced similar cyclization reactions.
- Published
- 2019
43. High-Throughput Evaluation Method for Drug Association with Pregnane X Receptor (PXR) Using Differential Scanning Fluorometry
- Author
-
Hiroyuki Moriguchi, Yoshihiro Kobashigawa, Masamichi Yuda, Masashi Kawasaki, Fuyuhiko Inagaki, Mitsuhiro Sekiguchi, and Toshio Teramura
- Subjects
Receptors, Steroid ,Stereochemistry ,Recombinant Fusion Proteins ,Biochemistry ,Fluorescence spectroscopy ,Analytical Chemistry ,chemistry.chemical_compound ,Nuclear Receptor Coactivator 1 ,Differential scanning calorimetry ,Escherichia coli ,Native state ,Cytochrome P-450 CYP3A ,Humans ,Fluorometry ,Fluorescent Dyes ,Pregnane X receptor ,Calorimetry, Differential Scanning ,Diphosphonates ,CYP3A4 ,biology ,Chemistry ,Anticholesteremic Agents ,Pregnane ,Pregnane X Receptor ,Cytochrome P450 ,Fluorescence ,High-Throughput Screening Assays ,Kinetics ,biology.protein ,Thermodynamics ,Molecular Medicine ,Protein Binding ,Biotechnology - Abstract
The pregnane xenobiotic receptor (PXR) is a key transcriptional regulator of cytochrome P450 (CYP) 3A, a crucial enzyme in the metabolism and detoxification of xenobiotics and endobiotics. PXR is activated by a wide variety of chemicals and serves as a master regulator of detoxification in mammals. Here, we report a fast evaluation method for PXR-drug interactions using differential scanning fluorometry (DSF). DSF analysis revealed that PXR associates with a fluorescence dye in the native state as well as in the unfolded state, which prevented precise evaluation of any shift in the transition midpoint (ΔT (m)) due to association with a drug. Hence, we defined a new parameter, (dF/dT)(50), where F is fluorescence intensity and T is temperature, to describe the ligand concentration. (dF/dT)(50) exhibited better correlation with EC(50) (r(2) = 0.84) than with ΔT m (r(2) = 0.71). The correlation of ΔT m measured using differential scanning calorimetry (DSC) with EC(50) (r(2) = 0.86) was similar to the above (dF/dT)(50) correlation. Therefore, the use of (dF/dT)(50) enables DSF to be used for the rapid evaluation of PXR-drug interactions and could provide prescreening to narrow down the collection of candidate ligands that most likely result in transcriptional activation of CYP3A4.
- Published
- 2013
44. Rhodium(I)-Catalyzed Cycloisomerization of Alkene-Substituted Allenylcyclopropanes: Stereoselective Formation of Bicyclo[4.3.0]nonadienes
- Author
-
Chiaki Matsumoto, Fukiko Omachi, Fuyuhiko Inagaki, Chisato Mukai, Yuuki Miyanaga, and Katsuya Sugikubo
- Subjects
chemistry.chemical_classification ,Bicyclic molecule ,Stereochemistry ,Alkene ,Allene ,chemistry.chemical_element ,General Medicine ,General Chemistry ,Catalysis ,Cyclopropane ,Stereocenter ,Rhodium ,chemistry.chemical_compound ,Cycloisomerization ,chemistry ,Stereoselectivity - Abstract
A productive channel for pent-up energy: The [{RhCl(CO)2 }2 ]-catalyzed ring-opening of both E and Z 1-cyclopropylocta-1,2,6-trienes exclusively produced cis-4,5-dimethylbicyclo[4.3.0]nona-1(9),2-dienes with three contiguous stereogenic centers. When this transformation was applied to the 1,2,7-triene double-bond isomers, the same products were formed in a completely stereoselective manner.
- Published
- 2013
45. Cyclopropanes in Nicholas reaction: formation of spiroketals with a five-membered and a seven- or an eight-membered ring
- Author
-
Takamasa Kawamura, Takahiro Kojima, Fuyuhiko Inagaki, and Chisato Mukai
- Subjects
chemistry.chemical_compound ,chemistry ,Organic Chemistry ,Drug Discovery ,Substituent ,Nicholas reaction ,Ring (chemistry) ,Biochemistry ,Medicinal chemistry ,Cyclopropane - Abstract
The consecutive treatment of 5-hydroxy-1-pentynyl 2,2-disubstituted-cyclopropyl ketones with Co2(CO)8 and BF3·OEt2 produced the corresponding Co2(CO)6-complexed dioxaspiro[4.6] derivatives. The one-carbon homologated substrates also afforded dioxaspiro[4.7]. It was found that this procedure can be applied to the substrates with gem-disubstituents as well as a mono-aryl substituent on the cyclopropane, but the mono-alkyl substituted cyclopropanes are insufficient.
- Published
- 2013
46. Atg18 phosphoregulation controls organellar dynamics by modulating its phosphoinositide-binding activity
- Author
-
Fuyuhiko Inagaki, Moemi Ito, Naoki Tamura, Masahide Oku, Nobuo N. Noda, and Yasuyoshi Sakai
- Subjects
Organelles ,Binding Sites ,Cell Biology ,Vacuole ,Biology ,Phosphatidylinositols ,Article ,Pichia ,Cell biology ,Dephosphorylation ,chemistry.chemical_compound ,chemistry ,Organelle ,Micropexophagy ,Phosphorylation ,Phosphatidylinositol ,sense organs ,Binding site ,skin and connective tissue diseases ,Carrier Proteins ,Intracellular ,Research Articles - Abstract
The PROPPIN family member Atg18 is a phosphoinositide-binding protein that is composed of a seven β-propeller motif and is part of the conserved autophagy machinery. Here, we report that the Atg18 phosphorylation in the loops in the propellar structure of blade 6 and blade 7 decreases its binding affinity to phosphatidylinositol 3, 5-bisphosphate in the yeast Pichia pastoris. Dephosphorylation of Atg18 was necessary for its association with the vacuolar membrane and caused septation of the vacuole. Upon or after dissociation from the vacuolar membrane, Atg18 was rephosphorylated, and the vacuoles fused and formed a single rounded structure. Vacuolar dynamics were regulated according to osmotic changes, oxidative stresses, and nutrient conditions inducing micropexophagy via modulation of Atg18 phosphorylation. This study reveals how the phosphoinositide-binding activity of the PROPPIN family protein Atg18 is regulated at the membrane association domain and highlights the importance of such phosphoregulation in coordinated intracellular reorganization., 神経疾患関連タンパク質のリン酸化による生体膜相互作用とオートファジーの制御メカニズム. 京都大学プレスリリース. 2013-08-12.
- Published
- 2013
47. Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action
- Author
-
Kumi Kimura, Shun-ichiro Asahara, Yoshiaki Kido, Tomokazu Matsuda, Hajime Nakabayashi, Masato Kasuga, Yusuke Nakamura, Yuka Inaba, Kiyoshi Takeda, Fuyuhiko Inagaki, Hiroshi Inoue, Michihiro Matsumoto, Chisato Mukai, Akifumi Maeda, Shuichi Kaneko, Tsuguhito Ota, Shizuo Akira, and Hiroshi Watanabe
- Subjects
STAT3 Transcription Factor ,medicine.medical_specialty ,Kupffer Cells ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Histamine H1 receptor ,Biology ,chemistry.chemical_compound ,Mice ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Insulin ,Histidine ,Receptors, Histamine H1 ,Phosphorylation ,Receptor ,Original Research ,Mice, Knockout ,Neurons ,Gluconeogenesis ,Receptor, Insulin ,Insulin receptor ,Endocrinology ,Metabolism ,Glucose ,chemistry ,Liver ,biology.protein ,Histamine - Abstract
Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.
- Published
- 2013
48. Atg12–Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site
- Author
-
Hitoshi Nakatogawa, Hiromi Kirisako, Kazuaki Matoba, Nobuo N. Noda, Eri Asai, Fuyuhiko Inagaki, Junko Ishii, Machiko Sakoh-Nakatogawa, and Yoshinori Ohsumi
- Subjects
Models, Molecular ,Phosphatidylethanolamine ,Saccharomyces cerevisiae Proteins ,Protein Conformation ,Stereochemistry ,Ubiquitin-Protein Ligases ,ATG8 ,ATG5 ,Autophagy-Related Proteins ,Crystallography, X-Ray ,Autophagy-Related Protein 5 ,ATG12 ,chemistry.chemical_compound ,Residue (chemistry) ,chemistry ,Structural Biology ,Catalytic Domain ,Ubiquitin-Conjugating Enzymes ,Threonine ,Molecular Biology ,Autophagy-Related Protein 12 ,Conjugate ,Cysteine - Abstract
Two autophagy-related ubiquitin-like systems have unique features: the E2 enzyme Atg3 conjugates the ubiquitin-like protein Atg8 to the lipid phosphatidylethanolamine, and the other ubiquitin-like protein conjugate Atg12-Atg5 promotes that conjugase activity of Atg3. Here, we elucidate the mode of this action of Atg12-Atg5 as a new E3 enzyme by using Saccharomyces cerevisiae proteins. Biochemical analyses based on structural information suggest that Atg3 requires a threonine residue to catalyze the conjugation reaction instead of the typical asparagine residue used by other E2 enzymes. Moreover, the catalytic cysteine residue of Atg3 is arranged in the catalytic center such that the conjugase activity is suppressed; Atg12-Atg5 induces a reorientation of the cysteine residue toward the threonine residue, which enhances the conjugase activity of Atg3. Thus, this study reveals the mechanism of the key reaction that drives membrane biogenesis during autophagy.
- Published
- 2013
49. Syntheses of 6-8-5 tricyclic ring systems by carbonylative [2+2+1] cycloaddition of bis(allene)s
- Author
-
Takamasa Kawamura, Fuyuhiko Inagaki, M. T. Soraya Shafawati, and Chisato Mukai
- Subjects
Bicyclic molecule ,Allene ,Organic Chemistry ,chemistry.chemical_element ,Ring (chemistry) ,Biochemistry ,Medicinal chemistry ,Cycloaddition ,Rhodium ,chemistry.chemical_compound ,chemistry ,Dimedone ,Intramolecular force ,Drug Discovery ,Carbon - Abstract
The synthetic route for the construction of the 6-8-5 tricyclic carbon frameworks has been developed. The [RhCl(CO)dppp]2-catalyzed intramolecular Pauson–Khand-type reaction of the bis(allene)s, derived from dimedone, provided the corresponding bicyclo[6.3.0] skeleton in one operation.
- Published
- 2013
50. Characterization and Functionality of Immidazolium Ionic Liquids Modified Magnetic Nanoparticles
- Author
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Ning Tang, Fuyuhiko Inagaki, Chisato Mukai, Ying Li, and Kazuichi Hayakawa
- Subjects
chemistry.chemical_classification ,Thermogravimetric analysis ,Article Subject ,General Chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,Adsorption ,lcsh:QD1-999 ,chemistry ,Chemical engineering ,Ionic liquid ,Magnetic nanoparticles ,Organic chemistry ,Fourier transform infrared spectroscopy ,Solubility ,Alkyl ,Superparamagnetism - Abstract
1,3-Dialkylimidazolium-based ionic liquids were chemically synthesized and bonded on the surface of magnetic nanoparticles (MNPs) with easy one-step reaction. The obtained six kinds of ionic liquid modified MNPs were characterized with transmission electron microscopy, thermogravimetric analysis, magnetization, and FTIR, which owned the high adsorption capacity due to the nanometer size and high-density modification with ionic liquids. Functionality of MNPs with ionic liquids greatly influenced the solubility of the MNPs with organic solvents depending on the alkyl chain length and the anions of the ionic liquids. Moreover, the obtained MNPs showed the specific extraction efficiency to organic pollutant, polycyclic aromatic hydrocarbons, while superparamagnetic property of the MNPs facilitated the convenient separation of MNPs from the bulks water samples. © 2013 Ying Li et al.
- Published
- 2013
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