Faculty Profiles - OMOTE Hiroshi

MISC - OMOTE Hiroshi

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神経因性・炎症性疼痛に有効な小胞型ヌクレオチドトランスポーターの特異的阻害剤の同定

加藤百合, 日浅未来, 市川玲子, 蓮澤奈央, 門脇敦志, 岩槻健, 島和弘, 遠藤康男, 北原吉朗, 井上剛, 野村政壽, 表弘志, 森山芳則, 宮地孝明

脂質生化学研究 60 54 - 56 2018.5

Language：Japanese Publisher：日本脂質生化学会

神経・内分泌細胞は分泌小胞に充填したATPを開口放出し、プリン受容体を介して痛覚等の多彩な生理機能を制御する。我々は、ATPを分泌小胞に充填する小胞型ヌクレオチドトランスポーター(VNUT)を同定し、VNUTはプリン作動性化学伝達の必須因子であること、VNUTには塩素イオン(ON)とケトン体(OFF)によるアロステリックな代謝スイッチがあることを見出した。このスイッチを特異的にOFFできる化合物は画期的な鎮痛薬になると期待できる。骨粗鬆症治療薬の第一世代ビスホスホネート製剤は骨吸収抑制作用や副作用が弱く、鎮痛効果があることが報告されていたが、その作用機構は不明であった。我々は、このうちクロドロン酸が低濃度でVNUTを阻害することを見出した。興味深いことに、クロドロン酸はVNUTの代謝スイッチを選択的にOFFするアロステリック薬剤であった。神経因性と炎症性疼痛モデルマウスにクロドロン酸を投与したところ、鎮痛効果と抗炎症効果を発揮することを見出した。VNUT-/-マウスではクロドロン酸の効果が消失していた。以上より、クロドロン酸の鎮痛・抗炎症効果の分子標的はVNUTであり、クロドロン酸は副作用の少ない神経因性・炎症性疼痛の画期的治療薬になると期待できる。今後、ドラッグリポジショニングによる新規鎮痛薬のトランスポーター創薬が期待される。(著者抄録)

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骨粗鬆症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

加藤百合, 日浅未来, 市川玲子, 蓮澤奈央, 門脇敦史, 岩槻健, 島和弘, 遠藤康男, 北原吉郎, 井上剛, 野村政壽, 表弘志, 森山芳則, 宮地孝明

生命科学系学会合同年次大会 2017年度 [2AT26 - 03(2P 2017.12

骨粗鬆症症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

加藤百合, 日浅未来, 市川玲子, 蓮澤奈央, 門脇敦史, 岩槻健, 島和弘, 遠藤康男, 北原吉郎, 井上剛, 野村政壽, 表弘志, 森山芳則, 宮地孝明

生命科学系学会合同年次大会 2017年度 [2P - 1053(2AT26 2017.12

小胞型ヌクレオチドトランスポーター特異的阻害剤を用いたプリン作動性化学伝達のin vivo制御

加藤百合, 日浅未来, 門脇敦志, 島和弘, 市川玲子, 岩槻健, 北原吉朗, 井上剛, 遠藤康男, 表弘志, 森山芳則, 宮地孝明

日本生化学会大会プログラム・講演要旨集 89回 [1P - 308] 2016.9

小胞型ヌクレオチドトランスポーター特異的阻害剤の同定とプリン作動性化学伝達のin vivo制御

加藤百合, 日浅未来, 門脇敦志, 島和弘, 市川玲子, 岩槻健, 北原吉朗, 井上剛, 遠藤康男, 表弘志, 森山芳則, 宮地孝明

日本薬学会年会要旨集 136年会 ( 3 ) 77 - 77 2016.3

葉緑体ビタミンCトランスポーターの同定とその生理的役割

宮地孝明, 黒森崇, 竹内優, 山地直樹, 横正健剛, 嶋澤厚, 杉本絵理子, 表弘志, 馬建鋒, 篠崎一雄, 森山芳則, 森山芳則

トランスポーター研究会年会抄録集 10th 41 2015.6

小胞型ヌクレオチドトランスポーター(VNUT)は血糖値の制御に関わる

表弘志, 坂本昌平, 宮地孝明, 日浅未来, 市川玲子, 岩槻健, 畝山寿之, 高柳涼一, 野村政壽, 森山芳則

日本薬学会年会要旨集 135年会 ( 3 ) 62 - 62 2015.3

葉緑体のアスコルビン酸トランスポーターの同定とその生理的役割

宮地孝明, 黒森崇, 竹内優, 山地直樹, 横正健剛, 嶋澤厚, 杉本絵理子, 表弘志, 馬建鋒, 篠崎一雄, 森山芳則

日本薬学会年会要旨集(CD-ROM) 135th ROMBUNNO.26P-PM12 2015

葉特異的な発現をするタバコMATE型トランスポーターNt-JAT2の機能解析

士反伸和, 南翔太, 森田匡彦, 林田南帆, 伊藤慎悟, 高梨功次郎, 杉山暁史, 表弘志, 森山芳則, GOOSSENS Alain, 守安正恭, 矢崎一史

日本農芸化学会大会講演要旨集(Web) 2015 2015

Inhibitors of ATP release inhibit vesicular nucleotide transporter

Yuri Kato, Hiroshi Omote, Takaaki Miyaji

PURINERGIC SIGNALLING 10 ( 4 ) 787 - 788 2014.12

Vesicular nucleotide transporter (Vnut) regulates glucose metabolism.

Shohei Sakamoto, Takaaki Miyaji, Miki Hiasa, Reiko Ichikawa, Akira Uematsu, Ken Iwatsuki, Atsushi Shibata, Hisayuki Uneyama, Ryoichi Takayanagi, Akitsugu Yamamoto, Hiroshi Omote, Masatoshi Nomura, Yoshinori Moriyama

PURINERGIC SIGNALLING 10 ( 4 ) 670 - 670 2014.12

Divalent cation transport by vesicular nucleotide transporter

Takaaki Miyaji, Keisuke Sawada, Hiroshi Omote, Yoshinori Moriyama

PURINERGIC SIGNALLING 10 ( 4 ) 788 - 788 2014.12

NPT homologue (SLC17A4) is an intestinal urate exporter

Natsuko Togawa, Takaaki Miyaji, Hiroshi Omote, Yoshinori Moriyama

PURINERGIC SIGNALLING 10 ( 4 ) 789 - 789 2014.12

恒常性維持のためのホルモン分泌調節小胞型ヌクレオチドトランスポーター(VNUT)による内分泌制御

表弘志, 坂本昌平, 宮地孝明, 日浅未来, 市川玲子, 岩槻健, 畝山寿之, 高柳涼一, 野村政壽, 森山芳則

日本内分泌学会雑誌 90 ( 1 ) 207 - 207 2014.4

Vesicular neurotransmitter transporters : their structure and function

245 ( 1 ) 69 - 73 2013.4

神経伝達物質トランスポーターの新展開小胞型神経伝達物質トランスポーター小胞型グルタミン酸トランスポーターの機能と制御

表弘志, 宮地孝明

脳21 14 ( 4 ) 2011

Characterization of transport properties of purified vesicular inhibitory amino acid transporter (VIAAT)

Narinobu Juge, Akiko Muroyama, Miki Hiasa, Hiroshi Omote, Yoshinori Moriyama

NEUROSCIENCE RESEARCH 65 S77 - S77 2009

Identification and characterization of a vesicular nucleotide transporter

Keisuke Sawada, Miki Hiasa, Noriko Echigo, Narinobu Juge, Takaaki Miyaji, Hiroshi Omote, Yoshinori Moriyama

NEUROSCIENCE RESEARCH 65 S77 - S77 2009

Biochemical characterization of purified vesicular inhibitory amino acid transporter (VIAAT)

O. Narinobu Juge, Akiko Muroyama, Miki Hiasa, Hiroshi Omote, Yoshinori Moriyama

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 67 - 68 2008

Identification and characterization of a vesicular nucleotide transporter

Keisuke Sawada, Noriko Echigo, Narinobu Juge, Takaaki Miyaji, Miki Hiasa, Masato Otsuka, Hiroshi Omote, Yoshinori Moriyama

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 65 - 66 2008

Functional characterization of mouse MATE2: a class 3 MATE-type polyspecific H+/organic cation exporter

Miki Hiasa, Takuya Matsumoto, Toshinori Komatsu, Kojiro Ishikawa, Hiroshi Omote, Yoshinori Moriyama

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 127 39 - 40 2007

A novel variant of mouse MATE-1 H+/organic cation exporter

Ayumi Kobara, Miki Hiasa, Takuya Matsumoto, Masato Otsuka, Hiroshi Omote, Yoshinori Moriyama

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 127 37 - 38 2007

L-glutamate signaling regulates transcytotic vesicle function in osteoclasts.

S. Uehara, R. Morimoto, S. Yatsushiro, N. Juge, M. Hayashi, S. Senoh, T. Mizoguchi, T. Ninomiya, N. Udagawa, Z. Hua, H. Omote, A. Yamamoto, R. H. Edwards, Y. Moriyama

JOURNAL OF BONE AND MINERAL RESEARCH 21 S401 - S401 2006.9

Molecular dynamics and essential dynamics studies of the interaction of transported drugs with p-glycoprotein

MK Al-Shawi, H Omote

BIOPHYSICAL JOURNAL 88 ( 1 ) 25A - 25A 2005.1

Interaction of transported drugs with the lipid bilayer and pglycoprotein: Drug transport is mediated by a hydration exchange mechanism

H Omote, MK Al-Shawi

BIOPHYSICAL JOURNAL 86 ( 1 ) 610A - 610A 2004.1

A novel EPR approach to determine the mechanism of drug transport by P-glycoprotein

MK Al-Shawi, H Omote

BIOPHYSICAL JOURNAL 82 ( 1 ) 563A - 563A 2002.1

Coupling of drug transport to ATP hydrolysis by P-glycoprotein

MK Al-Shawi, MK Polar, H Omote, RA Figler

BIOPHYSICAL JOURNAL 80 ( 1 ) 18A - 19A 2001.1

Synthase (H+ ATPase): coupling between catalysis, mechanical work, and proton translocation

M Futai, H Omote, Y Sambongi, Y Wada

BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 1458 ( 2-3 ) 276 - 288 2000.5

Language：English Publishing type：Book review, literature introduction, etc. Publisher：ELSEVIER SCIENCE BV

Coupling with electrochemical proton gradient, ATP synthase (F0F1) synthesizes ATP from ADP and phosphate. Mutational studies on high-resolution structure have been useful in understanding this complicated membrane enzyme. We discuss mainly the mechanism of catalysis in the beta subunit of F-1 sector and roles of the gamma subunit in energy coupling. The gamma-subunit rotation during catalysis is also discussed. (C) 2000 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0005-2728(00)00080-3

Web of Science

CiNii Article

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Escherichia coli ATP synthase alpha subunit Arg-376: The catalytic site arginine does not participate in the hydrolysis/synthesis reaction but is required for promotion to the steady state

NP Le, H Omote, Y Wada, MK Al-Shawi, RK Nakamoto, M Futai

BIOCHEMISTRY 39 ( 10 ) 2778 - 2783 2000.3

Language：English Publisher：AMER CHEMICAL SOC

The three catalytic sites of the FOF1 ATP synthase interact through a cooperative mechanism that is required for the promotion of catalysis. Replacement of the conserved alpha subunit Arg-376 in the Escherichia coli F-1 catalytic site with Ala or Lys resulted in turnover rates of ATP hydrolysis that were 2 x 10(3)-fold lower than that of the wild type. Mutant enzymes catalyzed hydrolysis at a single site with kinetics similar to that of the wild type; however, addition of excess ATP did not chase bound ATP, ADP, or Pi from the catalytic site, indicating that binding of ATP to the second and third sites failed to promote release of products from the first site. Direct monitoring of nucleotide binding in the alpha R376A and alpha R376K mutant F-1 by a tryptophan in place of beta Tyr-331 (Weber et al. (1993) J. Biol. Chem. 268, 20126-20133) showed that the catalytic sites of the mutant enzymes, like the wild type, have different affinities and therefore, are structurally asymmetric. These results indicate that alpha Arg-376, which is close to the beta- or gamma-phosphate group of bound ADP or ATP, respectively, does not make a significant contribution to the catalytic reaction, but coordination of the arginine to nucleotide filling the low-affinity sites is essential for promotion of rotational catalysis to steady-state turnover.

DOI： 10.1021/bi992530h

Regulation and reversibility of vacuolar H+-ATPase

T Hirata, N Nakamura, H Omote, Y Wade, M Futai

JOURNAL OF BIOLOGICAL CHEMISTRY 275 ( 1 ) 386 - 389 2000.1

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Arabidopsis thaliana vacuolar H+-translocating pyrophosphatase (V-PPase) was expressed functionally in yeast vacuoles with endogenous vacuolar H+-ATPase (V-ATPase), and the regulation and reversibility of V-ATPase were studied using these vacuoles. Analysis of electrochemical proton gradient (Delta mu H) formation with ATP and pyrophosphate indicated that the proton transport by V-ATPase or V-PPase is not regulated strictly by the proton chemical gradient (Delta pH). On the other hand, vacuolar membranes may have a regulatory mechanism for maintaining a constant membrane potential (Delta Psi). Chimeric vacuolar membranes showed ATP synthesis coupled with Delta mu H established by V-PPase. The ATP synthesis was sensitive to bafilomycin A(1) and exhibited two apparent K-m values for ADP. These results indicate that V-ATPase is a reversible enzyme. The ATP synthesis was not observed in the presence of nigericin, which dissipates Delta pH but not Delta Psi, suggesting that Delta pH is essential for ATP synthesis.

DOI： 10.1074/jbc.275.1.386

The gamma-subunit rotation and torque generation in F-1-ATPase from wild-type or uncoupled mutant Escherichia coli

H Omote, N Sambonmatsu, K Saito, Y Sambongi, A Iwamoto-Kihara, T Yanagida, Y Wada, M Futai

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 96 ( 14 ) 7780 - 7784 1999.7

Language：English Publisher：NATL ACAD SCIENCES

The rotation of the gamma-subunit has been included in the binding-change mechanism of ATP synthesis/hydrolysis by the proton ATP synthase (FOF1), The Escherichia coli ATP synthase was engineered for rotation studies such that its ATP hydrolysis and synthesis activity is similar to that of wild type. A fluorescently labeled actin filament connected to the gamma-subunit of the F-1 sector rotated on addition of ATP, This progress enabled us to analyze the gamma M23K (the gamma-subunit Met-23 replaced by Lys) mutant, which is defective in energy coupling between catalysis and proton translocation. We found that the F-1 sector produced essentially the same frictional torque, regardless of the mutation. These results suggest that the gamma M23K mutant is defective in the transformation of the mechanical work into proton translocation or vice versa.

DOI： 10.1073/pnas.96.14.7780

Mutations in the ATP synthase gene suppress the lethal effect by human Bax against bacteria

NISHIMAKI Kiyomi, ASOH Sadamitu, OMOTE Hiroshi, HUTAI Masamitu, OHTA Shigeo

21 570 - 570 1998.12