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  • Hiroyuki Kamiya, Chieko Ishiguro, Hideyoshi Harashima
    The Journal of Biochemistry
    2004年 136 巻 3 号 359-362
    発行日: 2004/09/01
    公開日: 2008/06/30
    ジャーナル フリー
    The Escherichia coli
    MutT
    protein hydrolyzes 8-hydroxy-dGTP (8-OH-dGTP) in vitro, and
    mutT
    gene deficiencies cause increased spontaneous A: T→C: G mutations. However, no direct evidence exists for enhanced mutagenicity of 8-OH-dGTP in
    mutT
    cells. In this study, 8-OH-dGTP was introduced into wild type and
    mutT
    E. coli
    cells, and mutations of a chromosomal gene were monitored. 8-OH-dGTP induced muta-tions of the rpoB gene, the degree of the mutation induction in the
    mutT
    strain being_??_6-fold higher than that in the wild type strain. On the other hand, 2-hydroxy-dATP, which is not a substrate of the
    MutT
    protein, increased the mutation to similar degrees in the two strains. These results constitute the first evidence that the
    MutT
    protein suppresses mutation by 8-OH-dGTP in vivo.
  • *菊地 政弘, 米倉 慎一郎, 中村 允耶, 米井 修治, 張 秋梅
    日本放射線影響学会大会講演要旨集
    2007年 2007 巻 DO-030
    発行日: 2007年
    公開日: 2007/10/20
    会議録・要旨集 フリー
    細胞内の代謝活動や電離放射線、化学物質など細胞外の環境要因によって活性酸素が細胞内に生じる。活性酸素による核酸、脂質やタンパク質など生体分子の酸化は突然変異や発ガンを誘発する。その中でもグアニン塩基が酸化された8- オキソグアニンは生成量、突然変異原性ともに高いDNA損傷の一つとして知られている。この8- オキソグアニンはDNA上のグアニンが酸化を受けて生成する場合と、ヌクレオチドプール中の dGTPの酸化により8 oxo-dGTPが生じ、DNAにとりこまれる場合がある。8-oxo-dGTPを加水分解する酵素として、大腸菌では
    MutT
    タンパク質が知られている。この
    MutT
    はヒトやマウスでもホモログ(MTH1)が見つかっている。また、
    MutT
    やMTH1が欠損すると突然変異や腫瘍形成の増加が見られることも報告されている。これらの事実から、ヌクレオチドプールの酸化的損傷は生物全般にとって大きな脅威となっており、ヌクレオチドプールの浄化は生物にとって重要な防御であると考えられる。本研究では線虫C.elegansおよびホヤC.intestinalisを対象にデータベースを用いて検索し、相同性の高いものを
    MutT
    ホモログ候補として取り上げ、それらの構造および機能の解析を行った。本学会ではそれぞれのホモログの構造とHPLCを用いた8-oxo-dGTPに対するin vitroでの反応の解析、線虫の変異体の表現解析の結果を発表する。
  • *Hiroyuki Kamiya, Chieko Ishiguro, Hideyoshi Harashima
    日本放射線影響学会大会講演要旨集
    2004年 2004 巻 1A-04
    発行日: 2004年
    公開日: 2005/05/10
    会議録・要旨集 フリー
    The Escherichia coli
    MutT
    protein hydrolyzes 8-hydroxy-dGTP (8-OH-dGTP) in vitro, and
    mutT
    gene deficiencies cause increased spontaneous A:T to C:G mutations. However, no direct evidence exists for the enhanced mutagenicity of 8-OH-dGTP in
    mutT
    cells. In this study, 8-OH-dGTP was introduced into wild type and
    mutT
    E. coli
    cells, and mutations on a chromosomal gene were monitored. 8-OH-dGTP induced mutations in the rpoB gene, and the degree of the mutation induction in the
    mutT
    strain was ~6-fold higher than that in the wild type strain. On the other hand, 2-hydroxy-dATP, which is not a substrate of the
    MutT
    protein, increased mutations to similar degrees in both strains. These results provide the first evidence showing that the
    MutT
    protein suppresses mutations by 8-OH-dGTP in vivo.
  • Hiroyuki Kamiya, Emiko Iida, Hideyoshi Harashima
    Genes and Environment
    2007年 29 巻 2 号 63-66
    発行日: 2007年
    公開日: 2007/06/05
    ジャーナル フリー
    The Escherichia coli Orf135 (NudG) protein, a
    MutT
    -type enzyme, catalyzes the hydrolysis of 2-hydroxy-dATP and 8-hydroxy-dGTP, and its deficiency causes an increase in the mutation frequency. In this study, Orf135 proteins with substitutions at the Gly-36, Gly-37, Lys-38, Glu-43, Arg-51, Glu-52, Leu-53, Glu-55, and Glu-56 residues, which are conserved in three
    MutT
    -type proteins (Orf135,
    MutT
    , and MTH1), were each expressed in the orf135- strain, and the rpoB mutant frequency upon H2O2 treatment was examined. The in vivo mutation suppression abilities and the in vitro enzymatic activities obtained in a previous study were compared. The expression of the enzymatically active Orf135 mutants in the orf135- strain tended to reduce the rpoB mutant frequency induced by H2O2. This result suggests the importance of the phosphohydrolase activity in the suppression of mutations by the Orf135 protein.
  • Mika Hori, Taketoshi Asanuma, Osamu Inanami, Mikinori Kuwabara, Hideyoshi Harashima, Hiroyuki Kamiya
    Biological and Pharmaceutical Bulletin
    2006年 29 巻 6 号 1087-1091
    発行日: 2006年
    公開日: 2006/06/01
    ジャーナル フリー
    The Escherichia coli Orf17 (NtpA, NudB) protein, a
    MutT
    -type enzyme, hydrolyzes oxidized deoxyribonucleotides, including 8-hydroxy-2′-deoxyadenosine 5′-triphosphate and 8-hydroxy-2′-deoxyguanosine 5′-triphosphate, in vitro. To examine its in vivo role(s) in bacteria, plasmid DNAs containing the orf17 gene in the sense and antisense orientations were introduced. When the Orf17 protein was overexpressed in
    mutT
    cells, the rpoB mutant frequency was decreased. On the other hand, similar effects were not observed when Orf17 was overexpressed in wild type and orf135 cells. Expression of the antisense RNA of the orf17 gene did not produce an obvious phenotype, such as increased mutant frequency and resistance to ionizing radiation. These results suggest that the role of the Orf17 protein is to back up the
    MutT
    function, and to assist in the elimination of 8-hydroxy-2′-deoxyguanosine nucleotides.
  • 中村 照也
    日本結晶学会誌
    2014年 56 巻 2 号 123-128
    発行日: 2014/04/30
    公開日: 2014/05/01
    ジャーナル フリー
    DNA, which carries genetic information, is easily damaged by reactive oxygen species,UV radiation and chemical agents, and DNA integrity is maintained by various nucleic acid enzymes. We carried out X-ray crystallographic studies of two types of nucleic acid enzymes, oxidative nucleotide hydrolase
    MutT
    and translesion DNA polymerase η. In this review, I will describe the mechanism of high substrate specificity for oxidative nucleotides by E. coli
    MutT
    and the visualization of nucleotidyl transfer reaction by human DNA polymerase η.
  • Mayumi Sasaki, Yuri Yonemura, Yasurou Kurusu
    The Journal of General and Applied Microbiology
    2000年 46 巻 3 号 183-187
    発行日: 2000年
    公開日: 2005/11/02
    ジャーナル フリー
  • Hiroyuki Kamiya
    Genes and Environment
    2007年 29 巻 4 号 133-140
    発行日: 2007年
    公開日: 2007/12/04
    ジャーナル フリー
    Base oxidation occurs in the cellular nucleotide pool as well as in DNA, and the oxidized DNA precursors induce mutagenic events. 8-Hydroxy-dGTP (8-OH-dGTP) and 2-hydroxy-dATP (2-OH-dATP) have been identified as the major products of in vitro oxidation reactions with Fe2+. The mutagenic potentials of many oxidized DNA precursors have been examined in various experimental systems. Accumulating evidence indicates the importance of 8-OH-dGTP and 2-OH-dATP in the mutation process. In addition, nucleotide pool sanitization enzymes, such as
    MutT
    and MTH1, have been identified as a defense against the mutagenesis induced by these oxidized DNA precursors. In this review, the mutagenicities of 8-OH-dGTP and 2-OH-dATP and the functions of
    MutT
    -type nucleotide pool sanitization enzymes will be summarized.
  • Yoshio Kimura, Sayaka Kajimoto, Yuuka Yamamoto, Naotaka Tanaka
    The Journal of General and Applied Microbiology
    2020年 66 巻 1 号 46-50
    発行日: 2020年
    公開日: 2020/04/13
    [早期公開] 公開日: 2019/07/09
    ジャーナル フリー
    電子付録

    Myxococcus xanthus Nudix hydrolase 2 (Nud2) hydrolyzed oxidized deoxynucleotides, such as 8-oxo-dGTP, 8-oxo-dGDP, 8-OH-dTP, and 2-OH-dATP, and showed the highest specific activity toward 8-oxo-dGTP. Mn2+ was the most effective co-factor for stimulating oxidized deoxynucleotide hydrolase activity. The Km of Nud2 with 8-oxo-dGTP for Mn2+ was 19-fold lower than that for Mg2+, and was 2-fold lower than that with dGTP for Mn2+. The specificity constant (kcat/Km) for 8-oxo-dGTP was 6-fold higher than that for dGTP. Nud2 contains a similar Nudix motif (84AX590GX7REX2EEXGX). Replacement of Ala84 and/or Gly90 in the Nudix motif of Nud2 by Gly or Glu had negligible effects on 8-oxo-dGTP hydrolase activity, suggesting that a strict Nudix motif sequence is not essential for complete hydrolase activity of Nud2.

  • —DNA修復欠損マウスにおける突然変異と発がんの解析—
    續 輝久, 山内 一己, 磯田 拓郎, 江頭 明典, 藏 忍, 中津 可道
    環境変異原研究
    2005年 27 巻 2 号 101-110
    発行日: 2005年
    公開日: 2005/12/26
    ジャーナル フリー
    Oxygen radicals are produced through normal cellular metabolism, and formation of such radicals is further enhanced by ionizing radiation and by various chemicals. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most abundant, and appears to play important roles in mutagenesis and carcinogenesis. Enzymatic activities that may be responsible for preventing 8-oxoG-evoked mutations were identified in mammalian cells. We have focused on following the two enzymes. MTH1 (Mth1) protein is the mammalian counterpart of E. coli
    MutT
    protein, which hydrolyzes 8-oxo-dGTP to its monophosphate form in the nucleotide pool, thereby preventing the incorporation of the mutagenic substrate into DNA. On the other hand, MUTYH (Mutyh) protein, a counterpart of E. coli MutY protein, having adenine/2-hydroxyadenine DNA glycosylase activity, is expected to prevent G:C to T:A transversions, by excising adenine from G:A mismatches induced by 8-oxoG and 2-OH-A. To analyze the function of the mammalian Mth1 and Mutyh proteins in vivo, we established gene-knockout mice for these two enzymes by gene targeting, and investigated spontaneous tumorigenesis as well as mutagenesis. Here we discuss our recent progress on spontaneous and oxidative stress-induced mutagenesis with these mutant mouse lines.
  • 中村 照也
    日本結晶学会誌
    2013年 55 巻 Supplement 号 s1-
    発行日: 2013/10/12
    公開日: 2013/11/27
    ジャーナル フリー
  • Yosomatsu TAKAMURA
    Nippon Sugaku-Buturigakkwai Kizi Dai 3 Ki
    1931年 13 巻 10 号 282-286
    発行日: 1931年
    公開日: 2009/06/09
    ジャーナル フリー
    The paper ineludes goine- experiniental invertigations on the varlations of the negative thermionic enriesion power of Wehnelt filament due to an auxiliary filament of heated platinum and etc. The
    mutt
    important effect eras a considerable general deerease of the erission power
  • Mutsuo SEKIGUCHI
    Proceedings of the Japan Academy, Series B
    2006年 82 巻 8 号 278-296
    発行日: 2006年
    公開日: 2006/12/02
    ジャーナル フリー
    Certain types of DNA lesions, produced through cellular metabolic processes and also by external environmental stresses, are responsible for the induction of mutations as well as of cancer. Most of these lesions can be eliminated by DNA repair enzymes, and cells carrying the remaining DNA lesions are subjected to apoptosis. The persistence of damaged bases in RNA can cause errors in gene expression, and the cells appear to possess a mechanism which can prevent damaged RNA molecules from entering the translation process. We have investigated these processes for high fidelity of DNA replication and gene expression, by using both biochemical and genetic means. We herein describe (1) the molecular mechanisms for accurate DNA synthesis, (2) mammalian proteins for sanitizing the DNA precursor pool, (3) error avoidance mechanisms for gene expression under oxidative stress, and (4) the roles of DNA repair and apoptosis in the prevention of cancer.

    (Communicated by Takao SEKIYA, M.J.A.)
  • Shin-Ichiro Yonekura, U Sanada, Qiu-Mei Zhang-Akiyama
    Genes & Genetic Systems
    2010年 85 巻 4 号 287-295
    発行日: 2010年
    公開日: 2010/12/20
    ジャーナル フリー HTML
    The oxidized nucleotide precursors 7, 8-dihydro-8-oxo-dGTP (8-oxo-dGTP) and 1, 2-dihydro-2-oxo-dATP (2-oxo-dATP) are readily incorporated into nascent DNA strands during replication, which would cause base substitution mutations. E. coli
    MutT
    and human homologue hMTH1 hydrolyze 8-oxo-dGTP, thereby preventing mutations. In this study, we searched for hMTH1 homologues in the ascidian Ciona intestinalis using the NCBI-BLAST database. Among several candidates, we focused on one open reading frame, designated as CiMutT, because of its high degree of identity (41.7%) and similarity (58.3%) to the overall amino acid sequence of hMTH1, including the Nudix box. CiMutT significantly suppressed the mutator activity of E. coli
    mutT
    mutant. Purified CiMutT had a pyrophosphohydrolase activity that hydrolyzed 8-oxo-dGTP to 8-oxo-dGMP and inorganic pyrophosphate. It had a pH optimum of 9.5 and Mg++ requirement with optimal activity at 5 mM. The activity of CiMutT for 8-oxo-dGTP was comparable to that of hMTH1, while it was 100-fold lower for 2-oxo-dATP than that of hMTH1. These facts indicate that CiMutT is a functional homologue of E. coli
    MutT
    . In addition, the enzyme hydrolyzed all four of the unoxidized nucleoside triphosphates, with a preference for dATP. The specific activity for 8-oxo-dGTP was greater than that for unoxidized dATP and dGTP. These results suggest that CiMutT has the potential to prevent mutations by 8-oxo-dGTP in C. intestinalis.
  • Yoshio Kimura, Yuuka Yamamoto, Sayaka Kajimoto, Ai Sakai, Kaoru Takegawa
    The Journal of General and Applied Microbiology
    2018年 64 巻 2 号 94-98
    発行日: 2018年
    公開日: 2018/05/21
    [早期公開] 公開日: 2018/01/25
    ジャーナル フリー
    電子付録
  • Andrzej GURANOWSKI
    Journal of Clinical Biochemistry and Nutrition
    2000年 28 巻 3 号 177-189
    発行日: 2000年
    公開日: 2010/02/25
    ジャーナル フリー
    Dinucleoside 5′, 5′′′-Pα, Pω-polyphosphates have been found in all cells examined. So far, the only known specific enzyme that catalyzes the synthesis of these polyphosphates is GTP:GTP guanylyltransferase. This enzyme produces Gp4G, Gp3G, and various Np3-4Gs. The adenylated counterparts, such as Ap3A and Ap4A, are synthesized by ligases, at least by some aminoacyl-tRNA synthetases. Ap4A phosphorylase, firefly luciferase, acyl-CoA synthetase, and the DNA- and RNA-ligases are also able to produce Np3-6As. By contrast, in addition to nonspecific enzymes such as phosphodiesterase I and nucleotide pyrophosphatase, there occur in all types of organism specific enzymes that degrade Np3-6N's. These are the Np3N′ hydrolases, the asymmetrically and symmetrically acting Np4N′ hydrolases, the NpnN′ phosphorylases, and recently described hydrolases that prefer Ap6A and Ap5A as substrates. Human Fhit protein, a putative tumor suppressor, behaves as a typical Np3N′ hydrolase and is a member of the HIT (histidine triad) protein family. The human Np4N′ hydrolase belongs to the
    MutT
    motif or Nudix (nucleoside diphosphate attached to “x”) hydrolase protein family. The level of Np3-6N's in the cells increases dramatically under stress. It is suggested that these minor nucleotides act as both intra- and extracellular signalling molecules. ApnAs interact with purine receptors and affect vascular tone. Chemically synthesized analogues of NpnN's help us to understand the mechanism of action of the enzymes mentioned, and some of them are candidates for drugs.
  • *上田 弥生, 三宅 弘恵, 小川 貴央, 吉村 和也, 重岡 成
    日本植物生理学会年会およびシンポジウム 講演要旨集
    2006年 2006 巻
    発行日: 2006年
    公開日: 2006/12/27
    会議録・要旨集 フリー
    酸化的ストレス下で生じる活性酸素はDNAやヌクレオチドを酸化し、突然変異を引き起こす。
    MutT
    /Nudixタンパク質はヌクレオシド2リン酸由来の物質(nucleoside diphosphate linked some moiety X)を加水分解するタンパク質ファミリーであり、特に大腸菌
    MutT
    やヒト
    MutT
    ホモログ/MTH1は酸化ヌクレオチドを加水分解することで突然変異を抑制する。シロイヌナズナにも局在性の異なる24種類の
    MutT
    /nudixタンパク質ホモログが存在するが、その機能はほとんど明らかになっていない。そこで、植物の酸化ヌクレオチド修復機構を明らかにするために、シロイヌナズナ細胞質型
    MutT
    /nudixタンパク質(AtNUDX1-11)の機能解析を試みた。リコンビナントタンパク質を用いて基質特異性を検討した結果、AtNUDX1のみが8-oxo-dGTP、8-oxo-GTPに対する加水分解活性を示した。また、大腸菌
    MutT
    欠損による突然変異を抑制したことから、シロイヌナズナにおいてAtNUDX1が酸化ヌクレオチドによる突然変異の抑制に機能していることが示唆された。そこで、シロイヌナズナ野生株とAtNUDX1破壊株間の酸化ストレス(2μMパラコート)耐性能を評価した結果、表現型に顕著な差は認められなかった。現在、ストレス下における両株のDNA中の酸化ヌクレオチド量の定量を行っている。
  • 中山 沃, 福田 博之
    The Japanese Journal of Physiology
    1966年 16 巻 2 号 185-193
    発行日: 1966年
    公開日: 2011/06/07
    ジャーナル フリー
    1. In dogs anesthetized with pentobarbital sodium the intravenous administration of 0.5 to 1 Ivy dog unit/kg CCKV (Cecekin Vitrum) produced the excitation of the movements of the gall bladder, stomach and small intestine. After the administration of atropine or hexamethonium the excitatory effect was not abolished.
    2. The motility of the isolated duodenal loop of a rabbit was increased by the administration of CCKV. The excitatory effect of the agent on the excised muscle strip of the dog jejunum was less than that in the rabbit intestine.
    3. On the other hand, about 1.5 minutes after purfusing the lumen of the isolated jejunum with N/10 HCl solution, the gall bladder began to contract and several minutes later the contraction reached its maximum, while there occurred no response in the jejunal movements.
    4. From the results described above it may be concluded that pure cholecystokinin exerts no effect on the motility of the small intestine, and that a potent preparation of cholecystokinin (Cecekin Vitrum) is not a purified cholecystokinin, but it contains some unknown substance to excite movements of the small intestine and stomach.
  • MARIANNE SCHUTZBERG, TOMAS HOKFELT, JAN M. LUNDBERG, KJELL FUXE, VIKTOR
    MUTT
    , SAMI SAID
    Endocrinologia Japonica
    1980年 27 巻 Supplement 号 23-30
    発行日: 1980年
    公開日: 2011/01/25
    ジャーナル フリー
    Vasoactive intestinal polypeptide (VIP) was isolated from porcine intestine in 1970 by Said &
    Mutt
    (1970). Characterization showed that it consists of 28 amino acids (
    Mutt
    & Said, 1974). Antibodies were raised against the peptide (Said & Faloona, 1975) and radioimmunological determinations revealed high concentrations of VIP in the gastro-intestinal tract (Polak et al., 1974 ; Said, 1975), in neural cell lines (Said & Rosenberg, 1976) and in the central nervous system (Bryant et al., 1976 ; Larsson et al., 1976b ; Said & Rosenberg, 1976). Immunohistochemical studies located the VIP-like immunoreactivity to gastro-intestinal neurons (Bryant et al., 1976; Larsson et al., 1976b ; Fuxe et al., 1977), cerebrovascular nerves (Larsson et al., 1976a) and central neurons (Fuxe et al., 1977 ; Larsson et al., 1976b).
    The present paper gives a brief account of the distribution of VIP immunoreactive neurons in the central and peripheral nervous system as revealed by immunohistochemistry.
  • IROKI ITOH, TOSHIAKI NAGANO, TETSUJI HAYASHI, MASAHARU TAKEYAMA
    病院薬学
    1999年 25 巻 2 号 162-168
    発行日: 1999年
    公開日: 2011/08/11
    ジャーナル フリー
    A sensitive and specific enzyme immunoassay (EIA) for a secretin-like immunoreactive substance (secretin-IS) was developed using a synthetic carboxy-terminal (C-terminal) fragment (residue 5-27) of a porcine secretin conjugated with β-D-galactosidase and an anti-rabbit lgG coated immunoplate. The activity of the enzyme on the plate was fluorometrically determined. The present immunoassay allows the detection of 1.7 to 67 fmol/ml (0.068 to 2.7 fmol/well) of secretin. Using the present EIA, the secretin-ISs in human plasma were determined.
    Moreover, significant changes in the plasma secretin-IS levels were found after the oral administration of famotidine (vs.placebo).
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