Structures and clinical significance of polymorphism of human dihydrodiol dehydrogenase

人二氢二醇脱氢酶多态性的结构及临床意义

基本信息

  • 批准号:
    09672240
  • 负责人:
  • 金额:
    $ 2.05万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    1997
  • 资助国家:
    日本
  • 起止时间:
    1997 至 1998
  • 项目状态:
    已结题

项目摘要

Four isozymes (DD1-DD4) of human dihydrodiol dehydrogenase share 83-97% amino acid sequence identity and belong to the aldo-keto reductase fhaiily, but differ in specificity for endogenous substrates and effects by modulators. In addition, nine cDNAs similar to that for the four isozymes have recently been reported, which suggests the existence of genetic polymorphism of the respective isozymes. This study was performed to elucidate structural determinants for the functional difference among the four isozymes, genetic polymorphism of the respective isozymes, and clinical significance of the variant gene. The results obtained are summarized as follows :1. Kinetic analyses of recombinant DD3 and AKRlC3, which differs by 3 amino acids from DD3, indicated that they are functionally identical and the 3 residues are not involved in the active site. Substrate specificity study suggested that the enzymes physiologically act as prostaglandin D2 1 1-ketoreductase rather than hydroxysteroid dehyd … More rogenase.2. Site-directed mutagenesis of the isozymes and formation of chimeric enzymes suggested several amino acid residues, which interact with substrates and modulators, and are responsible for the binding and/or orientation of the coenzyme and activators.3. Anti-hyperlipidemic clofibrate derivatives and anti-inflammatory 2-arylpropionic acid derivatives were identified as activators specific for DD4. In addition, thyroxin, a thyroid hormone, was found to be the physiological activator of this isozyme. The mechanism of activation by these compounds was kinetically elucidated and residues in the activator-binding site of the isozyme were suggested by site-directed mutagenesis.4. We established the RT-PCR and RFLP methods to discriminate the 13 cDNAs reported for the dihydrodiol dehydrogenase isozymes. Only one mRNA species for DDl, DD2 and DD3, respectively, were detected in 50 human tissue samples. The result suggested that the cDNAs for DDI, DD2 and DD3 are the principal alleles of the three genes, and the other cDNAs reported are derived from rare variants of the respective isozyme genes or could be sequencing errors. On the other hand, about 20% of the samples showed heterozygous expression of mRNAs for DD4 and a variant that differs by 2 amino acids from DD4. Analysis of genomic DNA for 137 blood samples confirms this variant DD4 gene, and one of the samples showed homozygous expression of this variant gene. The frequency of this variant allele in Japanese was about 9%. The physiological effect of this variant gene and its relationship to hepatic diseases are not unclear at present. Less
人二氢二醇脱氢酶的四种同工酶(DD 1-DD 4)具有83-97%的氨基酸序列同一性,属于醛酮还原酶家族,但对内源性底物的特异性和调节剂的作用不同。此外,最近还报道了9个与这4种同工酶相似的cDNA,这表明各同工酶存在遗传多态性。本研究旨在阐明四种同工酶之间功能差异的结构决定因素、各同工酶的遗传多态性以及变异基因的临床意义。主要研究结果如下:1.重组DD 3和AKR 1C 3的动力学分析表明,它们在功能上是相同的,并且这3个残基不参与活性位点,AKR 1C 3与DD 3相差3个氨基酸。底物特异性研究表明,该酶在生理上起前列腺素D2 1 1-酮还原酶的作用,而不是羟基类固醇脱氢酶。 ...更多信息 rogenase. 2.同工酶的定点突变和嵌合酶的形成提示了几个氨基酸残基,它们与底物和调节剂相互作用,并负责辅酶和激活剂的结合和/或定位.抗高血压的氯贝特衍生物和抗炎的2-芳基丙酸衍生物被鉴定为对DD 4特异的活化剂。此外,甲状腺素,甲状腺激素,被发现是该同工酶的生理激活剂。动力学上阐明了这些化合物的激活机制,并通过定点突变提出了同工酶激活剂结合位点的残基.我们建立了RT-PCR和RFLP的方法来区分已报道的13个二氢二醇脱氢酶同工酶的cDNA。在50个人组织样品中分别仅检测到DD 1、DD 2和DD 3的一种mRNA种类。结果表明,DD 1、DD 2和DD 3基因的cDNA是这3个基因的主要等位基因,其它已报道的cDNA可能是各自基因的罕见变异体或测序错误。另一方面,约20%的样品显示DD 4和与DD 4相差2个氨基酸的变体的mRNA的杂合表达。对137份血液样本的基因组DNA分析证实了该变异DD 4基因,其中一份样本显示该变异基因的纯合表达。该变异等位基因在日本人中的频率约为9%。目前,该变异基因的生理作用及其与肝脏疾病的关系尚不清楚。少

项目成果

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专著数量(0)
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专利数量(0)
Shiraishi Hiroaki: "Sequence of the cDNA of a human liver dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA" Biochem.J.334. 399-405 (1998)
Shiraishi Hiroaki:“人肝二氢二醇脱氢酶异构体 (AKR1C2) 的 cDNA 序列及其 mRNA 的组织分布”Biochem.J.334。
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    0
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Matsuura Kazuya: "Activation of human 3α-hydroxysteroid dehydrogenase by clofibrate derivatives" J.Pharmacol.Exp.Ther.発表予定(印刷中). (1998)
Matsuura Kazuya:“氯贝特衍生物激活人 3α-羟基类固醇脱氢酶”J.Pharmacol.Exp.Ther. 预定演示(1998 年)。
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    0
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Matsuura Kazuya: "Identification of a principal mRNA species for human 3α-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D_2 11-ketoreductase activity" J.Biochem.124. 940-946 (1998)
Matsuura Kazuya:“具有高前列腺素 D_2 11-酮还原酶活性的人 3α-羟基类固醇脱氢酶亚型 (AKR1C3) 的主要 mRNA 种类的鉴定”J.Biochem.124 (1998)。
  • DOI:
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  • 影响因子:
    0
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Matsuura Kazuya: "Identification of a principal mRNA species for human 3α-hydroxysteroid dehydrogenase isoform(AKRIC3)that exhibits high prostaglandin D_2 II-ketoreductase activity" J.Biochem.124・5. 940-946 (1998)
松浦和也:“具有高前列腺素 D_2 II-酮还原酶活性的人 3α-羟基类固醇脱氢酶亚型 (AKRIC3) 的主要 mRNA 种类的鉴定”J.Biochem.124·5 (1998)。
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  • 影响因子:
    0
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Matsuura Kazuya: "Roles of the C-terminal domains of human dihydrodiol dehydrogenase isoforms In the binding of substrates and modulators" Biochem.J.336. 429-436 (1998)
Matsuura Kazuya:“人二氢二醇脱氢酶亚型的 C 末端结构域在底物和调节剂结合中的作用”Biochem.J.336。
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    0
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HARA Akira其他文献

HARA Akira的其他文献

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{{ truncateString('HARA Akira', 18)}}的其他基金

Automatic Generation of Graph-structural Programs by Using Swarm Intelligence of Ants
利用蚂蚁群体智能自动生成图结构程序
  • 批准号:
    25730149
  • 财政年份:
    2013
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
DEVELOPMENT OF ANTITUMOR DRUGS TARGETING TUMOR MARKERALDO-KETO REDUCTASES
开发针对肿瘤标记酮还原酶的抗肿瘤药物
  • 批准号:
    22590102
  • 财政年份:
    2010
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The market economy and the system design of 20th century Japan
市场经济与20世纪日本的制度设计
  • 批准号:
    20243023
  • 财政年份:
    2008
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Neuron-Like Differentiation and Selective Ablation of Undifferentiated Embryonic Stem Cells Containing Suicide Gene with Oct-4 Promoter
含有Oct-4启动子自杀基因的未分化胚胎干细胞的神经元样分化和选择性消融
  • 批准号:
    19592012
  • 财政年份:
    2007
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Firms and Industrial Association in the Period of the Second World War and the Postwar Economic Recovery
第二次世界大战期间的企业和工业协会以及战后经济复苏
  • 批准号:
    16203025
  • 财政年份:
    2004
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Study on the uronate-cycle oxidoreductases that are expressed highly in kidney
肾脏高表达糖醛酸循环氧化还原酶的研究
  • 批准号:
    13672290
  • 财政年份:
    2001
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Study of tissue-specific dihydrodiol dehydrogenase
组织特异性二氢二醇脱氢酶的研究
  • 批准号:
    11672175
  • 财政年份:
    1999
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of drugs targeting neurosteroid-metabolizing enzymes
开发针对神经类固醇代谢酶的药物
  • 批准号:
    11557195
  • 财政年份:
    1999
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Cochlear Dysfunction and Free Radicals : hydroxyl radicals, metallic elements, steroid hormones and SOD
耳蜗功能障碍和自由基:羟基自由基、金属元素、类固醇激素和 SOD
  • 批准号:
    10470351
  • 财政年份:
    1998
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
The decontrol and the restoration to the market economy after The World War II
二战后放松管制和恢复市场经济
  • 批准号:
    09430014
  • 财政年份:
    1997
  • 资助金额:
    $ 2.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)

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Aldo-keto reductase family 1 member B10 AKR1B10 in pancreatic carcinogenesis
醛酮还原酶家族 1 成员 B10 AKR1B10 在胰腺癌发生中的作用
  • 批准号:
    8220421
  • 财政年份:
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醛酮还原酶家族 1 成员 B10 AKR1B10 在胰腺癌发生中的作用
  • 批准号:
    8862423
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    2012
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Aldo-keto reductase family 1 member B10 AKR1B10 in pancreatic carcinogenesis
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  • 批准号:
    8527744
  • 财政年份:
    2012
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    $ 2.05万
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Aldo-keto reductase family 1 member B10 AKR1B10 in pancreatic carcinogenesis
醛酮还原酶家族 1 成员 B10 AKR1B10 在胰腺癌发生中的作用
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    2012
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    $ 2.05万
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