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Induction mechanism of cyanide-resistant respiration in the yeast, Hansenula anomala

异常汉逊酵母中抗氰化物呼吸的诱导机制

基本信息

批准号：
07660123
负责人：
MINAGAWA Nobuko
金额：
$ 1.41万
依托单位：
Niigata College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

1) An antibiotic, ascochlorin, somehow acts on the cytochrome bc_1 complex. This antibiotic exhibited similar effects to those by Qo site inhibitors, on the reduction of Cyt.b_<560> by succinate, whereas ascochlorin induced the expression of nuclear-encoded alternative oxidase gene, similarly to antimycin A,Qi site inhibitors. Ca ionophores and membrane permeable Ca chelating agents inhibited the antimycin A_<3->, dithiothreitol-, and ascochlorin-dependent induction of alternative oxidase. Cysteine-specific modifying reagents strongly inhibited the induction and dithiothreitol exhibited protective effects on the modification. The induction was sensitive to staurosporine and calyculin A.These results suggest that intracellular Ca^<2+>, certain sulfhydryl group (s), protein phosphorylation, and dephosphorylation are involved in the signaling mechanism toward nuclei to express the alternative oxidase gene.2) We have cloned genomic clones encoding alternative oxidase from Hansenula anomala. In the upstream region from the transcription start site, a UAS2-like sequence was found. This sequence is suggested to control the alternative oxidase gene expression regulated by carbon source in this organism.3) An antibiotic, ascofuranone, specifically inhibits the ubiquinone redox machinery in the mitochondrial electron transport system in the long slender bloodstream forms of Trypanosoma brucei brucei. Futher, ascofuranone in combination with glycerol potently inhibited the in vitro growth of the parasite. The in vivo trypanocidal activity of ascofuranone in combination with glycerol was very powerful in mice. Our results strongly suggest that ascofuranone may be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.

1)一种抗生素，子囊二氢卟酚，以某种方式作用于细胞色素bc_1复合体。该抗生素对琥珀酸还原Cyt.B_的作用与Qo位点抑制剂相似<560>，而子囊二氢菌素对核编码的交替氧化酶基因的诱导作用与Qi位点抑制剂抗霉素A相似。钙离子载体和膜渗透性钙螯合剂抑制抗霉素A、<3->二硫苏糖醇和抗坏血酸依赖的交替氧化酶的诱导。半胱氨酸特异性修饰剂强烈抑制诱导和二硫苏糖醇表现出保护作用的修饰。这些结果表明细胞内Ca^2+、巯基、蛋白磷酸化和去磷酸化参与了向细胞核传递信号以表达交替氧化酶基因的机制。2）我们从异常汉逊酵母中克隆了编码交替氧化酶的基因组克隆。在转录起始位点的上游区域，发现了一个类似UAS 2的序列，该序列可能控制着该生物体中受碳源调控的交替氧化酶基因的表达。3）抗生素Ascofuranone特异性地抑制细长血流型布氏锥虫线粒体电子传递系统中的泛醌氧化还原机制。此外，Ascofuranone与甘油组合有效地抑制寄生虫的体外生长。子囊呋喃酮与甘油组合的体内杀锥虫活性在小鼠中非常强大。我们的研究结果强烈表明，Ascofuranone可能是一个有前途的非洲锥虫的化疗药物的候选人。