Search for NADH-fumarate reductase produced by microorganisms

寻找微生物产生的NADH-富马酸还原酶

基本信息

批准号：
14593006
负责人：
SHIOMI Kazuro
金额：
$ 2.24万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14593006/
关键词：
NADH-fumarate reductase Electron transport Enzyme inhibitor Bioactive compound Screening Isolation Parasite Helminth 〓虫

项目摘要

NADH-fumarate reductase (complex I+II) is a key enzyme of anaerobic energy metabolism in many adult helminths. In the course of the, screening of NADH-fumarate reductase inhibitors from adult roundworm, Ascaris suum, we have isolated harzianopyridone from Trichoderma sp. FTD-0795. We studied the target enzyme using atpenin A5, a more potent inhibitor of harzianopyridone analog, and found that it specifically inhibited complex II. Though atpenin A5 did not show selectivity between helminths and mammals, it showed 300 times more potent complex II inhibition than carboxin the most potent known inhibitor of complex II. Therefore, atpenin A5 may be a useful tool for biochemical study of complex II.Our continuous screening achieved the finding of another five inhibitors, glisoprenin A, paecilaminol, verticipyrorie, decursin, and decursinol angelate. Among them, paecilaminol and verticipyrone are new compounds, and verticipyrone showed potent inhibition against A. suum NADH-fumarate reductase with IC_<50> value of 4.1 nM and weak inhibition to mammal bovine heart NADH oxidase (complex I+III+IV) with IC_<50> value of 56.0 nM. We are evaluating anthelmintic activities of these compounds now.We found selective helminth complex I inhibitor, nafuredin, previously. Alkaline treatment of nafuredin yielded a new compound nafuredin-γ that showed almost the same complex I inhibition and anthelmintic activity as nafuredin. We have already finished the total synthesis of nafuredin-γ, and we will prepare more potent analogs of nafuredin-γ.

NADH-FUMARATE还原（复合物I+II）是许多成年蠕虫中厌氧能量代谢的关键酶。在筛查NADH-Fumarate的过程中，降低了成人round虫的抑制剂，Ascaris suum，我们从Trichoderma sp中分离了Harzianopyridone。 FTD-0795。我们使用Atpenin A5研究了靶酶，Atpenin A5是Harzianopidone类似物的潜在抑制剂，发现它特别抑制了复合物II。尽管ATPENIN A5没有显示出蠕虫和哺乳动物之间的选择性，但它显示出比箱子最有可能的复合物II抑制剂的潜在复合物II抑制作用的300倍。因此，Atpenin A5可能是复合物II的生化研究的有用工具。我们的持续筛查实现了另外五个抑制剂，葡萄干A，paeclaminol，verticipyrorie，decursin和decursinol Angelate。其中，paeclaminol和verticipyrone是新化合物，肉黄酮在IC_ <50>值为4.1 nm的值中显示出潜在的抑制作用，对4.1 nm的suum nadh-fumarate还原，对哺乳动物牛心NADH氧化物的抑制作用弱（复杂的I+III+IV），IC_ <50>含量为56.0 nm。我们现在正在评估这些化合物的驱虫活性。碱性纳芬蛋白的治疗产生了一种新的化合物Nafuredin-γ，该复合蛋白-γ几乎显示出与Nafuredin的I抑制和驱虫活性。我们已经完成了Nafuredin-γ的总合成，我们将准备更多的Nafuredin-γ的潜在类似物。