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-富马酸还原酶（复合物I+II）是许多成虫蠕虫厌氧能量代谢的关键酶。在对猪蛔虫成虫中NADH-富马酸还原酶抑制剂的筛选过程中，我们从木霉中分离到了哈齐亚吡啶酮。 FTD-0795 我们使用 atpenin A5（一种更有效的 harzianopyridone 抑制剂）研究了目标酶。类似物，并发现它特异性地抑制复合物 II。虽然 atpenin A5 在蠕虫和哺乳动物之间没有表现出选择性，但它对复合物 II 的抑制作用比已知的最强的复合物 II 抑制剂 carboxin 强 300 倍。复合物 II 生化研究的有用工具。我们的连续筛选发现了另外五种抑制剂：格列素 A、paecilaminol、verticipyrorie、decursin 和其中，paecilaminol 和 verticipyrone 为新化合物，其中 verticipyrone 对 A. suum NADH-富马酸还原酶具有强效抑制作用，IC_<50>值为 4.1 nM，对哺乳动物牛心脏 NADH 氧化酶（复合物 I+III+ IV）具有弱抑制作用。），IC_<50>值为56.0 nM 我们正在评估这些化合物的驱虫活性。我们发现了选择性蠕虫复合物I抑制剂——萘呋定，之前对萘呋定进行碱处理，得到了一种新型化合物萘呋定-γ，其具有与萘呋定-γ几乎相同的复合物I抑制作用和驱虫活性。我们已经完成了萘呋定-γ的全合成。，我们将制备更有效的 nafuredin-γ 类似物。