Search for NADH-fumarate reductase produced by microorganisms

nadh -富马酸还原酶（复合体I+II）是许多成虫体内厌氧能量代谢的关键酶。在从猪蛔虫（Ascaris suum）中筛选nadh -富马酸还原酶抑制剂的过程中，我们从木霉（Trichoderma sp. FTD-0795）中分离出了harzianopyridone。我们使用atpenin A5（一种更有效的harzianopyridone类似物抑制剂）研究靶酶，发现它特异性抑制复合物II。虽然atpenin A5在蠕虫和哺乳动物之间没有选择性，但它对复合物II的抑制作用比已知最有效的复合物II抑制剂carboxin强300倍。因此，atpenin A5可能成为复合体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，glisoprenin A, paecilaminol, vertical - yrorie， decursin和decursinol angelate。其中对青霉胺和垂直旋酮为新化合物，垂直旋酮对A. suum NADH-富马酸还原酶有较强的抑制作用，IC_<50>值为4.1 nM，对哺乳牛心脏NADH氧化酶（复合物I+III+IV）有较弱的抑制作用，IC_<50>值为56.0 nM。我们正在评价这些化合物的驱虫活性。我们之前发现了选择性蠕虫复合体I抑制剂，nafureredin。天然红素经碱性处理得到一种新的化合物天然红素-γ，它具有与天然红素几乎相同的复合物I抑制作用和驱虫活性。我们已经完成了天然红素-γ的全合成，我们将制备更有效的天然红素-γ类似物。

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.