Studies on inhibition of respiratory cytochrome bc1 complex by the fungicide pyrimorph suggest a novel inhibitory mechanism.
Studies on inhibition of respiratory cytochrome bc1 complex by the fungicide pyrimorph suggest a novel inhibitory mechanism.
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DOI：
10.1371/journal.pone.0093765
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Xia D
中科院分区：
文献类型：
--
作者：
Xiao YM;Esser L;Zhou F;Li C;Zhou YH;Yu CA;Qin ZH;Xia D
呼吸链细胞色素bc 1复合物（cyt bc 1）是许多抗生素和杀真菌剂的主要靶标。所有的cyt bc 1抑制剂作用于泛醇氧化（QP）或泛醌还原（QN）位点。对bc 1抑制剂产生耐药性的主要原因是靶点突变，这就需要一种作用于细胞色素bc 1内替代位点的新型药物来克服耐药性。吡吗啉是一种人工合成的杀菌剂，可抑制多种植物病原真菌的生长，但其作用机制尚不清楚。在这项研究中，使用从病原真菌辣椒疫霉分离的线粒体，我们表明，丁酰吗啉通过影响细胞色素bc 1的功能来阻断线粒体电子传递。实际上，丁酰吗啉抑制纯化的11-亚基线粒体和4-亚基细菌bc 1的活性，IC 50值分别为85.0 μM和69.2 μM，表明其靶向细胞色素bc 1复合物的基本亚基。使用一系列的生物化学和光谱方法，我们表明，啶虫吗啉作用于QP网站附近的区域和福尔斯到一类的混合型，非竞争性抑制剂相对于底物泛醇。在计算机分子对接的嘧啶吗啉细胞色素B从哺乳动物和细菌来源也表明，嘧啶吗啉结合在附近的醌醇氧化位点。
The respiratory chain cytochrome bc 1 complex (cyt bc 1) is a major target of numerous antibiotics and fungicides. All cyt bc 1 inhibitors act on either the ubiquinol oxidation (QP) or ubiquinone reduction (QN) site. The primary cause of resistance to bc 1 inhibitors is target site mutations, creating a need for novel agents that act on alternative sites within the cyt bc 1 to overcome resistance. Pyrimorph, a synthetic fungicide, inhibits the growth of a broad range of plant pathogenic fungi, though little is known concerning its mechanism of action. In this study, using isolated mitochondria from pathogenic fungus Phytophthora capsici, we show that pyrimorph blocks mitochondrial electron transport by affecting the function of cyt bc 1. Indeed, pyrimorph inhibits the activities of both purified 11-subunit mitochondrial and 4-subunit bacterial bc 1 with IC50 values of 85.0 μM and 69.2 μM, respectively, indicating that it targets the essential subunits of cyt bc 1 complexes. Using an array of biochemical and spectral methods, we show that pyrimorph acts on an area near the QP site and falls into the category of a mixed-type, noncompetitive inhibitor with respect to the substrate ubiquinol. In silico molecular docking of pyrimorph to cyt b from mammalian and bacterial sources also suggests that pyrimorph binds in the vicinity of the quinol oxidation site.
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影响因子：
3.5
作者：
MITCHELL, P
通讯作者：
MITCHELL, P
影响因子：
4.8
作者：
Esser, Lothar;Elberry, Maria;Xia, Di
通讯作者：
Xia, Di
影响因子：
5.8
作者：
Laurie, ATR;Jackson, RM
通讯作者：
Jackson, RM
影响因子：
4.3
作者：
Berry, Edward A.;Huang, Li-shar;Lee, Dong-Woo;Daldal, Fevzi;Nagai, Kazuo;Minagawa, Nobuko
通讯作者：
Minagawa, Nobuko
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH