Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening.
Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening.
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DOI：
10.1016/j.freeradbiomed.2013.08.170
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Brand, Martin D.
中科院分区：
文献类型：
--
作者：
Orr, Adam L.;Ashok, Deepthi;Sarantos, Melissa R.;Shi, Tong;Hughes, Robert E.;Brand, Martin D.
关键词：
线粒体产生活性氧通常被认为是有氧代谢不可避免的结果，目前无法在不干扰氧化磷酸化的情况下对其进行操纵。抗氧化剂广泛用于抑制活性氧形成后的影响，但它们永远无法完全防止生产现场的直接影响。为了确定不干扰线粒体能量代谢的线粒体超氧化物/H2O2 产生的位点选择性抑制剂，我们开发了强大的小分子筛选和二次分析策略。我们描述了一种化合物（N-环己基-4-(4-硝基苯氧基)苯磺酰胺；CN-POBS）的发现和表征，该化合物选择性抑制复合物 I 泛醌结合位点（IQ 位点）产生超氧化物/H2O2，而对其他位点的超氧化物/H2O2 产生或氧化磷酸化没有影响。结构/活性研究确定了一个对于位点 IQ 的效力和选择性非常重要的核心结构。通过在线粒体中使用 CN-POBS 进行 NADH 生成底物的呼吸，我们发现在谷氨酸和苹果酸的正向电子传输过程中，位点 IQ 不会产生大量的超氧化物/H2O2。我们的筛选平台有望促进进一步发现线粒体源性氧化损伤的直接调节剂，并提高我们理解和操纵正常和病理条件下线粒体活性氧产生的能力。
Mitochondrial production of reactive oxygen species is often considered an unavoidable consequence of aerobic metabolism and currently cannot be manipulated without perturbing oxidative phosphorylation. Antioxidants are widely used to suppress effects of reactive oxygen species after formation, but they can never fully prevent immediate effects at the sites of production. To identify site-selective inhibitors of mitochondrial superoxide/H2O2 production that do not interfere with mitochondrial energy metabolism, we developed a robust small-molecule screen and secondary profiling strategy. We describe the discovery and characterization of a compound (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide; CN-POBS) that selectively inhibits superoxide/H2O2 production from the ubiquinone-binding site of complex I (site IQ) with no effects on superoxide/H2O2 production from other sites or on oxidative phosphorylation. Structure/activity studies identified a core structure that is important for potency and selectivity for site IQ. By employing CN-POBS in mitochondria respiring on NADH-generating substrates, we show that site IQ does not produce significant amounts of superoxide/H2O2 during forward electron transport on glutamate plus malate. Our screening platform promises to facilitate further discovery of direct modulators of mitochondrially-derived oxidative damage and advance our ability to understand and manipulate mitochondrial reactive oxygen species production in both normal and pathological conditions.
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影响因子：
4.8
作者：
Orr, Adam L.;Quinlan, Casey L.;Brand, Martin D.
通讯作者：
Brand, Martin D.
DOI：
10.1523/jneurosci.6303-11.2012
发表时间：
2012-02-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Niatsetskaya ZV;Sosunov SA;Matsiukevich D;Utkina-Sosunova IV;Ratner VI;Starkov AA;Ten VS
通讯作者：
Ten VS
DOI：
10.1074/jbc.m110.186841
发表时间：
2011-05-20
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Pryde KR;Hirst J
通讯作者：
Hirst J
DOI：
10.1152/ajpheart.00699.2006
发表时间：
2007-01-01
影响因子：
4.8
作者：
Hoffman, David L.;Salter, Jason D.;Brookes, Paul S.
通讯作者：
Brookes, Paul S.
影响因子：
7.8
作者：
Lambert, Adrian J.;Buckingham, Julie A.;Brand, Martin D.
通讯作者：
Brand, Martin D.