定义S1QEL的作用机理，即线粒体复合体I醌反应位点中超氧化物生成的特异性抑制剂。,Journal of Biological Chemistry

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定义S1QEL的作用机理，即线粒体复合体I醌反应位点中超氧化物生成的特异性抑制剂。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2019-03-01 , DOI: 10.1074/jbc.ra119.007687
Atsushi Banba ₁ , Atsuhito Tsuji ₁ , Hironori Kimura ₁ , Masatoshi Murai ₁ , Hideto Miyoshi ₂

Affiliation

先前已经报道了逆向电子传递过程中线粒体呼吸复合体I醌反应位点中超氧化物生成的位点特异性抑制剂（称为S1QELs）。但是，它们的作用机理仍然难以捉摸。我们使用牛心脏线粒体颗粒，研究了S1QEL对复杂I功能的影响。我们发现S1QELs对复合物I的抑制作用与其他已知的醌位抑制剂明显不同。例如，S1QEL的抑制能力会根据电子传输的方向（正向或反向）而显着变化。S1QELs通过甲苯磺酰基化学试剂AL1抑制了49kDa亚基中Asp160的特定化学修饰，该亚基位于醌结合袋的深处。S1QEL还不能抑制光反应性喹唑啉型抑制剂（[125I] AzQ）与49 kDa亚基的结合。此外，使用光反应性S1QEL衍生物的光亲和性标记实验表明，它们与ND1亚基中的一个片段结合，该片段不被认为构成了醌或抑制剂的结合口袋。这些结果表明，与已知的醌位抑制剂不同，S1QEL不占据醌或抑制剂的结合口袋。相反，它们可能通过与ND1结合诱导口袋的结构变化，从而间接调节醌-氧化还原反应。我们得出的结论是，这种间接效应可能是S1QELs依赖于方向的电子转移调制的先决条件。反过来，

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Defining the mechanism of action of S1QELs, specific suppressors of superoxide production in the quinone-reaction site in mitochondrial complex I.

Site-specific suppressors of superoxide production (named S1QELs) in the quinone-reaction site in mitochondrial respiratory complex I during reverse electron transfer have been previously reported; however, their mechanism of action remains elusive. Using bovine heart submitochondrial particles, we herein investigated the effects of S1QELs on complex I functions. We found that the inhibitory effects of S1QELs on complex I are distinctly different from those of other known quinone-site inhibitors. For example, the inhibitory potencies of S1QELs significantly varied depending on the direction of electron transfer (forward or reverse). S1QELs marginally suppressed the specific chemical modification of Asp160 in the 49-kDa subunit, located deep in the quinone-binding pocket, by the tosyl chemistry reagent AL1. S1QELs also failed to suppress the binding of a photoreactive quinazoline-type inhibitor ([125I]AzQ) to the 49-kDa subunit. Moreover, a photoaffinity labeling experiment with photoreactive S1QEL derivatives indicated that they bind to a segment in the ND1 subunit that is not considered to make up the binding pocket for quinone or inhibitors. These results indicate that unlike known quinone-site inhibitors, S1QELs do not occupy the quinone- or inhibitor-binding pocket; rather, they may indirectly modulate the quinone-redox reactions by inducing structural changes of the pocket through binding to ND1. We conclude that this indirect effect may be a prerequisite for S1QELs' direction-dependent modulation of electron transfer. This, in turn, may be responsible for the suppression of superoxide production during reverse electron transfer without significantly interfering with forward electron transfer.

更新日期：2019-04-20

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