Mitochondrial respiratory complex I can be inhibited via bypassing the ubiquinone-accessing tunnel

IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology FEBS Letters Pub Date : 2024-06-25 DOI:10.1002/1873-3468.14967
Ryohei Otani, Takahiro Masuya, Hideto Miyoshi, Masatoshi Murai
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Abstract

Mitochondrial NADH–ubiquinone oxidoreductase (complex I) couples electron transfer from NADH to ubiquinone with proton translocation in its membrane part. Structural studies have identified a long (~ 30 Å), narrow, tunnel-like cavity within the enzyme, through which ubiquinone may access a deep reaction site. Although various inhibitors are considered to block the ubiquinone reduction by occupying the tunnel's interior, this view is still debatable. We synthesized a phosphatidylcholine-quinazoline hybrid compound (PC-Qz1), in which a quinazoline-type toxophore was attached to the sn-2 acyl chain to prevent it from entering the tunnel. However, PC-Qz1 inhibited complex I and suppressed photoaffinity labeling by another quinazoline derivative, [125I]AzQ. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone-accessing tunnel model.

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线粒体呼吸复合体 I 可通过绕过泛醌通道而受到抑制。
线粒体 NADH-泛醌氧化还原酶(复合物 I)将 NADH 到泛醌的电子传递与膜部分的质子转运结合起来。结构研究发现,酶内有一个长(约 30 Å)、窄、隧道状的空腔,泛醌可通过该空腔进入深层反应位点。虽然各种抑制剂被认为可以通过占据隧道内部来阻止泛醌还原,但这种观点仍有争议。我们合成了一种磷脂酰胆碱-喹唑啉杂化化合物(PC-Qz1),其中的 sn-2 乙酰基链上附有一个喹唑啉型毒物团,以阻止其进入隧道。然而,PC-Qz1 会抑制复合体 I 并抑制另一种喹唑啉衍生物 [125I]AzQ 的光亲和标记。这项研究提供了更多的实验证据,这些证据很难与典型的泛醌进入隧道模型相一致。
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来源期刊
FEBS Letters
FEBS Letters 生物-生化与分子生物学
CiteScore
7.00
自引率
2.90%
发文量
303
审稿时长
1.0 months
期刊介绍: FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.
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