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A Structural Perspective on Respiratory Complex I pp 81–98Cite as

Current Topics of the Inhibitors of Mitochondrial Complex I

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Abstract

Acetogenins isolated from Annonaceous plants are very potent inhibitors of bovine heart mitochondrial complex I and unique in chemical structure among a wide variety of inhibitors of the enzyme. The structure-activity studies of numerous acetogenins revealed that the inhibitors exhibit potent inhibition only when the two pharmacophores (i.e. the γ-lactone and the hydroxylated THF moieties) are directly linked by the alkyl spacer and cooperatively bind to the two putative binding sites. Regardless of marked changes in the conformation and/or the length of the spacer region, the spacer dynamically regulates the cooperative binding of the two pharmacophores to the sites. Through structural modification of acetogenins, we developed new types of inhibitors termed Δlac-acetogenins and piperazine-type inhibitors, whose inhibitory effects on complex I significantly differ from those of traditional inhibitors. In particular, examination of the inhibition mechanism of Δlac-acetogenins provided valuable insights into the terminal electron transfer step of complex I including a mechanism of the generation of superoxide in the presence of inhibitor. Using a photoaffinity labeling technique, the binding sites of the new inhibitors (Δlac-acetogenin and piperazine) as well as traditional inhibitors (acetogenin and quinazoline) were identified at sub-subunit level. The photoaffinity labeling studies clearly indicated that the 49 kDa and ND1 subunits construct a large inhibitor binding pocket in bovine complex I.

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  1. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan

    Hideto Miyoshi

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  1. , Mitochondrial Biology Unit, Medical Research Council, Hills road, Cambridge, CB2 0XY, Cambridgeshire, United Kingdom

    Leonid Sazanov

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Miyoshi, H. (2012). Current Topics of the Inhibitors of Mitochondrial Complex I. In: Sazanov, L. (eds) A Structural Perspective on Respiratory Complex I. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4138-6_4

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