Duval Romain A, Lewin Guy, Peris Eva, Chahboune Nadia, Garofano Aurelio, Dröse Stefan, Cortes Diego, Brandt Ulrich, Hocquemiller Reynald
Laboratoire de Pharmacognosie (BioCIS, UMR 8076 CNRS), Faculté de Pharmacie, University Paris-Sud, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
Biochemistry. 2006 Feb 28;45(8):2721-8. doi: 10.1021/bi051261u.
Heterocyclic analogues of squamocin have been semisynthesized by condensation reactions between squamocin-derived alpha-keto esters and heterodinucleophiles. The strong complex I inhibitory potency of squamocin-benzimidazole, a hybrid derivative, illustrates for the first time the functional analogy existing between the terminal butenolide of annonaceous acetogenins and heteroaromatic substructures of classic inhibitors of the enzyme. This finding supports the categorization of this atypical group of inhibitors as antagonists of the ubiquinone substrates. In addition, competition experiments of squamocin-benzimidazole versus squamocin and rolliniastatin-2 suggest that the binding of this hybrid inhibitor is responsible for a negative allosteric effect at the level of the first ubiquinone-binding site (A site) of mitochondrial complex I. This result supports the existence of a large cooperatively regulated inhibitor/ubiquinone-binding pocket located within the catalytic core of the enzyme, consisting of the association of the previously defined affinity sites A and B.
通过鳞始草素衍生的α-酮酯与杂二亲核试剂之间的缩合反应，半合成了鳞始草素的杂环类似物。杂合衍生物鳞始草素-苯并咪唑具有很强的复合体I抑制活性，首次说明了番荔枝内酯的末端丁烯内酯与该酶经典抑制剂的杂芳族亚结构之间存在功能相似性。这一发现支持将这类非典型抑制剂归类为泛醌底物的拮抗剂。此外，鳞始草素-苯并咪唑与鳞始草素和罗利抑素-2的竞争实验表明，这种杂合抑制剂的结合导致线粒体复合体I的第一个泛醌结合位点（A位点）水平上的负变构效应。这一结果支持了在该酶催化核心内存在一个由先前定义的亲和位点A和B结合而成的、受协同调节的大型抑制剂/泛醌结合口袋。
