Upon farnesylation by protein farnesyltransferase (FTase), key proteins become compartmentalized in cells. For example, cell membrane localization is essential for the mitogenic role of mutant Ras protein, which acts as a switch for cancer cell proliferation. We report that α‐dicarbonyl compounds derived from the isoprenoid skeleton or other hydrophobic groups potently obstruct farnesylation of a Ras model peptide by human recombinant FTase in vitro. A geranyl‐derived isoprenoid diketone, 5,9‐dimethyl‐8‐decene‐2,3‐dione, at 17 μM caused a 62% reduction in FTase activity after 30 minutes. A farnesyl‐derived isoprenoid diketone, 5,9,13‐trimethyl‐8,12‐tetradecadiene‐2,3‐dione, at 93 μM caused a 94% reduction after 30 minutes. Other dicarbonyl compounds found to be effective against FTase in vitro were (±)‐6‐(camphorquinone‐ 10‐sulfonamido)‐hexanoic acid, 4,4′‐biphenyldiglyoxaldehyde, dehydroascorbic acid 6‐palmitate, 2‐oxododecanal, and phenylglyoxal. Higher concentrations of the α‐dicarbonyl compound resulted in more rapid and more extensive inactivation. These findings demonstrate that α‐dicarbonyl compounds targeted to FTase interfere with protein farnesylation in vitro and may lead to derivatives that have utility as chemotherapeutic agents.

中文翻译：

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通过活性位点靶向二羰基化合物灭活蛋白质法呢基转移酶

通过蛋白质法呢基转移酶 (FTase) 进行法尼基化后，关键蛋白质在细胞中被分隔开。例如，细胞膜定位对于突变 Ras 蛋白的促有丝分裂作用至关重要，Ras 蛋白充当癌细胞增殖的开关。我们报告说，衍生自类异戊二烯骨架或其他疏水基团的 α-二羰基化合物在体外有效阻碍了人重组 FTase 对 Ras 模型肽的法呢基化。香叶基衍生的类异戊二酮，5,9-二甲基-8-癸烯-2,3-二酮，浓度为 17 μM，30 分钟后导致 FTase 活性降低 62%。法呢基衍生的类异戊二酮，5,9,13-三甲基-8,12-十四二烯-2,3-二酮，浓度为 93 μM，30 分钟后减少了 94%。在体外发现对 FTase 有效的其他二羰基化合物是 (±)-6-(樟脑醌-10-磺酰氨基)-己酸、4,4'-联苯二乙醛、脱氢抗坏血酸 6-棕榈酸酯、2-氧十二醛和苯乙二醛。较高浓度的 α-二羰基化合物导致更快和更广泛的失活。这些发现表明，靶向 FTase 的 α-二羰基化合物会在体外干扰蛋白质法呢基化，并可能产生可用作化学治疗剂的衍生物。