Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1α (HIF1α) in Cells,Biochemistry

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Streptonigrin Inhibits SENP1 and Reduces the Protein Level of Hypoxia-Inducible Factor 1α (HIF1α) in Cells
Biochemistry ( IF 2.9 ) Pub Date : 2018-02-26 00:00:00 , DOI: 10.1021/acs.biochem.7b00947
Nigus Ambaye ₁ , Chih-Hong Chen ₁ , Swati Khanna ₁ , Yi-Jia Li ₁ , Yuan Chen ₁

Affiliation

Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have antitumor activities in clinical trials conducted in the 1960s–1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin antitumor effects remain poorly defined. Despite its lack of current clinical use, efforts on its total synthesis have continued. Here, we show that streptonigrin binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1–SUMO1 interaction. Site-directed mutations in combination with NMR chemical shift perturbation suggest key roles of aromatic π stacking interactions in binding streptonigrin. Treatment of cells with streptonigrin resulted in increased global SUMOylation levels and reduced level of hypoxia inducible factor alpha (HIF1α). These findings inform both the design of SENP1 targeting strategy and the modification of streptonigrin to improve its efficacy for possible future clinical use.

中文翻译：

Streptonigrin 抑制 SENP1 并降低细胞中缺氧诱导因子 1α (HIF1α) 的蛋白质水平

Streptonigrin（CAS 编号 3930-19-6）是一种天然产物，在 1960 年代至 1970 年代进行的临床试验中显示出具有抗肿瘤活性。然而，它在临床研究中的应用最终逐渐淡出，链黑素抗肿瘤作用的分子机制仍未明确。尽管目前缺乏临床使用，但对其全合成的努力仍在继续。在这里，我们表明链黑素结合并抑制 SUMO 特异性蛋白酶 SENP1。NMR 研究发现，链霉菌素与 SUMO 结合并破坏 SENP1–SUMO1 相互作用的表面上的 SENP1 结合。定点突变与 NMR 化学位移扰动相结合表明芳香族 π 堆积相互作用在结合链黑素中的关键作用。用链霉菌素处理细胞导致整体 SUMO 化水平升高和缺氧诱导因子 α (HIF1α) 水平降低。这些发现为 SENP1 靶向策略的设计和链黑素的修饰提供了信息，以提高其未来可能的临床使用的疗效。

更新日期：2018-02-26

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