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

Abstract

Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have anti-tumor activities in clinical trials conducted in the 1960s–1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin anti-tumor effects remain poorly defined. Despite the lack of its 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 pi 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.

Targeting the MYC Ubiquitination-Proteasome Degradation Pathway for Cancer Therapy

“…In addition, lanatoside C, a cardiac glycoside, has been shown to reduce MYC levels and suppress gastric cancer cell proliferation by inhibiting USP28 binding to MYC, thereby destabilizing MYC, although it remains to be determined whether lanatoside C directly targets USP28(102).Given that SENP1 positively regulates MYC levels and activity, SENP1 is an interesting cancer therapeutic target. Several SENP1 inhibitors have been reported(103)(104)(105). Streptonigrin (SN), a natural product isolated from Streptomyces flocculus, has been shown to inhibit SENP1 activity (IC 50 = 0.518 µM towards SENP1, IC 50 = 6.919 µM towards SENP2)(103).…”

A Unique SUMO-Interacting Motif of Trx2 Is Critical for Its Mitochondrial Presequence Processing and Anti-oxidant Activity

“…Ginkgolic Acid [GA, 2-hydroxy-6-(8-pentadecenyl)] could specifically and directly bind to SUMO-activating enzyme E1, blocking formation of the E1-SUMO1 intermediate (Fukuda et al, 2009). On the contrary, streptonigrin (SN), a natural product isolated from Streptomyces flocculus , acts as an inhibitor of SENPs by disrupting SENP1-SUMO1 interaction, with higher inhibitory effect against SENP1 than other SENPs (Ambaye et al, 2018). Its inhibitory effect on SUMO-2/3 was also detected in different cell lines (Liu et al, 2018; Qiu et al, 2018).…”

Evaluating enzyme activities and structures of DUBs

“…Well-defined substrate-bound DUB complexes can be studied with solution and crystallographic structural methods. Depending on size and behavior, NMR can be a useful tool for understanding DUB dynamics and regulation in solution, as shown for the DUBs AMSH and Cezanne (Hologne et al, 2016;Mevissen et al, 2016) as well as the UBL protease SENP1 (Ambaye, Chen, Khanna, Li, & Chen, 2018). Hydrogen-deuterium exchange mass spectrometry can also be used to monitor conformational changes associated with substrate recognition (Gersch et al, 2017;Mevissen et al, 2016).…”