Inhibition of protein SUMOylation by natural quinones

Conjugation of small ubiquitin-related modifier (SUMO) to target proteins (SUMOylation) is a posttranslational modification that regulates a wide range of biological processes, including transcription, intracellular transport, DNA repair, DNA replication and cell signaling.¹ SUMOylation is catalyzed by a multi-step enzymatic cascade that resembles ubiquitination: the process involves an E1-activating enzyme (a heterodimer consisting of Aos1 and Uba2), an E2-conjugating enzyme (Ubc9) and various E3 ligases.¹ E3s catalyze SUMO conjugation to target proteins and may contribute to substrate specificity. SUMO is subsequently cleaved from target proteins by SUMO-specific isopeptidases. Because SUMO modifications have been implicated in a variety of disorders such as cancers² and neurodegenerative diseases,³ the enzymes involved in SUMOylation are promising targets for therapeutic agents.

Several small-molecule inhibitors of SUMOylation have been identified. The first class of SUMOylation inhibitors to be characterized were ginkgolic acid and anacardic acid, which are isolated from the extract of Ginkgo biloba leaves.⁴ Subsequently, natural products, including two antibiotics (kerriamycin B⁵ and spectomycin B1⁶) and davidiin from the plant Davidia involucrata,⁷ as well as synthetic compounds,^{8, 9, 10, 11} have been shown to inhibit protein SUMOylation. In this study, we identified another class of natural products, which includes nocardione A and β-lapachone, that act as SUMOylation inhibitors. The results of mode-of-action studies suggested that these quinone-related compounds inhibit SUMOylation by oxidizing thiols of E1 and E2 enzymes through reactive oxygen species (ROS).

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