Inhibition of protein SUMOylation by davidiin, an ellagitannin from Davidia involucrata

Conjugation of small ubiquitin-related modifier (SUMO) to lysine residues in target proteins is a multistep enzymatic reaction analogous to ubiquitination.¹ Protein SUMOylation regulates numerous biological processes including transcription, the cell cycle, DNA repair and innate immunity.¹ In the first step of the reaction, SUMO is cleaved from the SUMO precursor by SUMO-specific proteases. Next, SUMO is bound to the cysteine residue of the SUMO-activating enzyme (E1), forming a thioester linkage in an ATP-dependent manner. SUMO is then transferred from E1 to the cysteine residue of the SUMO-conjugating enzyme (E2). Finally, SUMO ligase (E3) catalyzes the SUMOylation of specific substrates via a direct interaction with E2 and the substrates. Like ubiquitination, SUMOylation is reversible; the deSUMOylation process is mediated by SUMO-specific proteases. Abnormal SUMOylation is implicated in various diseases including neurodegenerative disease,² viral infection³ and cancer.^{4, 5} Therefore, enzymes responsible for the SUMO conjugation pathway represent potential targets for drug discovery.

To date, several natural products including ginkgolic acid,⁶ anacardic acid,⁶ kerriamycin B⁷ and spectomycin B1⁸ as well as synthetic compounds,⁹ have been reported to inhibit protein SUMOylation. Here, we report another natural product that functions as a SUMOylation inhibitor: davidiin, purified from the plant Davidia involucrata. Although most known SUMOylation inhibitors function in the micromolar range, davidiin is particularly potent, inhibiting at sub-micromolar concentrations.

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