Post-translational conjugation of small ubiquitin-related modifier protein (SUMO) to protein substrates (SUMOylation) has been revealed as one of the major post-translational regulatory systems in animals and other eukaryotes. SUMO conjugation is catalyzed by a multi-step enzymatic reaction cascade similar to ubiquitinylation.1 In the first step, the SUMO precursor is cleaved near the C-terminus by SUMO-specific proteases to expose a C-terminal diglycine. The C-terminal glycine of mature SUMO then forms a thioester linkage to the cysteine residue of SUMO-activating enzyme (E1), the Aos1/Uba2 heterodimer, to generate the E1-SUMO intermediate in an ATP-dependent manner. Next, SUMO is transferred to the active site of the cysteine residue of the SUMO-conjugating enzyme (E2), Ubc9, through another thioester bond. In the last step, E2 and the SUMO ligase (E3) catalyze SUMOylation of substrate proteins at the ɛ-amino group of internal lysine residues. Although enzymatic reactions by E1 and E2 are sufficient for catalyzing in vitro SUMOylation in most cases, E3s facilitate both in vivo and in vitro conjugation and are important for substrate specificity.1

The structure of SUMO is similar to that of ubiquitin, but its functions are different. SUMOylation regulates protein subcellular localization, enzymatic activity and protein stability, which are associated with the cell cycle, transcription, DNA repair and innate immunity.2, 3 In addition, SUMOylation has been recently linked causally to diseases, such as Alzheimer's and Huntington's diseases,4 viral infection5 and cancer.6, 7 Notwithstanding the importance of SUMOylation in regulating diverse life phenomena and diseases, small molecule inhibitors of SUMOylation have been unexplored. Here, we report novel activity of kerriamycin B that inhibits protein SUMOylation, which will provide useful information about the role of SUMOylation in cells and drug development.

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