Figure 3.

Small molecules targeting the SUMO pathway. In step 1: SUMO E1 (SAE1/SAE2 heterodimer) activates mature SUMO through an ATP-dependent reaction. SAE1 catalyzes adenylation of the C-terminus of SUMO to form a SUMO-AMP intermediate, which then transfers SUMO to SAE2 and forms a thioester bond. In step 2: SUMO is transferred from SAE2 to SUMO E2 (UBC9), which in turn forms a thioester bond. In steps 3 and 4: UBC9 catalyzes the formation of an isopeptide bond between the C-terminal glycine of SUMO and a lysine residue on the substrate. Certain SUMO E3 ligases are often involved in this process. In step 5: SUMO is removed from the lysine residue of the target proteins by a de-SUMOylation enzyme (DS), such as SENP, sentrin-specific protease. SENP also catalyzes SUMO maturation by cleaving the precursor SUMO at C-terminus, exposing two glycine residues required for conjugation.