SUMO-activating enzyme E1 (SAE1/UBA2 (in human))

SUMO-activating enzyme E1 is a large, multidomain heterodimeric complex, composed in humans of Sae1 and Uba2 subunits, that catalyzes the initial activation step in the SUMO (Small Ubiquitin-like Modifier) conjugation pathway. E1 binds ATP and SUMO, forming a SUMO-adenylate intermediate, then generates a thioester bond between the SUMO C-terminus and a catalytic cysteine in E1. The activated SUMO is subsequently transferred to the E2 conjugating enzyme (Ubc9), which then facilitates substrate sumoylation. The SUMO E1 complex regulates essential processes in eukaryotic cells, such as DNA repair, cell division, transcription, and stress responses. Given its pivotal roles in cellular integrity and disease (especially cancer), SUMO E1 is under investigation as a therapeutic target, with inhibitors such as COH000 demonstrating its druggability by allosteric inhibition. Structural studies reveal modular domains responsible for adenylation, thioester formation, and E2 recruitment, offering mechanistic insight into selective inhibitor design.

Other names

Sae1/Uba2 heterodimer (human)Aos1/Uba2 (yeast)SUMO E1SUMO-activating enzymeSUMO E1 complexUbiquitin-like modifier activating enzyme E1 (in context of SUMO pathway)

Inhibition through covalent or non-covalent blockage of SUMO E1 catalytic activity (adenylation and thioester bond formation domains). Allosteric inhibition (COH000: locks enzyme in inactive conformation distinct from adenylation active site). Competition for SUMO binding or disruption of E1–E2 enzyme interaction.