SAE1SAE2

SAE1SAE2, also written as SAE1/SAE2, is the heterodimeric SUMO-activating enzyme that catalyzes the first step of the SUMOylation pathway in eukaryotic cells. The complex is composed of two subunits, SAE1 (also known as Aos1 in yeast) and SAE2 (also known as Uba2), which together form the E1 activating enzyme for SUMO (Small Ubiquitin-like Modifier).

In structure and assembly, SAE1 serves as the regulatory subunit that assists in recognizing SUMO and guiding the reaction, while SAE2 contains the catalytic machinery, including the active-site cysteine essential for thioester formation. The two subunits assemble to create an active site capable of processing SUMO in an ATP-dependent cycle.

The mechanism of action involves three key steps. First, SUMO is adenylated by ATP in the presence of the SAE1–SAE2 complex, forming a SUMO-adenylate intermediate. Second, the SUMO moiety is transferred to the catalytic cysteine of SAE2, generating a high-energy SUMO–SAE2 thioester. Third, SUMO is transferred from SAE2 to the E2 conjugating enzyme, UBC9, creating the E2–SUMO thioester that can subsequently be transferred to target proteins, often with the help of E3 ligases.

Biological relevance of SAE1SAE2 is substantial, as SUMOylation regulates diverse cellular processes, including transcription, DNA repair, signal transduction, and stress responses. Proper function of the SAE1/SAE2 complex is essential for normal cell physiology, and dysregulation of SUMO activation has been linked to diseases such as cancer and neurodegeneration. In humans, SAE1 and UBA2 form the active complex, while in other organisms they are referred to as Aos1 and Uba2, respectively. Research continues into regulatory mechanisms and inhibitors targeting the SUMO activation pathway.