Ubiquitinactivating

Ubiquitinactivating, in the context of ubiquitin biology, refers to ubiquitin-activating enzymes (E1). These enzymes initiate the ubiquitination cascade by activating ubiquitin in an ATP-dependent reaction, enabling its covalent attachment to target proteins. Activation of ubiquitin by E1 is the first step that ultimately marks proteins for diverse cellular outcomes, most notably proteasomal degradation.

The canonical mechanism begins with E1 binding ubiquitin and ATP, leading to adenylation of the ubiquitin C-terminus and the formation of a ubiquitin-adenylate intermediate. The active-site cysteine of E1 then attacks this intermediate, forming a high-energy thioester bond between ubiquitin and E1 and releasing AMP. The activated ubiquitin is subsequently transferred from E1 to a ubiquitin-conjugating enzyme (E2), generating an E2–ubiquitin thioester. E3 ubiquitin ligases then facilitate the transfer of ubiquitin from E2 to substrates, or in some cases form an intermediate with ubiquitin themselves, guiding substrate specificity and polyubiquitin chain formation.

In eukaryotes, two main families of ubiquitin-activating enzymes exist in humans: UBA1 and UBA6, reflecting redundancy and specialization in ubiquitin signaling. E1 enzymes are large, highly conserved proteins that set the pace for ubiquitination by controlling ubiquitin availability. Dysregulation of ubiquitin-activating activity can impact protein homeostasis and has been linked to various diseases, including cancer and neurodegenerative disorders. Because they sit at the entry point of ubiquitin signaling, E1 enzymes are of interest as potential therapeutic targets in conditions where ubiquitin pathways are perturbed.