UbiquitinAMP

Ubiquitin-AMP, also called ubiquitin adenylate, is a transient intermediate in the initial step of the ubiquitin–proteasome system. It is the activated form of ubiquitin created during ATP-dependent priming by the ubiquitin-activating enzyme (E1). In the first phase of ubiquitin activation, E1 catalyzes the transfer of an adenylate group from ATP to the C-terminus of ubiquitin, producing ubiquitin-AMP and releasing pyrophosphate. This ubiquitin-AMP is typically formed within the E1 active site and serves as the substrate for the next reaction.

In the subsequent step, the catalytic cysteine residue of E1 attacks the ubiquitin-AMP to form a thioester bond between ubiquitin and E1 (Ub–S–E1), releasing AMP. The ubiquitin is then transferred from the E1 thioester to a ubiquitin-conjugating enzyme (E2) or directly to a substrate with the help of E3 ligases, continuing the ubiquitination cascade. Ubiquitin-AMP is therefore a fleeting, intermediate compound rather than a freely circulating molecule in cells.

Biological significance and context: Ub-AMP is essential for the proper initiation of ubiquitination, a post-translational modification that regulates protein degradation, signaling, and cellular responses. The formation and consumption of Ub-AMP are tightly coordinated and conserved across eukaryotes. Because Ub-AMP is a transient intermediate, it is typically studied indirectly through the activity of E1 enzymes and the overall ubiquitination flux. Inhibitors targeting the E1 activation step can disrupt Ub-AMP formation and downstream ubiquitin transfer, with implications for research and therapeutic strategies.