Ubiquitin-like modifier activating enzyme 3 (UBA3)

UBA3 (Ubiquitin-like modifier activating enzyme 3) is the catalytic subunit of the NEDD8-activating enzyme E1, a dimeric enzyme complex (with APPBP1/NAE1 as the regulatory subunit) responsible for activating NEDD8, a ubiquitin-like modifier that regulates protein degradation and protein homeostasis[1][3][4][6]. UBA3 catalyzes the first critical step in the *neddylation* cascade, which is essential for proper function of cullin-RING E3 ubiquitin ligases (CRLs) and, consequently, cell cycle regulation, signal transduction, and embryogenesis[6]. UBA3-mediated neddylation modifies protein activity, localization, and stability, and dysregulation is implicated in cancer and potentially other diseases. The critical nature of this pathway makes UBA3 a promising anti-cancer drug target, with small-molecule inhibitors (such as pevonedistat/MLN4924) in clinical studies[6]. Inhibition of UBA3 leads to suppression of cullin-RING ligase activity, resulting in cell cycle arrest and apoptosis, though safety concerns exist due to its fundamental roles in normal cellular physiology.

Other names

NEDD8-activating enzyme E1 catalytic subunitUBE1ChUba3NAE2NEDD8-activating enzyme E1CNEDD8-activating enzyme E1 subunit 2Ubiquitin-activating enzyme E1CUbiquitin-like modifier-activating enzyme 3Ubiquitin-activating enzyme 3ubiquitin-activating enzyme E1C (UBA3 homolog, yeast)ubiquitin-activating enzyme E1C (homologous to yeast UBA3)

Inhibition of enzymatic activity (neddylation blockade), suppression of cullin-RING ligase activation, cell cycle arrest, apoptosis induction