Ubiquitin-like modifier-activating enzyme 1 (UBA1)

Ubiquitin-like modifier-activating enzyme 1 (UBA1), encoded by the *UBA1* gene, is the canonical E1 enzyme that catalyzes the first step in the ubiquitin-proteasome pathway, essential for marking cellular proteins for degradation. UBA1 activates ubiquitin in an ATP-dependent reaction and transfers it to E2 conjugating enzymes, initiating the ubiquitin cascade, which regulates numerous critical cellular processes, including cell cycle, DNA repair, apoptosis, and protein homeostasis[1][3][4][5]. UBA1 also participates in NEDD8 pathway regulation, especially under stress conditions[3][5]. Dysfunction or mutations in UBA1 are implicated in neurodegenerative diseases, cancers, and the autoinflammatory VEXAS syndrome[3][4][5]. It is a validated therapeutic target, with several small molecule inhibitors under investigation for selective anti-cancer and anti-inflammatory applications[3][1][7].

Other names

UBE1UBE1XPOC20CFAP124Protein A1S9TBN75 temperature sensitivity complementingA1S9A1S9TAMCX1GXP1VEXASUBA1Atesticular secretory protein Li 63Ubiquitin-activating enzyme E1POC20 centriolar protein homologUbiquitin-activating enzyme E1 homolog (yeast)POC20 centriolar protein homolog (Chlamydomonas)

Inhibitors block the adenylation step of ubiquitin attachment to UBA1, preventing downstream ubiquitination and proteasome-mediated degradation of target proteins[3][1]. Some inhibitors also act by interfering in the ligation process of UBA1 and ubiquitin, disrupting the protein homeostasis needed for cancer cell viability[3].