Ubiquitin-like modifier activating enzyme 1 (UBA1) (UBA1)

Ubiquitin-like modifier activating enzyme 1 (UBA1) is the primary E1 enzyme responsible for initiating the ubiquitination cascade, a fundamental cellular process for protein homeostasis, cell cycle control, and immune signaling. It functions by activating ubiquitin in an ATP-dependent manner and transferring it to E2 conjugating enzymes. Somatic mutations in the UBA1 gene, particularly at the Met41 residue, have been identified as the genetic driver of VEXAS syndrome, a severe adult-onset autoinflammatory disease characterized by systemic inflammation and hematologic abnormalities. In this context, UBA1 acts as a driver-mutant protein similar to oncogenes in cancer, making it a high-priority therapeutic target for precision medicine. Drugs targeting UBA1, such as the small molecule inhibitor TAK-243, aim to selectively induce proteotoxic stress and apoptosis in mutant cells by disrupting the ubiquitin-proteasome system. Companies like Relay Therapeutics are leveraging advanced computational platforms to develop next-generation, potentially allosteric or mutant-selective inhibitors to treat VEXAS and other UBA1-driven conditions while minimizing off-target toxicity.

Other names

E1 ubiquitin-activating enzymeUbiquitin-activating enzyme E1A1S9G1S8POC20SMAX2UBE1UBA1AUBA1B