The protein encoded by this gene catalyzes the first step in ubiquitin conjugation, or ubiquitination, to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin (Ub), thereby forming a thioester bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier. UBA1 is one of only two human ubiquitin-activating enzymes (E1), the other being UBA6, and thus is largely responsible for protein ubiquitination in humans. Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation. Additionally, UBE1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.
Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2. UBA1 has also been implicated in neurodegenerative diseases and cancer and, thus, presents a promising a therapeutic target for inhibiting tumor growth. However, because UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of targeting UBA1 for cancer treatment Moreover, the UBA1 inhibitors Largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically by blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials.
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