UBA1

UBA1 Full Name

ubiquitin-like modifier activating enzyme 1

UBA1 Introduction

Ubiquitin like modified activating enzyme 1, commonly referred to as UBA1, is the primary initiating enzyme of the ubiquitin proteasome system (UPS). It belongs to the E1 enzyme family and is responsible for the crucial first step of the ubiquitination cascade reaction, which is the main pathway for targeted protein degradation and signal transduction in eukaryotic cells. All eukaryotic UBA1 contains a double repeat of a domain derived from bacterial MoeB and ThiF proteins. Ub's UBA1 has a repeat at the N-terminus and C-terminus, while NEDD8 and SUMO's UBA1 also have a separate subunit. UBA1 specifically activates small protein ubiquitin in an ATP dependent manner, forming high-energy thioester bonds to prepare for the downstream transfer of ubiquitin. As the only E1 enzyme of ubiquitin in many cases, UBA1 serves as the gatekeeper and fundamental bottleneck for all ubiquitin dependent processes, making its function crucial for cell homeostasis, protein quality control, DNA repair, immune response, and cell cycle progression.

Figure. Proteomic strategies for characterizing ubiquitin-like modifications .(Source: .Li C, et al, 2021)

Function
Adenylation: The protein encoded by this gene catalyzes the first step of ubiquitin binding or ubiquitination, marking the degradation of cellular proteins. UBA1 first binds to ubiquitin molecules and ATP. It catalyzes the adenylation of the C-terminus of ubiquitin, forming the intermediate ubiquitin adenosine monophosphate (Ub AMP) and releasing pyrophosphate (PPi).
Thioester bond formation: UBA1 catalyzes ATP dependent adenylation of ubiquitin, thereby forming a thioester bond between the two. It continues to participate in subsequent ubiquitination steps as an Ub carrier.. This reaction forms a high-energy thioester bond between the C-terminus of ubiquitin and the thiol group of UBA1 cysteine.
E2 thioester exchange reaction: UBA1 then transfers activated ubiquitin from its own cysteine to the active site cysteine of E2 enzyme through a thioester conversion reaction. Through its core role in ubiquitination, UBA1 is associated with cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.

Clinical Significance
The dysregulation of UBA1 is closely related to human diseases, most directly through somatic mutations. Impairment of ubiquitin proteasome function is a common feature of diseases such as Alzheimer's and Parkinson's disease. Although there is no direct mutation, changes in UBA1 activity or expression may lead to the accumulation of toxic protein aggregates characteristic of these diseases. The mutation of UBA1 is associated with X-linked type 2 spinal muscular atrophy. [5] UBA1 is also associated with other neurodegenerative diseases, including spinal muscular atrophy, as well as cancer and tumors. Due to the involvement of UBA1 in various biological processes, people are concerned that inhibiting UBA1 may also damage normal cells.

Alternate Names for UBA1

UBA1; ubiquitin-like modifier activating enzyme 1; A1S9; A1ST; GXP1; UBE1; A1S9T; AMCX1; POC20; SMAX2; UBA1A; UBE1X; ubiquitin-like modifier-activating enzyme 1; POC20 centriolar protein homolog; UBA1, ubiquitin-activating enzyme E1 homolog A; A1S9T and BN75 temperature sensitivity complementing;

• 1.Li C, Nelson TG, Vertegaal AC, Thibault P. Proteomic strategies for characterizing ubiquitin-like modifications. Nature Reviews Methods Primers. 2021,1(1):53.