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02
Feb
Ubiquitin-Activating Enzyme E1: Function and Disease
Published by BioFargo Editorial | Category: Proteomics & Cell Biology
The Ubiquitin-activating enzyme (E1) is the essential gatekeeper of the ubiquitin–proteasome system (UPS). By initiating the ubiquitination cascade, E1 governs selective protein turnover, regulating everything from protein stability to cellular homeostasis. Understanding E1 is critical for research into cancer, neurodegeneration, and immune disorders.
Core Molecular Functions
ATP-dependent Activation
E1 catalyzes the adenylation of ubiquitin using ATP, forming a high-energy thioester bond. This process activates ubiquitin for downstream transfer.
Cascade Initiation
Activated ubiquitin is transferred to E2 (conjugating enzymes) and then to E3 (ligases), ensuring precise substrate targeting.
Biological Significance
- ● Protein Homeostasis: Maintains intracellular quality by degrading misfolded or damaged proteins.
- ● Cellular Regulation: Controls cell cycle progression, DNA repair, and immune responses.
- ● Disease Pathways: Linked to Alzheimer’s, Parkinson’s, and the newly discovered VEXAS syndrome.
E1 & Cancer Biology: A Double-Edged Sword
The UBA1 enzyme regulates the stability of both oncoproteins and tumor suppressors.
1. Stabilization of Oncoproteins:
In triple-negative breast cancer, aberrant E1 dynamics impair the degradation of Cyclin E1 (CCNE1), leading to genomic instability and chemotherapy resistance.
2. Degradation of Tumor Suppressors:
Elevated E1 activity accelerates MDM2-mediated polyubiquitination, leading to the rapid clearance of p53, thereby silencing the cell's natural apoptosis triggers.
Therapeutic Potential
As the rate-limiting enzyme of the UPS, E1 is a high-value therapeutic target. Pharmacological inhibition of E1 offers a strategic advantage: it can simultaneously suppress oncogenic stabilization and restore tumor suppressor functions. While E1 inhibitors are currently in the research phase, they represent a new frontier in broad-spectrum anticancer therapy.
Biofargo team
