enzymesE1

EnzymesE1, commonly referred to as E1 enzymes, form the first step in the ubiquitin-proteasome system and related pathways. They are ubiquitin-activating enzymes found in eukaryotic cells. Their primary role is to activate ubiquitin or ubiquitin-like modifiers, enabling subsequent transfer to substrate proteins through E2 and E3 enzymes.

Mechanism: E1 catalyzes two ATP-dependent reactions. First, it adenylates the C-terminal glycine of ubiquitin to form a ubiquitin-adenylate intermediate. Second, the catalytic cysteine in E1 attacks the intermediate, creating a thioester bond between the enzyme and ubiquitin. The activated ubiquitin is then transferred to an E2 conjugating enzyme through transthiolation. The E2–ubiquitin complex works with an E3 ligase to transfer ubiquitin to substrate lysines. Some E1 enzymes also activate ubiquitin-like modifiers, such as NEDD8 or SUMO, with variant specificities.

Structure and diversity: E1 enzymes are generally large, multidomain proteins containing catalytic adenylation domains, a catalytic cysteine domain, and ubiquitin-binding regions. In many organisms, more than one E1 gene exists, providing specificity for ubiquitin and some ubiquitin-like proteins. In humans, UBA1 and UBA6 act as ubiquitin-activating enzymes, with other E1s specialized for particular modifiers.

Function and significance: By initiating ubiquitination, E1 enzymes regulate protein turnover, signal transduction, DNA repair, and other cellular processes. Because they sit at the apex of the conjugation cascade, E1 activity influences numerous pathways, and dysregulation can contribute to disease. Inhibitors of E1 enzymes are under investigation as potential therapeutic agents for cancer and other disorders.

Evolution and research: Ubiquitin-related E1 enzymes are conserved across eukaryotes, reflecting the essential nature of protein modification systems. Research on E1 enzymes covers biochemistry, structural biology, and drug discovery, including studies of substrate specificity, interaction with E2s, and regulation of activity.