Ubiquitin-Proteasome System
The primary cellular pathway for degrading damaged, misfolded, or unneeded proteins. Proteins are tagged with ubiquitin chains and then degraded by the proteasome. Bortezomib and carfilzomib inhibit the proteasome component, causing toxic protein accumulation that kills cancer cells.
Technical Context
The UPS pathway: E1 ubiquitin-activating enzyme (ATP-dependent, 2 human E1s) → E2 ubiquitin-conjugating enzyme (~40 human E2s) → E3 ubiquitin ligase (~600 human E3s — providing substrate specificity) → polyubiquitin chain assembly on target protein (K48-linked chains signal proteasomal degradation) → recognition by 19S proteasome regulatory particle (deubiquitination, unfolding, threading into 20S core) → proteolysis by 20S core particle (three catalytic activities: chymotrypsin-like/β5, trypsin-like/β2, caspase-like/β1). Bortezomib primarily inhibits the β5 chymotrypsin-like activity (IC50 ~0.6 nM, reversible). Carfilzomib also primarily targets β5 but binds irreversibly (epoxyketone warhead). Proteasomal degradation controls: cell cycle (cyclin degradation), transcription (NF-κB activation requires proteasomal IκB degradation), DNA repair, apoptosis regulation, and antigen presentation (proteasome-generated peptides are presented on MHC class I). The UPS handles approximately 80-90% of intracellular protein degradation.