Category: catabolism
Primary cellular protein degradation pathway. E1 activates ubiquitin (ATP-dependent thioester); E2 conjugating enzymes carry activated ubiquitin; E3 ligases (~600 in humans — APC/C, SCF, MDM2, VHL, RNF, etc.) determine substrate specificity. Substrate proteins receive K48-linked polyubiquitin chains → recognized by the 19S regulatory cap of the 26S proteasome → unfolding + threading + 20S core proteolysis → peptides. Distinct K63-linked ubiquitination signals trafficking + autophagy, not degradation. Pharmacology: BORTEZOMIB (Velcade) + CARFILZOMIB + IXAZOMIB = 26S proteasome inhibitors for multiple myeloma + mantle cell lymphoma (myeloma plasma cells are exquisitely dependent on protein turnover). Thalidomide / lenalidomide / pomalidomide bind cereblon → redirect CRBN E3 ligase to ubiquitinate IKZF1/3 (immunomodulatory mechanism for myeloma + MDS).