title: Bacterial self-resistance to the natural proteasome inhibitor salinosporamide A.
abstract: Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self-resistance. We identified a redundant proteasome β-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI β-subunit has an altered substrate specificity profile, 30-fold resistance to salinosporamide A, and cross-resistance to the FDA-approved proteasome inhibitor bortezomib. An A49V mutation in SalI correlates to clinical bortezomib resistance from a human proteasome β5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.
authors: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography.
authors: Andrew J
authors: AJ
authors: Kale
authors: Ryan P
authors: RP
authors: McGlinchey
authors: Anna
authors: A
authors: Lechner
authors: Bradley S
authors: BS
authors: Moore
mesh_terms: D039903:Actinobacteria / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000302:isolation & purification; D061988:Proteasome Inhibitors; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D001688:Biological Products; D001897:Boronic Acids; D007783:Lactones; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex