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Bacterial Self-Resistance to the Natural Proteasome Inhibitor Salinosporamide A
journal contribution
posted on 2011-11-18, 00:00 authored by Andrew J. Kale, Ryan P. McGlinchey, Anna Lechner, Bradley S. MooreProteasome 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.
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bortezomib resistanceNatural Proteasome Inhibitor Salinosporamide AProteasome inhibitorsdrug resistance limitssubstrate specificity profile49T mutation20 S proteasome machinery49V mutationsubunitsalinosporamide biosynthetic gene clustermarine actinobacterium Salinispora tropicacancer chemotherapyproteasome inhibitorsSalI correlatesNPISalI proteasomeproteasome inhibitor
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