title: Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica.
abstract: The natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. Using a comprehensive approach that combined chemical synthesis with metabolic engineering, we generated a series of salinosporamide analogues with altered proteasome binding affinity. One of the engineered compounds is equipotent to salinosporamide A in inhibition of the chymotrypsin-like activity of the proteasome yet exhibits superior activity in the cell-based HCT-116 assay.
authors.affiliation: Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Nett
authors.forename: Tobias A M
authors.initials: TA
authors.lastname: Gulder
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kale
authors.forename: Chambers C
authors.initials: CC
authors.lastname: Hughes
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D039903:Actinobacteria / Q000235:genetics*; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis*; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D061988:Proteasome Inhibitors; D015202:Protein Engineering; D011758:Pyrroles / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib