title: Selective overproduction of the proteasome inhibitor salinosporamide A via precursor pathway regulation.
abstract: The chlorinated natural product salinosporamide A is a potent 20S proteasome inhibitor currently in clinical trials as an anticancer agent. To deepen our understanding of salinosporamide biosynthesis, we investigated the function of a LuxR-type pathway-specific regulatory gene, salR2, and observed a selective effect on the production of salinosporamide A over its less active aliphatic analogs. SalR2 specifically activates genes involved in the biosynthesis of the halogenated precursor chloroethylmalonyl-CoA, which is a dedicated precursor of salinosporamide A. Specifically, SalR2 activates transcription of two divergent operons-one of which contains the unique S-adenosyl-L-methionine-dependent chlorinase encoding gene salL. By applying this knowledge to rational engineering, we were able to selectively double salinosporamide A production. This study exemplifies the specialized regulation of a polyketide precursor pathway and its application to the selective overproduction of a specific natural product congener.
authors.affiliation: Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0204, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lechner
authors.forename: Alessandra S
authors.initials: AS
authors.lastname: Eustáquio
authors.forename: Tobias A M
authors.initials: TA
authors.lastname: Gulder
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D007783:Lactones / Q000378:metabolism*; D008848:Micromonosporaceae / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D011758:Pyrroles / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D011994:Recombinant Proteins; C475865:marizomib; D046988:Proteasome Endopeptidase Complex