Sunday, August 10, 2008
P123
Regulation of salinosporamide biosynthesis in Salinispora tropica
The marine actinomycete Salinispora tropica is a proven source of novel natural products, including salinosporamide A (Sal A), a 26S proteasome inhibitor currently in development for multiple myeloma treatment. Sal A is 500-fold more potent than its deschloro analog Sal B. The sal biosynthetic gene cluster (41kb) dedicates a third of its genes to the assembly of the chlorinated precursor chloroethylmalonyl-CoA and ~10% to regulatory elements. Understanding the regulation of Sal A biosynthesis will facilitate genetic engineering of overproducing strains. As part of this study, inactivation of target genes and reverse transcription PCR has shed new light on the putative regulators of the sal cluster. The regulatory protein SalR2, a member of the LuxR-type family, was assigned as transcriptional activator of only Sal A biosynthesis, since salR2 knockout leads to abolishment of Sal A production but has no effect on Sal B yields. Analysis of gene transcription demonstrated that at least two genes necessary for biosynthesis of the Sal A precursor chloroethylmalonyl-CoA were not transcribed in the salR2 knockout mutant, while transcription of the polyketide synthase gene salA responsible for formation of the common γ-lactam-β-lactone nucleus was unaltered. Function of the other two putative regulators is currently under investigation.
Web Page: www.sio.ucsd.edu/
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See more of The Annual Meeting and Exhibition 2008 (August 10 - 14, 2008)
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