In vitro reconstruction study providing cool new insights into "AT-less" PKS. Internal KSo domains for non-elongating modules. #natprod
www.nature.com/articles/s41...
Brian O. Bachmann
Measuring the effect of complex metabolite mixtures directly in primary patient cells bridges a long-standing gap between product discovery and clinical relevance
Single-cell resolution adds mechanistic clarity that’s often missing in bulk
Thanks for sharing @brianobachmann.bsky.social
Wildtype One
Spirocyclic beta-lactones (SBLs) are a beautiful class of molecules produced by bacteria with a beta-lactone fused to a gamma-lactam with potent and selective activity against various cancer cell lines
Given the importance of RNA splicing to many cancers, we are continuing to work on identification of a discrete molecular target for SBLs to explain these data. Stay tuned!
This facilitated structure-activity relationship, verifying their potency against leukemia cell lines and the importance of the beta-lactone for cytotoxicity.
Congrats to Katie et al and special thanks to our collaborators in the Plate lab at Vanderbilt (TPP), and Irish Lab at U Colorado (flow)
We used a flow cytometry to investigate potential mechanistic possibilities of SBLs e induction showing inhibition of phospho-signaling related to nutrient signaling.
We are pleased to share our new work in @pnas.org investigating the discovery, biosynthesis, and mechanistic investigation of a class of molecules we call spirocyclic beta-lactones! Skeetorial to follow. #natprod 🧪
www.pnas.org/doi/full/10....
Natural products containing beta-lactones are covalent protein modifiers, & their unknown mechanism and electrophilic nature got us curious about their mechanism.
Using genome mining, and our single cell Multiplexed Activity Metabolomics, we identified a new producer and isolated a family of SBLs.
Decarboxylative condensation is essential for polyketide and fatty acid biosynthesis, yet the mechanism underlying nonelongating modules without this step remains elusive. Here the authors report a co...
We then used thermal proteome profiling to measure the perturbation of protein stability on induction with SBLs. Interestingly, we found perturbation in RNA processing and splicing effected on brief incubation SBLs. This was confirmed by mRNASeq and alternative splicing analysis.
