GNPSapplication/xmlftp://massive-ftp.ucsd.edu/v03/MSV000086958/primaryOK2000000MetabolomicsKoenig / CruesemannmicroTOF LCChromobacterium Vaccinii (ncbitaxon:1108595)Ardisia Crenata (ncbitaxon:13345)https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=1e5d230149ef43d9aad5b069c7339556wiebke.hanke@freenet.deUniversity of BonnGNPS65MS:1002864 - No post-translational-modifications are included in the identified peptides of this dataset0falseGNPS-FeaturebasedMolecularNetworkingFRDerivativesJNPBoth, the soil bacterium Chromobacterium vaccinii and the bacterial endosymbiont Candidatus Burkholderia crenata of the plant Ardisia crenata are producers of FR900359 (FR). This cyclic depsipeptide is a potent and selective Gq protein inhibitor and used extensively to investigate the intracellular signaling of G protein coupled receptors (GPCRs). In this study, the metabolomes of both FR producers were investigated and compared using feature-based molecular networking (FBMN). As a result, 30 to date unknown FR derivatives were identified, one third of which being unique to C. vaccinii. Guided by MS, a novel FR derivative, FR-6 (compound 1), was isolated, and its structure unambiguously established. In a whole cell biosensing assay based on detection of dynamic mass redistribution (DMR) as readout for Gq inhibition, FR-6 suppressed Gq signaling with micromolar potency (pIC50=5.56). This functional activity was confirmed in radioligand binding assays (pKi=7.50). This work demonstrates the power of molecular networking, guiding the way to a novel Gq inhibiting FR derivative, and underlining the potency of FR as Gq inhibitor.Fri Feb 26 02:33:00 GMT 2021MSV000086958