Direct Capture and Heterologous Expression of <i>Salinispora</i> Natural Product Genes for the Biosynthesis of Enterocin

Heterologous expression of secondary metabolic pathways is a promising approach for the discovery and characterization of bioactive natural products. Herein we report the first heterologous expression of a natural product from the model marine actinomycete genus <i>Salinispora</i>. Using the recently developed method of yeast-mediated transformation-associated recombination for natural product gene clusters, we captured a type II polyketide synthase pathway from <i>Salinispora pacifica</i> with high homology to the enterocin pathway from <i>Streptomyces maritimus</i> and successfully produced enterocin in two different <i>Streptomyces</i> host strains. This result paves the way for the systematic interrogation of <i>Salinispora</i>’s promising secondary metabolome

Applying Molecular Networking for the Detection of Natural Sources and Analogues of the Selective Gq Protein Inhibitor FR900359

The cyclic depsipeptide FR900359 (FR), isolated from the traditional Chinese medicine plant <i>Ardisia crenata</i>, is a potent Gq protein inhibitor and thus a valuable tool to study Gq-mediated signaling of G protein-coupled receptors. Two new FR analogues (<b>3</b> and <b>4</b>) were isolated from <i>A. crenata</i> together with the known analogues <b>1</b> and <b>2</b>. The structures of compounds <b>3</b> and <b>4</b> were established by NMR spectroscopic data and MS-based molecular networking followed by in-depth LCMS² analysis. The latter approach led to the annotation of further FR analogues <b>5</b>–<b>9</b>. Comparative bioactivity tests of compounds <b>1</b>–<b>4</b> along with the parent molecule FR showed high-affinity binding to Gq proteins in the low nanomolar range (IC₅₀ = 2.3–16.8 nM) for all analogues as well as equipotent inhibition of Gq signaling, which gives important SAR insights into this valuable natural product. Additionally, FR was detected from leaves of five other <i>Ardisia</i> species, among them the non-nodulated leaves of <i>Ardisia lucida</i>, implying a much broader distribution of FR than originally anticipated