posted on 2020-10-14, 22:51authored byJason
S. Hoki, Henry H. Le, Karlie E. Mellott, Ying K. Zhang, Bennett W. Fox, Pedro R. Rodrigues, Yan Yu, Maximilian J. Helf, Joshua A. Baccile, Frank C. Schroeder
Untargeted metabolomics indicates
that the number of unidentified
small-molecule metabolites may exceed the number of protein-coding
genes for many organisms, including humans, by orders of magnitude.
Uncovering the underlying metabolic networks is essential for elucidating
the physiological and ecological significance of these biogenic small
molecules. Here we develop a click-chemistry-based enrichment strategy,
DIMEN (deep interrogation of metabolism via enrichment), that we apply
to investigate metabolism of the ascarosides, a family of signaling
molecules in the model organism C. elegans.
Using a single alkyne-modified metabolite and a solid-phase azide
resin that installs a diagnostic moiety for MS/MS-based identification,
DIMEN uncovered several hundred novel compounds originating from diverse
biosynthetic transformations that reveal unexpected intersection with
amino acid, carbohydrate, and energy metabolism. Many of the newly
discovered transformations could not be identified or detected by
conventional LC-MS analyses without enrichment, demonstrating the
utility of DIMEN for deeply probing biochemical networks that generate
extensive yet uncharacterized structure space.