Eric Sembrat's Test Bonanza

Title:

Combinatorial assembly of primary metabolites in animal model systems

Abstract:

The widespread availability of high-resolution mass spectrometry has resulted in the detection of a vast space of unannotated metabolites in animal model systems, but it is unclear whether these represent functional products of specific biosynthetic pathways or simply biochemical “noise”. Our ongoing characterization efforts in C. elegans mouse have revealed combinatorial assembly of primary metabolic building blocks as a new strategy to generate structural and functional diversity. Examples include highly modified nucleosides and modular glycosides that integrate diverse building blocks from amino acid and fatty acid metabolism. These modular metabolites are involved in virtually every aspect of C. elegans life history, regulating e.g. development, aging, and behavior. Ongoing complementary analyses of mammalian metabolomes have started to reveal metabolites of similar biogenetic origin.

Genome-wide association studies revealed carboxylesterase (cest) homologs as the key enzymes mediating modular assembly in C. elegans. This unexpected finding suggested that modular metabolite biosynthesis originates from “hijacking” of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily PKS- and NRPS-derived universe of microbial natural products. While many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics, and genomic approaches can synergize to facilitate annotation of metabolic dark matter.

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