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De Novo Peptide Sequencing Reveals a Vast Cyclopeptidome in Human Gut and Other Environments

By Bahar Behsaz, Hosein Mohimani, Alexey Gurevich, Andrey Prjibelski, Mark F Fisher, Larry Smarr, Pieter C. Dorrestein, Joshua S. Mylne, Pavel A. Pevzner

Posted 16 Jan 2019
bioRxiv DOI: 10.1101/521872 (published DOI: 10.1016/j.cels.2019.11.007)

Cyclic and branch cyclic peptides (cyclopeptides) represent an important class of bioactive natural products that include many antibiotics and anti-tumor compounds. However, little is known about cyclopeptides in the human gut, despite the fact that humans are constantly exposed to them. To address this bottleneck, we developed the CycloNovo algorithm for de novo cyclopeptide sequencing that employs de Bruijn graphs, the workhorse of DNA sequencing algorithms. CycloNovo reconstructed many new cyclopeptides that we validated with transcriptome, metagenome, and genome mining analyses. Our benchmarking revealed a vast hidden cyclopeptidome in the human gut and other environments and suggested that CycloNovo offers a much-needed step-change for cyclopeptide discovery. Furthermore, CycloNovo revealed a wealth of anti-microbial cyclopeptides from food that survive the complete human gastrointestinal tract, raising the question of how these cyclopeptides might affect the human microbiome.

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