tRNA-Deacylase Directed Discovery of Biosynthetic Pathways

13 March 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Amino acids are one of nature’s most privileged building blocks for generating molecular diversity on length-scales ranging from small molecules to proteins. While amino acid products arising from certain class-defined biosynthetic pathways can be found with established bioinformatic strategies, those that fall outside of these types remain difficult to identify. To address this challenge, we have developed a new approach to find biosynthetic gene clusters (BGCs) that utilize and modify amino acid monomers while remaining agnostic to biosynthetic class. We demonstrate that tRNA deacylases (tRDs) specific for host-synthesized non-canonical amino acids (ncAAs) serve as a common genomic marker of ncAA metabolism. Using this approach, we show that thousands of cryptic BGCs can be identified and demonstrate the discovery of BGCs for several new ncAAs as well as a hydrazide-containing tripeptide. We anticipate this approach will have broad applications for discovering new natural products with ncAAs and beyond.

Keywords

tRNA-Deacylase
Biocatalysis
Enzyme Discovery
Natural Product Discovery
Biosynthetic Gene Clusters
Non-canonical Amino Acids

Supplementary materials

Title
Description
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Title
Supplementary Information for tRNA-Deacylase Directed Discovery of Biosynthetic Pathways
Description
Methods and Supplemental Figures
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