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bioRxiv · 10.1101/2024.04.29.591611

Functional Biosynthetic Stereodivergence in a Gene Cluster via a Dihydrosydnone N-oxide

Ren, J.·Mathew, A.·Rodriguez Garcia, M.·Kohler, T.·Blacque, O.·Linden, A.·Eberl, L.·Sieber, S.·Gademann, K.
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Abstract

Chirality features a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only few natural products have been obtained as racemates, e.g. the quorum-sensing signal valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated its biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen are obtained from the same pathway. This stereodivergence is based on the unusual heterocycle dihydrosydnone N-oxide intermediate, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthesis pathway, providing a deeper understanding of microbial secondary metabolism related to microbial communication. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/591611v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@11b63corg.highwire.dtl.DTLVardef@d339e6org.highwire.dtl.DTLVardef@17e34b1org.highwire.dtl.DTLVardef@b58692_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ren, J., Mathew, A., Rodriguez Garcia, M., Kohler, T., Blacque, O., Linden, A., Eberl, L., Sieber, S., Gademann, K.. 2024-04-29. Functional Biosynthetic Stereodivergence in a Gene Cluster via a Dihydrosydnone N-oxide. https://doi.org/10.1101/2024.04.29.591611

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