Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase

Garrett Deletti, Sajan D. Green, Caleb Weber, Kristen N. Patterson, Swapnil S. Joshi, Tushar M. Khopade, Mathew Coban, James Veek-Wilson, Thomas R. Caulfield, Rajesh Viswanathan () and Amy L. Lane ()
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Garrett Deletti: University of North Florida
Sajan D. Green: University of North Florida
Caleb Weber: University of North Florida
Kristen N. Patterson: University of North Florida
Swapnil S. Joshi: Indian Institute of Science Education and Research Tirupati
Tushar M. Khopade: Indian Institute of Science Education and Research Tirupati
Mathew Coban: Mayo Clinic
James Veek-Wilson: University of North Florida
Thomas R. Caulfield: Mayo Clinic
Rajesh Viswanathan: University of North Florida
Amy L. Lane: University of North Florida

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The 2,5-diketopiperazines are a prominent class of bioactive molecules. The nocardioazines are actinomycete natural products that feature a pyrroloindoline diketopiperazine scaffold composed of two D-tryptophan residues functionalized by N- and C-methylation, prenylation, and diannulation. Here we identify and characterize the nocardioazine B biosynthetic pathway from marine Nocardiopsis sp. CMB-M0232 by using heterologous biotransformations, in vitro biochemical assays, and macromolecular modeling. Assembly of the cyclo-L-Trp-L-Trp diketopiperazine precursor is catalyzed by a cyclodipeptide synthase. A separate genomic locus encodes tailoring of this precursor and includes an aspartate/glutamate racemase homolog as an unusual D/L isomerase acting upon diketopiperazine substrates, a phytoene synthase-like prenyltransferase as the catalyst of indole alkaloid diketopiperazine prenylation, and a rare dual function methyltransferase as the catalyst of both N- and C-methylation as the final steps of nocardioazine B biosynthesis. The biosynthetic paradigms revealed herein showcase Nature’s molecular ingenuity and lay the foundation for diketopiperazine diversification via biocatalytic approaches.

Date: 2023
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DOI: 10.1038/s41467-023-38168-3

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