Title
Unveiling an Indole Alkaloid Diketopiperazine Biosynthetic Pathway That Features a Unique Stereoisomerase and Multifunctional Methyltransferase
Author
Deletti, Garrett, 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
Year
2023
Journal
Nature Communications
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.
Full Article
Instrument
J-1500
Keywords
nocardioazines