NAD as a building block in natural product biosynthesis Ikuro Abe The University of Tokyo, Japan b-Nicotinamide adenine dinucleotide (b-NAD) is a pivotal metabolite for all living organisms and functions as a diffusible electron acceptor and carrier in the catabolic arms of metabolism. Furthermore, b-NAD is involved in diverse epigenetic, immunological, and stress-associated processes, where it is known to be sacrificially utilized as an ADP-ribosyl donor for protein and DNA modifications, or the generation of cell-signaling molecules. Here, we report the function of b-NAD in secondary metabolite biosynthetic pathways, in which the nicotinamide dinucleotide framework is heavily decorated and serves as a building block for the assembly of a novel class of natural products. The gatekeeping enzyme of the discovered pathway (SbzP) hereby catalyzes a sophisticated, pyridoxal phosphate (PLP)-dependent (3+2)-annulation reaction between b-NAD and S-adenosylmethionine (SAM), generating a 6-azatetrahydroindane scaffold. Members of this novel family of b-NAD-tailoring enzymes are widely distributed in the bacterial kingdom and encoded in diverse biosynthetic gene clusters (BGCs). The findings of this work set the stage for the discovery and exploitation of b-NAD-derived natural products. [1, 2] References 1. Hu, Z., Awakawa, T., Ma, Z. & Abe, I., Nat. Commun. 2019 , 10 , 184. 2. Barra, L., Awakawa, T., Shirai, K., Hu, Z., Bashiri,G. & Abe, I, Nature 2021 , 600 , 754.
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