β-NAD as a building block in natural product biosynthesis

Lena Barra, Takayoshi Awakawa (), Kohei Shirai, Zhijuan Hu, Ghader Bashiri and Ikuro Abe ()
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Lena Barra: The University of Tokyo
Takayoshi Awakawa: The University of Tokyo
Kohei Shirai: The University of Tokyo
Zhijuan Hu: The University of Tokyo
Ghader Bashiri: The University of Auckland
Ikuro Abe: The University of Tokyo

Nature, 2021, vol. 600, issue 7890, 754-758

Abstract: Abstratct β-Nicotinamide adenine dinucleotide (β-NAD) is a pivotal metabolite for all living organisms and functions as a diffusible electron acceptor and carrier in the catabolic arms of metabolism1,2. Furthermore, β-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-signalling molecules3,4. Here we report the function of β-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) catalyses a pyridoxal phosphate-dependent [3+2]-annulation reaction between β-NAD and S-adenosylmethionine, generating a 6-azatetrahydroindane scaffold. Members of this novel family of β-NAD-tailoring enzymes are widely distributed in the bacterial kingdom and are encoded in diverse biosynthetic gene clusters. The findings of this work set the stage for the discovery and exploitation of β-NAD-derived natural products.

Date: 2021
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DOI: 10.1038/s41586-021-04214-7

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