NAD acting as a building block in natural product biosynthesis Lena Barra 1 , Takayoshi Awakawa 2 , Kohei Shirai 2 , Zhijuan Hu 2 , Ikuro Abe 2 * 1 Universität Konstanz, Germany, 2 The University of Tokyo, Graduate School of Pharmaceutical Sciences, Japan *abei@mol.f.u-tokyo.ac.jp Nicotinamide adenine dinucleotide (NAD) is a pivotal metabolite for all living organisms and functions as a diffusible electron acceptor and carrier in central catabolic processes1. During biosynthetic investigations on the structurally unusual anti-cancer compound altemicidin (1) and the related isoleucyl-tRNA synthetase inhibitor SB-2032082, we discovered a novel function for NAD in secondary metabolite biosynthetic pathways, in which the nicotinamide dinucleotide framework is heavily decorated and serves as a building block for the natural product scaffold formation (Fig.1a)3 The gatekeeping enzyme of the pathway (SbzP) constitutes a novel family of pyridoxal phosphate-dependent proteins, catalyzing formation of the 6-azatetrahydroindane core scaffold via a sophisticated (2+3)-cycloaddition reaction at the pyridinium moiety, utilizing S-adenosyl methionine (SAM) as cosubstrate (Fig.1a). Enzymatic reconstitution of the complete downstream biosynthetic pathway revealed the function of several novel dinucleotide-processing enzymes. Intriguingly, functional SbzP homologs were found to be widely distributed in the bacterial kingdom and are encoded in diverse biosynthetic gene clusters (Fig.1b). The findings of this study fundamentally expand our understanding of the bacterial secondary metabolite repertoire and will facilitate the discovery and exploitation of a novel class of NAD-derived natural products3.
Fig.1 a. Discovered PLP-mediated 6-azatetrahydroindane scaffold formation by SbzP utilizing NAD and SAM as substrates. b. Phylogenetic tree of the aspartate aminotransferase superfamily and newly discovered SbzP-like family. References 1. Walsh, C. T. & Tang, Y. The Chemical Biology of Human Vitamins , RSC, (2019). 2. Hu, Z., Awakawa, T., Ma, Z. & Abe, I. Nat. Commun . 10 , 1-10 (2019). 3. Barra, L., Awakawa, T., Shirai, K., Hu, Z., Bashiri, G. & Abe, I. Nature 600 , 754-758 (2021).
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