[1S05a] 13. Microbial Engineering for Natural Products Synthesis - Part 2

2:00 PM - 2:30 PM JST(5:00 AM - 5:30 AM UTC)

[1MENP-06-KL] Biosynthsis of β-NAD-derived natural products

○Takayoshi Awakawa¹ (1. RIKEN Center for Sustainable Resource Science (Japan))

Keywords:

Co-factor,β-NAD,S-adenosylmethionine,Enzyme structure analysis

β-Nicotinamide adenine dinucleotide (β-NAD) is a pivotal metabolite for all living organisms and functions as a primary electron acceptor and carrier during central catabolic processes.¹ In this study, we demonstrate the first example that β-NAD functions as a building block for the assembly of potent and structurally intriguing bacterial secondary metabolites, such as the anti-cancer compound altemicidin² and the Ile-tRNA inhibitor SB-203208 from Streptomyces. Our biochemical analyses identified a PLP-dependent enzyme (SbzP) as a novel family of enzyme catalyzing the scaffold formation via (3+2)-annulation reaction at the pyridinium moiety of β-NAD, utilizing S-adenosyl methionine (SAM) as a co-substrate.^3,4 Furthermore, we clarified the structural basis and reaction mechanism of the (3+2)-annulation reaction between β-NAD and SAM, based on cryo-electron microscopy analysis, biophysical analysis, and computational analysis.⁵ In this presentation, the enzymatic synthesis of unnatural β-NAD derived compounds and identification of the products from the SbzP homolog gene cluster will be also presented.
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, 184 (2019).
3 Barra, L., Awakawa, T., Shirai, K., Hu, Z., Bashiri,G. & Abe, I Nature, 600, 754–758 (2021).
4 Barra, L., Awakawa, T. & Abe, I. JACS Au 2, 1950-1963 (2022)
5 Awakawa, T., Mori, T., Barra, L., Ahmed, Y., Ushimaru, R., Gao, Y., Adachi, N., Senda, T., Terada, T., Tantillo, D.J., Abe, I. Nat. Catalysis 7, 1099–1108 (2024)