β-NAD as a building block in natural product biosynthesis

Area of Science:

• Biochemistry and Natural Product Discovery

Background:

• Nicotinamide adenine dinucleotide (β-NAD) is a crucial metabolite involved in metabolism, epigenetics, immunity, and stress responses.
• β-NAD acts as an electron carrier and is sacrificially used in ADP-ribosylation and signaling molecule generation.

Purpose of the Study:

• To investigate the function of β-NAD in secondary metabolite biosynthesis.
• To identify and characterize novel natural products derived from β-NAD.

Main Methods:

• Enzyme assays using the gatekeeping enzyme SbzP.
• Characterization of reaction products from β-NAD and S-adenosylmethionine.
• Bioinformatic analysis of β-NAD-tailoring enzymes in bacterial genomes.

Main Results:

• β-NAD serves as a building block for a novel class of natural products.
• The enzyme SbzP catalyzes a pyridoxal phosphate-dependent [3+2]-annulation between β-NAD and S-adenosylmethionine.
• A 6-azatetrahydroindane scaffold is generated as the core structure.
• β-NAD-tailoring enzymes are widespread in bacteria and found in diverse gene clusters.

Conclusions:

• β-NAD plays a previously unrecognized role in secondary metabolite biosynthesis.
• A new family of natural products derived from β-NAD has been discovered.
• These findings pave the way for the discovery and utilization of β-NAD-derived natural products.