Biosynthesis of the tetrahydroxynaphthalene-derived meroterpenoid furaquinocin <i>via</i> reductive deamination and intramolecular hydroalkoxylation of an alkene

Hybrid isoprenoid-polyketides, known as meroterpenoids, are a family of natural products that exhibit various bioactivities and are promising drug scaffolds. Despite the structural diversity of 1,3,6,8-tetrahydroxynaphthalene (THN)-derived meroterpenoids, such as furaquinocin, naphterpin, and furanonaphthoquinone, several biosynthetic genes for these compounds are conserved, suggesting a shared biosynthetic mechanism. However, the common biosynthetic mechanism and pathway-specific structural diversification mechanisms of these meroterpenoids are not yet fully understood. This study reveals the biosynthetic pathway for furaquinocin, demonstrating that it involves reductive deamination to form a key hydroquinone intermediate essential for subsequent reactions, including a unique cyclization step. We identified the mechanism of reductive deamination of the biosynthetic intermediate 8-amino-flaviolin through transient diazotization, leading to the formation of the hydroquinone intermediate 1,2,4,5,7-pentahydroxynaphthalene (PHN). Structural and computational studies confirmed that PHN is a key substrate for the subsequent methylation. We also showed that the hydroquinone intermediates are prerequisites for the subsequent pathway-specific reactions, including prenylation and novel intramolecular hydroalkoxylation of an alkene. This hydroalkoxylation reaction is notable in that a methyltransferase homolog catalyzes it in an <i>S</i>-adenosylmethionine-independent manner. Our findings provide a new model for furaquinocin biosynthesis, offering insights into the biosynthetic strategies for THN-derived meroterpenoids.