Non-enzymatic pyridine ring formation in the biosynthesis of the rubrolone tropolone alkaloids.

Abstract:

:The pyridine ring is a potent pharmacophore in alkaloid natural products. Nonetheless, its biosynthetic pathways are poorly understood. Rubrolones A and B are tropolone alkaloid natural products possessing a unique tetra-substituted pyridine moiety. Here, we report the gene cluster and propose a biosynthetic pathway for rubrolones, identifying a key intermediate that accumulates upon inactivation of sugar biosynthetic genes. Critically, this intermediate was converted to the aglycones of rubrolones by non-enzymatic condensation and cyclization with either ammonia or anthranilic acid to generate the respective pyridine rings. We propose that this non-enzymatic reaction occurs via hydrolysis of the key intermediate, which possesses a 1,5-dione moiety as an amine acceptor capable of cyclization. This study suggests that 1,5-dione moieties may represent a general strategy for pyridine ring biosynthesis, and more broadly highlights the utility of non-enzymatic diversification for exploring and expanding natural product chemical space.

journal_name

Nat Commun

journal_title

Nature communications

authors

Yan Y,Yang J,Yu Z,Yu M,Ma YT,Wang L,Su C,Luo J,Horsman GP,Huang SX

doi

10.1038/ncomms13083

subject

Has Abstract

pub_date

2016-10-07 00:00:00

pages

13083

issn

2041-1723

pii

ncomms13083

journal_volume

7

pub_type

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