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.
Highlights
The pyridine ring is a potent pharmacophore in alkaloid natural products
Our strategy for identifying the rubrolone biosynthetic gene cluster was based on our hypotheses that (i) the aglycone of rubrolones A and B is of polyketide synthase origin[5], and (ii) a sugar 4,6-dehydratase installs the C-6 methyl group of the deoxysugar
Integration of p9B10 into the chromosome of Streptomyces albus J1074 by conjugation generated strain S. albus 9B10, from which heterologous expression of the putative rubrolone gene cluster could be monitored by a colour change on an agar plate; the recombinant strain produced a ruby red pigment, whereas control strain containing the relevant empty vector pJTU2554 did not (Supplementary Fig. 1)
Summary
The pyridine ring is a potent pharmacophore in alkaloid natural products. its biosynthetic pathways are poorly understood. We report the gene cluster and propose a biosynthetic pathway for rubrolones, identifying a key intermediate that accumulates upon inactivation of sugar biosynthetic genes 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. Inactivation of rubrolone sugar biosynthetic genes led to the accumulation of a key intermediate that was shown to react non-enzymatically with either ammonia or anthranilic acid to afford the respective aglycones of rubrolones A (1) and B (2). This study provides important new insight into the non-enzymatic and non-amino acid origins of the pyridyl moiety in alkaloid natural products
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