title: 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.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Zhiyin
authors.initials: Z
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Ya-Tuan
authors.initials: YT
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Can
authors.initials: C
authors.lastname: Su
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Chemistry &Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Horsman
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Sheng-Xiong
authors.initials: SX
authors.lastname: Huang
mesh_terms: D000470:Alkaloids / Q000096:biosynthesis*; D000586:Amination; D005798:Genes, Bacterial; D005810:Multigene Family; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000378:metabolism
chemical_list: D000470:Alkaloids; D011725:Pyridines; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C019082:rubrolone