Tropane alkaloids biosynthesis involves an unusual type III polyketide synthase and non-enzymatic condensation

Jian-Ping Huang, Chengli Fang, Xiaoyan Ma, Li Wang, Jing Yang, Jianying Luo, Yijun Yan, Yu Zhang () and Sheng-Xiong Huang ()
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Jian-Ping Huang: Chinese Academy of Sciences
Chengli Fang: Chinese Academy of Sciences
Xiaoyan Ma: Chinese Academy of Sciences
Li Wang: Chinese Academy of Sciences
Jing Yang: Chinese Academy of Sciences
Jianying Luo: Chinese Academy of Sciences
Yijun Yan: Chinese Academy of Sciences
Yu Zhang: Chinese Academy of Sciences
Sheng-Xiong Huang: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract The skeleton of tropane alkaloids is derived from ornithine-derived N-methylpyrrolinium and two malonyl-CoA units. The enzymatic mechanism that connects N-methylpyrrolinium and malonyl-CoA units remains unknown. Here, we report the characterization of three pyrrolidine ketide synthases (PYKS), AaPYKS, DsPYKS, and AbPYKS, from three different hyoscyamine- and scopolamine-producing plants. By examining the crystal structure and biochemical activity of AaPYKS, we show that the reaction mechanism involves PYKS-mediated malonyl-CoA condensation to generate a 3-oxo-glutaric acid intermediate that can undergo non-enzymatic Mannich-like condensation with N-methylpyrrolinium to yield the racemic 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid. This study therefore provides a long sought-after biosynthetic mechanism to explain condensation between N-methylpyrrolinium and acetate units and, more importantly, identifies an unusual plant type III polyketide synthase that can only catalyze one round of malonyl-CoA condensation.

Date: 2019
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DOI: 10.1038/s41467-019-11987-z

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