Discovering a mitochondrion-localized BAHD acyltransferase involved in calystegine biosynthesis and engineering the production of 3β-tigloyloxytropane

Junlan Zeng, Xiaoqiang Liu, Zhaoyue Dong, Fangyuan Zhang, Fei Qiu, Mingyu Zhong, Tengfei Zhao, Chunxian Yang, Lingjiang Zeng, Xiaozhong Lan, Hongbo Zhang, Junhui Zhou, Min Chen, Kexuan Tang and Zhihua Liao ()
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Junlan Zeng: Southwest University
Xiaoqiang Liu: Southwest University
Zhaoyue Dong: Southwest University
Fangyuan Zhang: Southwest University
Fei Qiu: Southwest University
Mingyu Zhong: Southwest University
Tengfei Zhao: Southwest University
Chunxian Yang: Southwest University
Lingjiang Zeng: Southwest University
Xiaozhong Lan: Xizang Agricultural and Animal Husbandry College
Hongbo Zhang: Tobacco Research Institute of Chinese Academy of Agricultural Sciences
Junhui Zhou: China Academy of Chinese Medical Sciences
Min Chen: Southwest University
Kexuan Tang: Southwest University
Zhihua Liao: Southwest University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Solanaceous plants produce tropane alkaloids (TAs) via esterification of 3α- and 3β-tropanol. Although littorine synthase is revealed to be responsible for 3α-tropanol esterification that leads to hyoscyamine biosynthesis, the genes associated with 3β-tropanol esterification are unknown. Here, we report that a BAHD acyltransferase from Atropa belladonna, 3β-tigloyloxytropane synthase (TS), catalyzes 3β-tropanol and tigloyl-CoA to form 3β-tigloyloxytropane, the key intermediate in calystegine biosynthesis and a potential drug for treating neurodegenerative disease. Unlike other cytosolic-localized BAHD acyltransferases, TS is localized to mitochondria. The catalytic mechanism of TS is revealed through molecular docking and site-directed mutagenesis. Subsequently, 3β-tigloyloxytropane is synthesized in tobacco. A bacterial CoA ligase (PcICS) is found to synthesize tigloyl-CoA, an acyl donor for 3β-tigloyloxytropane biosynthesis. By expressing TS mutant and PcICS, engineered Escherichia coli synthesizes 3β-tigloyloxytropane from tiglic acid and 3β-tropanol. This study helps to characterize the enzymology and chemodiversity of TAs and provides an approach for producing 3β-tigloyloxytropane.

Date: 2024
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DOI: 10.1038/s41467-024-47968-0

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