Machine learning discovery of missing links that mediate alternative branches to plant alkaloids

Christopher J. Vavricka (), Shunsuke Takahashi, Naoki Watanabe, Musashi Takenaka, Mami Matsuda, Takanobu Yoshida, Ryo Suzuki, Hiromasa Kiyota, Jianyong Li, Hiromichi Minami, Jun Ishii, Kenji Tsuge, Michihiro Araki (), Akihiko Kondo and Tomohisa Hasunuma ()
Additional contact information
Christopher J. Vavricka: Kobe University
Shunsuke Takahashi: Tokyo Denki University, Hatoyama, Hiki-gun
Naoki Watanabe: Kobe University
Musashi Takenaka: Kobe University
Mami Matsuda: Kobe University
Takanobu Yoshida: Kobe University
Ryo Suzuki: Kobe University
Hiromasa Kiyota: Okayama University
Jianyong Li: Virginia Polytechnic and State University
Hiromichi Minami: Ishikawa Prefectural University
Jun Ishii: Kobe University
Kenji Tsuge: Kobe University
Michihiro Araki: Kobe University
Akihiko Kondo: Kobe University
Tomohisa Hasunuma: Kobe University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Engineering the microbial production of secondary metabolites is limited by the known reactions of correctly annotated enzymes. Therefore, the machine learning discovery of specialized enzymes offers great potential to expand the range of biosynthesis pathways. Benzylisoquinoline alkaloid production is a model example of metabolic engineering with potential to revolutionize the paradigm of sustainable biomanufacturing. Existing bacterial studies utilize a norlaudanosoline pathway, whereas plants contain a more stable norcoclaurine pathway, which is exploited in yeast. However, committed aromatic precursors are still produced using microbial enzymes that remain elusive in plants, and additional downstream missing links remain hidden within highly duplicated plant gene families. In the current study, machine learning is applied to predict and select plant missing link enzymes from homologous candidate sequences. Metabolomics-based characterization of the selected sequences reveals potential aromatic acetaldehyde synthases and phenylpyruvate decarboxylases in reconstructed plant gene-only benzylisoquinoline alkaloid pathways from tyrosine. Synergistic application of the aryl acetaldehyde producing enzymes results in enhanced benzylisoquinoline alkaloid production through hybrid norcoclaurine and norlaudanosoline pathways.

Date: 2022
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DOI: 10.1038/s41467-022-28883-8

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