Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids

Christopher J. Vavricka, Takanobu Yoshida, Yuki Kuriya, Shunsuke Takahashi, Teppei Ogawa, Fumie Ono, Kazuko Agari, Hiromasa Kiyota, Jianyong Li, Jun Ishii, Kenji Tsuge, Hiromichi Minami, Michihiro Araki (), Tomohisa Hasunuma () and Akihiko Kondo
Additional contact information
Christopher J. Vavricka: Kobe University
Takanobu Yoshida: Kobe University
Yuki Kuriya: Kobe University
Shunsuke Takahashi: Kobe University
Teppei Ogawa: Mitsui Knowledge Industry Co., Ltd. (MKI)
Fumie Ono: Kyoto University
Kazuko Agari: Kobe University
Hiromasa Kiyota: Okayama University
Jianyong Li: Virginia Polytechnic and State University
Jun Ishii: Kobe University
Kenji Tsuge: Kobe University
Hiromichi Minami: Ishikawa Prefectural University
Michihiro Araki: Kobe University
Tomohisa Hasunuma: Kobe University
Akihiko Kondo: Kobe University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Previous studies have utilized monoamine oxidase (MAO) and L-3,4-dihydroxyphenylalanine decarboxylase (DDC) for microbe-based production of tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) precursor to opioid analgesics. In the current study, a phylogenetically distinct Bombyx mori 3,4-dihydroxyphenylacetaldehyde synthase (DHPAAS) is identified to bypass MAO and DDC for direct production of 3,4-dihydroxyphenylacetaldehyde (DHPAA) from L-3,4-dihydroxyphenylalanine (L-DOPA). Structure-based enzyme engineering of DHPAAS results in bifunctional switching between aldehyde synthase and decarboxylase activities. Output of dopamine and DHPAA products is fine-tuned by engineered DHPAAS variants with Phe79Tyr, Tyr80Phe and Asn192His catalytic substitutions. Balance of dopamine and DHPAA products enables improved THP biosynthesis via a symmetrical pathway in Escherichia coli. Rationally engineered insect DHPAAS produces (R,S)-THP in a single enzyme system directly from L-DOPA both in vitro and in vivo, at higher yields than that of the wild-type enzyme. However, DHPAAS-mediated downstream BIA production requires further improvement.

Date: 2019
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DOI: 10.1038/s41467-019-09610-2

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