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Acceptance and Kinetic Resolution of α-Methyl-Substituted Aldehydes by Norcoclaurine Synthases

Roddan, R; Gygli, G; Sula, A; Mendez-Sanchez, D; Pleiss, J; Ward, JM; Keep, NH; (2019) Acceptance and Kinetic Resolution of α-Methyl-Substituted Aldehydes by Norcoclaurine Synthases. ACS Catalysis , 9 (10) pp. 9640-9649. 10.1021/acscatal.9b02699. Green open access

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Abstract

Norcoclaurine synthase (NCS) catalyzes a stereoselective Pictet-Spengler reaction to give the key intermediate, (S)-norcoclaurine in benzylisoquinoline alkaloid (BIA) biosynthesis. This family of alkaloids contains many bioactive molecules including morphine and berberine. Recently, NCS has been demonstrated to accept a variety of aldehydes and some ketones as substrates, leading to a range of chiral tetrahydroisoquinoline (THIQ) products. Here, we report the unusual acceptance of α-substituted aldehydes, in particular α-methyl substituted aldehydes, by wild-type Thalictrum flavum NCS (33TfNCS) to give THIQ products. Moreover, the kinetic resolution of several α-substituted aldehydes to give THIQs with two defined chiral centers in a single step with high conversions was achieved. Several dopamine analogues were also accepted as substrates and reactions were amenable to scale-up. Active site mutants of TfNCS were then used which demonstrated the potential to enhance the stereoselectivities in the reaction and improve yields. Rationale for the acceptance of these substrates and improved activity with different mutants has been gained from a co-crystallized structure of 33TfNCS with a non-productive mimic of a reaction intermediate bound in the active site. Finally, molecular dynamics simulations were performed to study the binding of dopamine and an α-substituted aldehyde and provided further insight into the reaction with these substrates.

Type: Article
Title: Acceptance and Kinetic Resolution of α-Methyl-Substituted Aldehydes by Norcoclaurine Synthases
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acscatal.9b02699
Publisher version: https://doi.org/10.1021/acscatal.9b02699
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: biocatalysis, norcoclaurine synthase, tetrahydroisoquinoline, Pictet-Spengler, kinetic resolution.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10081482
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