Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase

Benjamin R. Lichman, Altin Sula, Thomas Pesnot, Helen C. Hailes, John M. Ward, Nicholas H. Keep*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocatalyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism-inspired ligand. The structure supports two key features of the NCS "dopamine-first" mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance. The catalytically vital residue Glu-110 occupies a previously unobserved ligand-bound conformation that may be catalytically significant. The potential roles of inhibitory binding and alternative amino acid conformations in the mechanism have also been revealed. This work significantly advances our understanding of the NCS mechanism and will aid future efforts to engineer the substrate scope and catalytic properties of this useful biocatalyst.

Original languageEnglish
Pages (from-to)5274-5277
Number of pages4
Issue number40
Early online date15 Sept 2017
Publication statusPublished - 10 Oct 2017

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© 2017 American Chemical Society.

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