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Structural evidence for the dopamine-first mechanism of norcoclaurine synthase

DOI: 10.1021/acs.biochem.7b00769 DOI Help

Authors: Benjamin R. Lichman (University College London) , Altin Sula (Birkbeck, University of London) , Thomas Pesnot (University College London) , Helen C. Hailes (University College London) , John M. Ward (University College London) , Nicholas H. Keep (Birkbeck, University of London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemistry

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 12305

Open Access Open Access

Abstract: 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.

Journal Keywords: Peptides and proteins; Amines; Ligands; Chemical structure; Conformation

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography

Added On: 27/09/2017 08:43


Discipline Tags:

Plant science Biotechnology Biochemistry Catalysis Chemistry Structural biology Engineering & Technology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)