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Structure of Papaver somniferum O-methyltransferase 1 reveals initiation of noscapine biosynthesis with implications for plant natural product methylation

DOI: 10.1021/acscatal.9b01038 DOI Help

Authors: Marc Cabry (University of York) , Wendy Offen (University of York) , Philip Saleh (University of York) , Yi Li (University of York) , Thilo Winzer (University of York) , Ian A. Graham (University of York) , Gideon J. Davies (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Catalysis

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 7864 , 9948

Abstract: The opium poppy, Papaver somniferum, has been a source of medicinal alkaloids since the earliest civilizations; ca. 3400 B.C. The benzylisoquinoline alkaloid noscapine is produced commercially in P. somniferum for use as a cough suppressant and it also has potential as an anticancer compound. The first committed step in the recently elucidated noscapine biosynthetic pathway involves the conversion of scoulerine to tetrahydrocolumbamine by 9-O-methylation, catalysed by O-methyltransferase 1 (PSMT1). We demonstrate, through protein structures (obtained through rational crystal engineering at resolutions from 1.5 to 1.2Å for the engineered variants) across the reaction coordinate, how domain closure allows specific methyl transfer to generate the product. SAM-dependent methyl transfer is central to myriad natural products in plants, analysis of amino-acid sequence, now taking the three-dimensional structure of PSMT1 and low identity homologs into account, begins to shed light on the structural features that govern substrate specificity in these key, ubiquitous, plant enzymes. We propose how “gatekeeper” residues can determine acceptor regiochemistry thus allowing prediction across the wide genomic resource.

Journal Keywords: Poppy; medicinal plants; enzyme; three-dimensional structure; enzymatic catalysis; alkaloid

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 18/03/2019 12:26

Discipline Tags:

Catalysis Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)