期刊
ACS CATALYSIS
卷 9, 期 5, 页码 3840-3848出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.9b01038
关键词
poppy; medicinal plants; enzyme; three-dimensional structure; enzymatic catalysis; alkaloid
资金
- Biotechnology and Biological Sciences Research Council [BB/M011151/1]
- BBSRC [BB/K018809/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1369847, BB/K018809/1] Funding Source: researchfish
The opium poppy, Popover 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, catalyzed by O-methyltransferase 1 (PSMT1). We demonstrate, through protein structures (obtained through rational crystal engineering at resolutions from 1.5 to 1.2 angstrom 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 homologues 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.
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