Structure of Papaver somniferum O-Methyltransferase 1 Reveals Initiation of Noscapine Biosynthesis with Implications for Plant Natural Product Methylation
Structure of Papaver somniferum O-Methyltransferase 1 Reveals Initiation of Noscapine Biosynthesis with Implications for Plant Natural Product Methylation
复制标题
DOI：
10.1021/acscatal.9b01038
复制
发表时间：
2019-05-01
期刊：
影响因子：
12.9
通讯作者：
Davies, Gideon J.
中科院分区：
文献类型：
--
作者：
Cabry, Marc P.;Offen, Wendy A.;Davies, Gideon J.
罂粟，罂粟，自公元前3400年最早的文明时期起就是药用生物碱的来源。苄基异喹啉生物碱诺斯卡因是在罂粟中商业生产的，用于止咳，它也有潜在的抗癌化合物。最近阐明的诺斯汀生物合成途径的第一步是在O-甲基转移酶1(PSMT1)的催化下，通过9-O-甲基化将Soulerine转化为四氢柱胺。我们通过反应坐标上的蛋白质结构(通过合理的晶体工程获得，工程变体的分辨率从1.5埃到1.2埃)，演示了结构域关闭如何允许特定的甲基转移生成产品。SAM依赖的甲基转移是植物中无数天然产物的中心；对氨基酸序列的分析，现在考虑到PSMT1的三维结构和低同源同源物，开始揭示控制这些关键的、普遍存在的植物酶底物特异性的结构特征。我们提出了“守门人”残基如何决定受体的区域化学，从而允许跨广泛的基因组资源进行预测。
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.