Department of Biological Sciences, University of Calgary, Calgary, Canada.
Epimeron Inc., Calgary, Canada.
Nat Chem Biol. 2018 Jul;14(7):738-743. doi: 10.1038/s41589-018-0059-7. Epub 2018 May 28.
The ultimate step in the formation of thebaine, a pentacyclic opiate alkaloid readily converted to the narcotic analgesics codeine and morphine in the opium poppy, has long been presumed to be a spontaneous reaction. We have detected and purified a novel enzyme from opium poppy latex that is capable of the efficient formation of thebaine from (7S)-salutaridinol 7-O-acetate at the expense of labile hydroxylated byproducts, which are preferentially produced by spontaneous allylic elimination. Remarkably, thebaine synthase (THS), a member of the pathogenesis-related 10 protein (PR10) superfamily, is encoded within a novel gene cluster in the opium poppy genome that also includes genes encoding the four biosynthetic enzymes immediately upstream. THS is a missing component that is crucial to the development of fermentation-based opiate production and dramatically improves thebaine yield in engineered yeast.
蒂巴因是一种五环阿片生物碱，极易在罂粟中转化为麻醉性镇痛药可待因和吗啡，其形成的最后一步长期以来一直被认为是一个自发反应。我们从罂粟乳浆中检测并纯化了一种新型酶，该酶能够有效地从（7S）-萨尔塔定醇 7-O-乙酸酯形成蒂巴因，而不稳定的羟基化副产物则优先通过自发烯丙基消除产生，这些副产物是由自发烯丙基消除产生的。值得注意的是，蒂巴因合酶（THS）是植物病理相关蛋白 10（PR10）超家族的成员，它编码在罂粟基因组中的一个新基因簇中，该基因簇还包括编码四个生物合成酶的基因，这些酶直接位于上游。THS 是一个缺失的成分，对基于发酵的阿片类药物生产至关重要，并显著提高了工程酵母中蒂巴因的产量。
