6ka2
Crystal structure of a Thebaine synthase from Papaver somniferum in complex with TBN
Structural highlights
FunctionTHS2_PAPSO Catalyzes the formation of thebaine from (7S)-salutaridinol 7-O-acetate at the expense of labile hydroxylated by-products, which are preferentially produced by spontaneous allylic elimination. No visible activity toward (7S)-salutaridinol (at pH 7).[1] Publication Abstract from PubMedThebaine synthase 2 (THS2) that can transform (7S)-salutaridinol 7-O-acetate to thebaine catalyzes the final step of thebaine biosynthesis in Papaver somniferum. Here, the crystal structures of THS2 and its complex with thebaine are reported, revealing the interaction network in the substrate-binding pocket. Subsequent docking and QM/MM studies was performed to further explore the catalytic mechanism of THS2. Our results suggest that T105 may abstract the proton of C4-OH from the substrate under the assistance of H89. The resulting C4-O(-) phenolate anion then attacks the nearby C5, and triggers intramolecular SN2' syn displacement with the elimination of O-acetyl group. Moreover, the latter SN2' reaction is the rate-determining step of the whole enzymatic reaction with an overall energy barrier of 18.8 kcal/mol. These findings are of pivotal importance to understand the mechanism of action of thebaine biosynthesis, and would guide enzyme engineering to enhance the production of opiate alkaloids via metabolic engineering. Structural insights into thebaine synthase 2 catalysis.,Chen CC, Xue J, Peng W, Wang B, Zhang L, Liu W, Ko TP, Huang JW, Zhou S, Min J, Ma L, Dai L, Guo RT, Yu X Biochem Biophys Res Commun. 2020 Aug 20;529(2):156-161. doi:, 10.1016/j.bbrc.2020.05.199. Epub 2020 Jun 22. PMID:32703404[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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