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Crystal structure of thebaine 6-O-demethylase from the morphine biosynthesis pathway

Kluza, Anna, Niedzialkowska, Ewa, Kurpiewska, Katarzyna, Wojdyla, Zuzanna, Quesne, Matthew, Kot, Ewa, Porebski, Przemyslaw J. and Borowski, Tomasz 2018. Crystal structure of thebaine 6-O-demethylase from the morphine biosynthesis pathway. Journal of Structural Biology 202 (3) , pp. 229-235. 10.1016/j.jsb.2018.01.007

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Abstract

Thebaine 6-O-demethylase (T6ODM) from Papaver somniferum (opium poppy) is a key enzyme in the morphine biosynthesis pathway that belongs to the non-heme 2-oxoglutarate/Fe(II)-dependent dioxygenases (ODD) family. Initially, T6ODM was characterized as an enzyme catalyzing Odemethylation of thebaine to neopinone and oripavine to morphinone, however recently the substrate range of T6ODM was expanded to a number of various benzylisoquinoline alkaloids. Here, we present crystal structures of T6ODM in complexes with 2-oxoglutarate (T6ODM:2OG, PDB: 5O9W) and succinate (T6ODM:SIN, PDB: 5O7Y). The arrangement of the T6ODM’s active site is typical for proteins from the ODD family, but the enzyme is characterized by a large substrate binding cavity, whose volume can partially explain the T6ODM promiscuity. Moreover, the size of the cavity allows for binding of multiple molecules at once, posing a question about substrate-driven specificity of the enzyme.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Elsevier
ISSN: 1047-8477
Date of First Compliant Deposit: 22 February 2018
Date of Acceptance: 28 January 2018
Last Modified: 14 Feb 2019 02:30
URI: http://orca-mwe.cf.ac.uk/id/eprint/109378

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