Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 14, Pages 4356-4363Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.05.042
Keywords
Hyoscyamine 6 beta-hydroxylase; Atropa belladonna; (-)-Hyoscyamine; 6 beta-Hydroxyhyoscyamine; Scopolamine; Tropane alkaloids
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canada Research Chair in Bioorganic and Medicinal Chemistry
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(-)-Hyoscyamine, the enantiomerically pure form of atropine, and its derivative scopolamine are tropane alkaloids that are extensively used in medicine. Hyoscyamine 6 beta-hydroxylase (H6H, EC 1.14.11.11), a monomeric alpha-ketoglutarate dependent dioxygenase, converts (-)-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps. In this study, H6H of Atropa belladonna (AbH6H) was cloned, heterologously expressed in Escherichia coli, purified and characterized. The catalytic efficiency of AbH6H, especially for the second oxidation, was found to be low, and this may be one of the reasons why Atropa belladonna produces less scopolamine than other species in the same family. 6,7-Dehydrohyoscyamine, a potential precursor for the last step of epoxidation, was shown not to be an obligatory intermediate in the biosynthesis of scopolamine using purified AbH6H with an in vitro O-18 labeling experiment. Moreover, the nitrogen atom in the tropane ring of (-)-hyoscyamine was found to play an important role in substrate recognition. (C) 2012 Elsevier Ltd. All rights reserved.
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