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Regioselectivity of hyoscyamine 6β-hydroxylase-catalysed hydroxylation as revealed by high-resolution structural information and QM/MM calculations

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Abstract

Hyoscyamine 6β-hydroxylase (H6H) is a bifunctional non-heme 2-oxoglutarate/Fe2+-dependent dioxygenase that catalyzes the two final steps in the biosynthesis of scopolamine. Based on high resolution crystal structures of H6H from Datura metel, detailed information on substrate binding was obtained that provided insights into the onset of the enzymatic process. In particular, the role of two prominent residues was revealed – Glu-116 that interacts with the tertiary amine located on the hyoscyamine tropane moiety and Tyr-326 that forms CH–π hydrogen bonds with the hyoscyamine phenyl ring. The structures were used as the basis for QM/MM calculations that provided an explanation for the regioselectivity of the hydroxylation reaction on the hyoscyamine tropane moiety (C6 vs. C7) and quantified contributions of active site residues to respective barrier heights.

Graphical abstract: Regioselectivity of hyoscyamine 6β-hydroxylase-catalysed hydroxylation as revealed by high-resolution structural information and QM/MM calculations

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Article information


Submitted
27 Jan 2020
Accepted
09 Mar 2020
First published
09 Mar 2020

Dalton Trans., 2020, Advance Article
Article type
Paper

Regioselectivity of hyoscyamine 6β-hydroxylase-catalysed hydroxylation as revealed by high-resolution structural information and QM/MM calculations

A. Kluza, Z. Wojdyla, B. Mrugala, K. Kurpiewska, P. J. Porebski, E. Niedzialkowska, W. Minor, M. S. Weiss and T. Borowski, Dalton Trans., 2020, Advance Article , DOI: 10.1039/D0DT00302F

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