Pang, Jiayun ORCID: https://orcid.org/0000-0003-0689-8440, Hay, Sam, Scrutton, Nigel S. and Sutcliffe, Michael J. (2008) Deep tunneling dominates the biologically important hydride transfer reaction from NADH to FMN in morphinone reductase. Journal of the American Chemical Society, 130 (22). pp. 7092-7097. ISSN 0002-7863 (Print), 1520-5126 (Online) (doi:10.1021/ja800471f)

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Abstract

The temperature dependence of the primary kinetic isotope effect (KIE), combined temperature−pressure studies of the primary KIE, and studies of the α-secondary KIE previously led us to infer that hydride transfer from nicotinamide adenine dinucleotide to flavin mononucleotide in morphinone reductase proceeds via environmentally coupled hydride tunneling. We present here a computational analysis of this hydride transfer reaction using QM/MM molecular dynamics simulations and variational transition-state theory calculations. Our calculated primary and secondary KIEs are in good agreement with the corresponding experimental values. Although the experimentally observed KIE lies below the semiclassical limit, our calculations suggest that 99% of the reaction proceeds via tunneling: this is the first “deep tunneling” reaction observed for hydride transfer. We also show that the dominant tunneling mechanism is controlled by the isotope at the primary rather than the secondary position: with protium in the primary position, large-curvature tunneling dominates, whereas with deuterium in this position, small-curvature tunneling dominates. Also, our study is consistent with tunneling being preceded by reorganization: in the reactant, the rings of the nicotinamide and isoalloxazine moieties are stacked roughly parallel to each other, and as the system moves toward a “tunneling-ready” configuration, the nicotinamide ring rotates to become almost perpendicular to the isoalloxazine ring.

Item Type:	Article
Additional Information:	[1] Publication Date (Web): May 10, 2008. Publication Date(Print): June 4, 2008. [2] Published in the Journal of the American Chemical Society, 2008, 130 (22), pp 7092–7097.
Uncontrolled Keywords:	hydride transfer reaction, morphinone reductase, primary kinetic isotope effect (KIE), enzymes
Subjects:	Q Science > QD Chemistry
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science > School of Science (SCI)
Related URLs:	Publisher Organisation
Last Modified:	21 Oct 2020 22:09
URI:	http://gala.gre.ac.uk/id/eprint/9555

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