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Amine oxidation mediated by lysine-specific demethylase 1 : quantum mechanics/molecular mechanics insights into mechanism and role of lysine 661
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Karasulu, Bora, Patil, Mahendra and Thiel, Walter (2013) Amine oxidation mediated by lysine-specific demethylase 1 : quantum mechanics/molecular mechanics insights into mechanism and role of lysine 661. Journal of the American Chemical Society, 135 (36). pp. 13400-13413. doi:10.1021/ja403582u ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/ja403582u
Abstract
We report classical molecular dynamics (MD) simulations and combined quantum mechanics/molecular mechanics (QM/MM) calculations to elucidate the catalytic mechanism of the rate-determining amine oxidation step in the lysine-specific demethylase 1 (LSD1)-catalyzed demethylation of the histone tail lysine (H3K4), with flavin adenine dinucleotide (FAD) acting as cofactor. The oxidation of substrate lysine (sLys) involves the cleavage of an α-CH bond accompanied by the transfer of a hydride ion equivalent to FAD, leading to an imine intermediate. This hydride transfer pathway is shown to be clearly favored for sLys oxidation over other proposed mechanisms, including the radical (or single-electron transfer) route as well as carbanion and polar-nucleophilic mechanisms. MD simulations on six NVT ensembles (covering different protonation states of sLys and K661 as well as the K661M mutant) identify two possible orientations of the reacting sLys and FAD subunits (called “downward” and “upward”). Calculations at the QM(B3LYP-D/6-31G*)/CHARMM22 level provide molecular-level insights into the mechanism, helping to understand how LSD1 achieves the activation of the rather inert methyl-CH bond in a metal-free environment. Factors such as proper alignment of sLys (downward orientation), transition-state stabilization (due to the protein environment and favorable orbital interactions), and product stabilization via adduct formation are found to be crucial for facilitating the oxidative α-CH bond cleavage. The current study also sheds light on the role of important active-site residues (Y761, K661, and W695) and of the conserved water-bridge motif. The steric influence of Y761 helps to position the reaction partners properly, K661 is predicted to get deprotonated prior to substrate binding and to act as an active-site base that accepts a proton from sLys to enable the subsequent amine oxidation, and the water bridge that is stabilized by K661 and W695 mediates this proton transfer.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||
Journal or Publication Title: | Journal of the American Chemical Society | ||||||
Publisher: | American Chemical Society | ||||||
ISSN: | 0002-7863 | ||||||
Official Date: | September 2013 | ||||||
Dates: |
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Volume: | 135 | ||||||
Number: | 36 | ||||||
Page Range: | pp. 13400-13413 | ||||||
DOI: | 10.1021/ja403582u | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Restricted or Subscription Access |
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