Investigation of the Hydroxylation Mechanism of Noncoupled Copper Oxygenases by Ab Initio Molecular Dynamics Simulations

In Nature, the family of copper monooxygenases comprised of peptidylglycine α‐hydroxylating monooxygenase (PHM), dopamine β‐monooxygenase (DβM), and tyramine β‐monooxygenase (TβM) is known to perform dioxygen‐dependent hydroxylation of aliphatic CH bonds by using two uncoupled metal sites. In spite...

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Bibliographic Details
Published in:Chemistry : a European journal 2013-12, Vol.19 (51), p.17328-17337
Main Authors: Meliá, Conchín, Ferrer, Silvia, Řezáč, Jan, Parisel, Olivier, Reinaud, Olivia, Moliner, Vicent, de la Lande, Aurélien
Format: Article
Language:English
Subjects:
ab initio calculations
Adducts
Aliphatic compounds
Catalytic Domain
Chemical bonds
Chemistry
Computer applications
Computer simulation
Copper
Dopamine
Dopamine beta-Hydroxylase - chemistry
Dopamine beta-Hydroxylase - metabolism
Electron transfer
Electron Transport
Enzymes
Hydrogen - chemistry
Hydrogen - metabolism
Hydrogen bonds
Hydroxylation
Mixed Function Oxygenases - chemistry
Mixed Function Oxygenases - metabolism
Molecular dynamics
Molecular Dynamics Simulation
Monooxygenase
Multienzyme Complexes - chemistry
Multienzyme Complexes - metabolism
Oxygenation
Proposals
Quantum Theory
reaction mechanisms
Substrates
Superoxide
Tyramine
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Summary:In Nature, the family of copper monooxygenases comprised of peptidylglycine α‐hydroxylating monooxygenase (PHM), dopamine β‐monooxygenase (DβM), and tyramine β‐monooxygenase (TβM) is known to perform dioxygen‐dependent hydroxylation of aliphatic CH bonds by using two uncoupled metal sites. In spite of many investigations, including biochemical, chemical, and computational, details of the CH bond oxygenation mechanism remain elusive. Herein we report an investigation of the mechanism of hydroxylation by PHM by using hybrid quantum/classical potentials (i.e., QM/MM). Although previous investigations using hybrid QM/MM techniques were restricted to geometry optimizations, we have carried out ab initio molecular dynamics simulations in order to include the intrinsic flexibility of the active sites in the modeling protocol. The major finding of this study is an extremely fast rebound step after the initial hydrogen‐ion step promoted by the cupric–superoxide adduct. The hydrogen‐ion/rebound sequence leads to the formation of an alkyl hydroperoxide intermediate. Long‐range electron transfer from the remote copper site subsequently triggers its reduction to the hydroxylated substrate. We finally show two reactivity consequences inherent in the new mechanistic proposal, the investigation of which would provide a means to check its validity by experimental means. Hydroxylating enzymes: Peptidylglycine α‐hydroxylating monooxygenase (PHM) has been investigated by means of molecular dynamics simulations based on density functional theory/molecular mechanics potentials. An extremely fast rebound step after the hydrogen‐ion step promoted by the CuII/O2.− adduct has been identified (see figure).
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201301000