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On the Catalytic Mechanism of ( S )‐2‐Hydroxypropylphosphonic Acid Epoxidase (HppE): A Hybrid DFT Study
Author(s) -
Miłaczewska Anna,
Broclawik Ewa,
Borowski Tomasz
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201202825
Subject(s) - chemistry , catalysis , protonation , stereochemistry , ligand (biochemistry) , reaction mechanism , substrate (aquarium) , crystal structure , bond cleavage , catalytic cycle , ring (chemistry) , medicinal chemistry , crystallography , organic chemistry , ion , biochemistry , oceanography , receptor , geology
The mechanism of oxidative epoxidation catalyzed by HppE, which is the ultimate step in the biosynthesis of fosfomycin, was studied by using hybrid DFT quantum chemistry methods. An active site model used in the computations was based on the available crystal structure for the HppE‐Fe II ‐( S )‐HPP complex and it comprised first‐shell ligands of iron as well as second‐shell polar groups interacting with the substrates. The reaction energy profiles were constructed for three a priori plausible mechanisms proposed in the literature, and it was found that the most likely scenario for the native substrate, that is, ( S )‐HPP, involves generation of the reactive Fe III O . /Fe IV O species, which is responsible for the CH bond‐cleavage. At the subsequent reaction stage, the OH‐rebound, which would lead to a hydroxylated product, is prevented by a fast protonation of the OH ligand and, as a result, ring closure is the energetically preferred step. For the R enantiomer of the substrate (( R )‐HPP), which is oxidized to a keto product, comparable barrier heights were found for the CH bond activation by both the Fe III O 2 . and Fe IV O species.