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Reaction mechanism of formate dehydrogenase studied by computational methods

Dong, Geng LU and Ryde, Ulf LU orcid (2018) In Journal of Biological Inorganic Chemistry 23(8). p.1243-1254
Abstract

Formate dehydrogenases (FDHs) are metalloenzymes that catalyse the reversible conversion of formate to carbon dioxide. Since such a process may be used to combat the greenhouse effect, FDHs have been extensively studied by experimental and theoretical methods. However, the reaction mechanism is still not clear; instead five putative mechanisms have been suggested. In this work, the reaction mechanism of FDH was studied by computational methods. Combined quantum mechanical and molecular mechanic (QM/MM) optimisations were performed to obtain the geometries. To get more accurate energies and obtain a detailed account of the surroundings, big-QM calculations with a very large (1121 atoms) QM region were performed. Our results indicate that... (More)

Formate dehydrogenases (FDHs) are metalloenzymes that catalyse the reversible conversion of formate to carbon dioxide. Since such a process may be used to combat the greenhouse effect, FDHs have been extensively studied by experimental and theoretical methods. However, the reaction mechanism is still not clear; instead five putative mechanisms have been suggested. In this work, the reaction mechanism of FDH was studied by computational methods. Combined quantum mechanical and molecular mechanic (QM/MM) optimisations were performed to obtain the geometries. To get more accurate energies and obtain a detailed account of the surroundings, big-QM calculations with a very large (1121 atoms) QM region were performed. Our results indicate that the formate substrate does not coordinate directly to Mo when it enters the oxidised active site of the FDH, but instead resides in the second coordination sphere. The sulfido ligand abstracts a hydride ion from the substrate, giving a Mo(IV)–SH state and a thiocarbonate ion attached to Cys196. The latter releases CO2 when the active site is oxidised back to the resting (MoVI) state. This mechanism is supported by recent experimental studies.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Density functional theory, Formate dehydrogenase, Molybdenum, QM/MM, Sulfur-shift mechanism
in
Journal of Biological Inorganic Chemistry
volume
23
issue
8
pages
1243 - 1254
publisher
Springer
external identifiers
  • scopus:85053293022
  • pmid:30173398
ISSN
0949-8257
DOI
10.1007/s00775-018-1608-y
language
English
LU publication?
yes
id
be2c9bd0-4862-4395-a5f3-d5154e8951ff
date added to LUP
2018-10-23 12:28:10
date last changed
2021-10-06 05:22:01
@article{be2c9bd0-4862-4395-a5f3-d5154e8951ff,
  abstract     = {<p>Formate dehydrogenases (FDHs) are metalloenzymes that catalyse the reversible conversion of formate to carbon dioxide. Since such a process may be used to combat the greenhouse effect, FDHs have been extensively studied by experimental and theoretical methods. However, the reaction mechanism is still not clear; instead five putative mechanisms have been suggested. In this work, the reaction mechanism of FDH was studied by computational methods. Combined quantum mechanical and molecular mechanic (QM/MM) optimisations were performed to obtain the geometries. To get more accurate energies and obtain a detailed account of the surroundings, big-QM calculations with a very large (1121 atoms) QM region were performed. Our results indicate that the formate substrate does not coordinate directly to Mo when it enters the oxidised active site of the FDH, but instead resides in the second coordination sphere. The sulfido ligand abstracts a hydride ion from the substrate, giving a Mo(IV)–SH state and a thiocarbonate ion attached to Cys196. The latter releases CO<sub>2</sub> when the active site is oxidised back to the resting (Mo<sup>VI</sup>) state. This mechanism is supported by recent experimental studies.</p>},
  author       = {Dong, Geng and Ryde, Ulf},
  issn         = {0949-8257},
  language     = {eng},
  number       = {8},
  pages        = {1243--1254},
  publisher    = {Springer},
  series       = {Journal of Biological Inorganic Chemistry},
  title        = {Reaction mechanism of formate dehydrogenase studied by computational methods},
  url          = {http://dx.doi.org/10.1007/s00775-018-1608-y},
  doi          = {10.1007/s00775-018-1608-y},
  volume       = {23},
  year         = {2018},
}