Abstract
The biological dehalogenation of fluoroacetate carried out by fluoroacetate dehalogenase is discussed by using quantum mechanical/molecular mechanical (QM/MM) calculations for a whole-enzyme model of 10800 atoms. Substrate fluoroacetate is anchored by a hydrogen-bonding network with water molecules and the surrounding amino acid residues of Arg105, Arg108, His149, Trp150, and Tyr212 in the active site in a similar way to haloalkane dehalogenase. Asp104 is likely to act as a nucleophile to attack the a-carbon of fluoroacetate, resulting in the formation of an ester intermediate, which is subsequently hydrolyzed by the nucleophilic attack of a water molecule to the carbonyl carbon atom. The cleavage of the strong C-F bond is greatly facilitated by the hydrogen-bonding interactions between the leaving fluorine atom and the three amino acid residues of Hisl49, Trp150, and Tyr212. The hydrolysis of the ester intermediate is initiated by a proton transfer from the water molecule to His271 and by the simultaneous nucleophilic attack of the water molecule. The transition state and produced tetrahedral intermediate are stabilized by Asp128 and the oxyanion hole composed of Phe34 and Arg105.
| Original language | English |
|---|---|
| Pages (from-to) | 7394-7403 |
| Number of pages | 10 |
| Journal | Chemistry - A European Journal |
| Volume | 15 |
| Issue number | 30 |
| DOIs | |
| Publication status | Published - Jul 27 2009 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
Cite this
The catalytic mechanism of fluoroacetate dehalogenase : a computational exploration of biological dehalogenation. / Kamachi, Takashi; Nakayama, Tomonori; Shitamichi, Osamu; Jitsumori, Keiji; Kurihara, Tatsuo; Esaki, Nobuyoshi; Yoshizawa, Kazunari.
In: Chemistry - A European Journal, Vol. 15, No. 30, 27.07.2009, p. 7394-7403.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The catalytic mechanism of fluoroacetate dehalogenase
T2 - a computational exploration of biological dehalogenation
AU - Kamachi, Takashi
AU - Nakayama, Tomonori
AU - Shitamichi, Osamu
AU - Jitsumori, Keiji
AU - Kurihara, Tatsuo
AU - Esaki, Nobuyoshi
AU - Yoshizawa, Kazunari
PY - 2009/7/27
Y1 - 2009/7/27
N2 - The biological dehalogenation of fluoroacetate carried out by fluoroacetate dehalogenase is discussed by using quantum mechanical/molecular mechanical (QM/MM) calculations for a whole-enzyme model of 10800 atoms. Substrate fluoroacetate is anchored by a hydrogen-bonding network with water molecules and the surrounding amino acid residues of Arg105, Arg108, His149, Trp150, and Tyr212 in the active site in a similar way to haloalkane dehalogenase. Asp104 is likely to act as a nucleophile to attack the a-carbon of fluoroacetate, resulting in the formation of an ester intermediate, which is subsequently hydrolyzed by the nucleophilic attack of a water molecule to the carbonyl carbon atom. The cleavage of the strong C-F bond is greatly facilitated by the hydrogen-bonding interactions between the leaving fluorine atom and the three amino acid residues of Hisl49, Trp150, and Tyr212. The hydrolysis of the ester intermediate is initiated by a proton transfer from the water molecule to His271 and by the simultaneous nucleophilic attack of the water molecule. The transition state and produced tetrahedral intermediate are stabilized by Asp128 and the oxyanion hole composed of Phe34 and Arg105.
AB - The biological dehalogenation of fluoroacetate carried out by fluoroacetate dehalogenase is discussed by using quantum mechanical/molecular mechanical (QM/MM) calculations for a whole-enzyme model of 10800 atoms. Substrate fluoroacetate is anchored by a hydrogen-bonding network with water molecules and the surrounding amino acid residues of Arg105, Arg108, His149, Trp150, and Tyr212 in the active site in a similar way to haloalkane dehalogenase. Asp104 is likely to act as a nucleophile to attack the a-carbon of fluoroacetate, resulting in the formation of an ester intermediate, which is subsequently hydrolyzed by the nucleophilic attack of a water molecule to the carbonyl carbon atom. The cleavage of the strong C-F bond is greatly facilitated by the hydrogen-bonding interactions between the leaving fluorine atom and the three amino acid residues of Hisl49, Trp150, and Tyr212. The hydrolysis of the ester intermediate is initiated by a proton transfer from the water molecule to His271 and by the simultaneous nucleophilic attack of the water molecule. The transition state and produced tetrahedral intermediate are stabilized by Asp128 and the oxyanion hole composed of Phe34 and Arg105.
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U2 - 10.1002/chem.200801813
DO - 10.1002/chem.200801813
M3 - Article
VL - 15
SP - 7394
EP - 7403
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 30
ER -