title: The catalytic mechanism of fluoroacetate dehalogenase: a computational exploration of biological dehalogenation.
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 10 800 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 alpha-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 His149, 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.
authors: Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka 819-0395, Japan.
authors: Takashi
authors: T
authors: Kamachi
authors: Tomonori
authors: T
authors: Nakayama
authors: Osamu
authors: O
authors: Shitamichi
authors: Keiji
authors: K
authors: Jitsumori
authors: Tatsuo
authors: T
authors: Kurihara
authors: Nobuyoshi
authors: N
authors: Esaki
authors: Kazunari
authors: K
authors: Yoshizawa
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000235:genetics*; D002384:Catalysis; D020134:Catalytic Domain; D039301:Computers, Molecular; D042742:Delftia / Q000201:enzymology; D005463:Fluoroacetates / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D014867:Water / Q000737:chemistry
chemical_list: D000596:Amino Acids; D005463:Fluoroacetates; D014867:Water; D006867:Hydrolases; C023098:haloacetate dehalogenase; C046137:haloalkane dehalogenase