SER-HIS-ASP catalytic triad in model non-aqueous solvent environment: A computational study

Lau, Justin Kai Chi; Cheng, Yuen Kit

doi:10.1016/j.bmcl.2006.08.083

Bioorganic & Medicinal Chemistry Letters

2006

DOI: 10.1016/j.bmcl.2006.08.083

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SER-HIS-ASP catalytic triad in model non-aqueous solvent environment: A computational study

Justin Kai Chi Lau¹,

Yuen Kit Cheng²

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2009

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“…This reaction is facilitated by a simultaneous proton transfer from the water molecule to histidine. The key structural parameters of transition state TS2 are close to the values reported in the previous studies; [65,66] . A proton transfer from the histidine to the oxygen atom originated from Asp104 and the heterolytic cleavage of the CÀO bond occur simultaneously in TS3 to form the product complex.…”

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confidence: 75%

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The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

Kamachi

Nakayama

Shitamichi

et al. 2009

Chemistry A European J

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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.

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supporting

confidence: 75%

“…[64][65][66] Daggett et al [64] carried out semiempirical calculations to look at the hydrolysis of amides and esters catalyzed by serine protease using a simplified active-site model. They considered the acetate anion for Asp, methylimidazole for His, and two water molecules for the oxyanion hole.…”

mentioning

confidence: 99%

The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

Kamachi

Nakayama

Shitamichi

et al. 2009

Chemistry A European J

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SER-HIS-ASP catalytic triad in model non-aqueous solvent environment: A computational study

Cited by 1 publication

References 22 publications

The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

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