Unraveling the Nature of the Catalytic Power of Fluoroacetate Dehalogenase

Abstract

Fluoroacetate dehalogenase is able to cleavage a carbon–fluoride bond, the strongest carbon–halogen bond in nature, in a process initiated by a SN2 reaction. The role of the enzyme machinery and particularly of the halogen pocket in the SN2 reaction is thoroughly explored by using state‐of‐the‐art computational tools. A comparison between the non‐catalyzed versus enzyme‐catalyzed reaction, as well as with a mutant of the enzyme (Tyr219Phe), is presented. The energy barrier changes are rationalized by means of reaction force analysis and the activation strain model coupled with energy decomposition analysis. The catalysis is in part caused by the reduction of structural work from bringing the reactant species towards the proper reaction orientation, and the reduction of the electrostatic repulsion between the nucleophile and the substrate, which are both negatively charged. In addition, catalysis is also driven by an important reduction of the electronic reorganization processes during the reaction, where Tyr from the halogen pocket acts as a charge acceptor from the SN2 reaction axis therefore reducing the electronic steric repulsion between the reacting parts.

Comprehensive Understanding of Fluoroacetate Dehalogenase-Catalyzed Degradation of Fluorocarboxylic Acids: A QM/MM Approach

“…Based on a FAcD monomer, previously we established the relation between key structural parameters and energy barriers for FAcD-catalyzed C–F bond cleavage . Similar relations in different enzymes have also been reported . To investigate the influence of dimer structure on catalytic reaction mechanisms, we studied the relation on the basis of FAcD dimer (Figure S3).…”

“…52 Similar relations in different enzymes have also been reported. 53 To investigate the influence of dimer structure on catalytic reaction mechanisms, we studied the relation on the basis of FAcD dimer (Figure S3). A similar trend has been observed that larger angle O 1 C 2 F of the reactant corresponds to lower energy barrier.…”

Nothing lasts forever: understanding microbial biodegradation of polyfluorinated compounds and perfluorinated alkyl substances

“…The nature of the relative catalytic efficiency with fluoroacetate has been most well‐studied with the enzyme denoted FacD from Burkholderia sp. FA1 via studies involving X‐ray crystallography, site‐directed mutagenesis, rapid synchotron crystallography and computational studies (Chan et al ., 2011 ; Miranda Rojas et al ., 2018 ; Schulz et al ., 2018 ). The reaction is known to proceed via nucleophilic attack of an aspartate nucleophile to generate an aspartate ester intermediate that is resolved by attack of water activated by an active site histidine.…”

Enzymatic synthesis of fluorinated compounds

“…Therefore, dehalogenation is an important measure to control environmental pollution (Yue et al 2020 ). Fluoroacetate dehalogenases (EC 3.8.1.3, FAcDs) are a class of enzymes that can cleave carbon-halogen bonds initiated by S N 2 substitution (Kim et al 2017 ; Miranda-Rojas et al 2018 ; Wang et al 2017 ). Accordingly, FAcD is an effective tool to control pollution through enzymatic biodegradation (Li et al 2019 ).…”