Defluorinase Reaction Mechanism is Mapped

X-ray crystal structure studies have revealed the first detailed molecular view of the biocatalytic activity of rare fluoroacetate dehalogenase enzymes, which represent one of the very few natural chemical species that can deconstruct the extremely strong carbon-fluorine bond. Peter W. Y. Chan, Emil F. Pai, and coworkers of the University of Toronto obtained high-resolution “snapshots” of a defluorinase in action and used them to map the reaction coordinates along each step of the defluorination pathway, from the free enzyme to enzyme-fluoro­acetate intermediates to the enzyme-product complex (J. Am. Chem. Soc., DOI: 10.1021/ja200277d). These pictures reveal that enzymatic defluorination requires a finely tailored halide pocket in which amino acid residues supply three hydrogen bonds to stabilize a fluoride ion when released from fluoroacetate—one of the few natural organofluorine compounds known. An aspartate residue serves as a nucleophile to eject the fluorine. The three H-bond contacts are similar to the fluo­rine binding of a single known fluorinase enzyme that forms C–F bonds, suggesting this setup is a common strategy for directing fluorine biochemistry, the researchers note. These observations may ultimately lead to engineered enzymes for the synthesis, disposal, and recycling of organofluorine chemicals, they add.