Insights into enzymatic halogenation from computational studies

Abstract

The halogenases are a group of enzymes that have only come to the fore over the last 10 years thanks to the discovery and characterization of several novel representatives. They have revealed the fascinating variety of distinct chemical mechanisms that nature utilizes to activate halogens and introduce them into organic substrates. Computational studies using a range of approaches have already elucidated many details of the mechanisms of these enzymes, often in synergistic combination with experiment. This Review summarizes the main insights gained from these studies. It also seeks to identify open questions that are amenable to computational investigations. The studies discussed herein serve to illustrate some of the limitations of the current computational approaches and the challenges encountered in computational mechanistic enzymology.

Formation and structure of the ferryl [FeO] intermediate in the non-haem iron halogenase SyrB2: classical and QM/MM modelling agree

“…Non-haem iron (NHFe) halogenases have been the focus of much attention due to their unique ability to install halogens at unreactive positions in complex substrates with exquisite chemo-and regioselectivity. The interest in biological halogenation generally has been boosted over the last decade by the discovery of several new classes and families of halogenases; the progress has been extensively reviewed, [1][2][3][4][5][6][7][8][9][10][11][12] most recently by Moore and co-workers. 12 Beyond the fundamental biosynthetic and mechanistic interest, halogenases have attracted attention as ''green'' catalysts for biotechnological and biocatalytic applications.…”

Halogenase engineering and its utility in medicinal chemistry

“…Upon comparison of the halide ion binding site, an attempt was made to convert the chlorinase to a fluorinase by substituting the respective halide-binding residues. 57,66 Structural 67,68 and computational studies 69 of the fluorinase and chlorinase provided insights into the mechanism of halide selection. Crystal structures of the fluorinase in complex with chloride ion (since F − is indistinguishable from water) showed that the halide coordination is reliant on S158 and T80 in the fluorinase which are substituted with G131 and Y70 in the chlorinase, respectively (Fig.…”

cis‐Dioxomolybdenum(VI) complexes with unsymmetric linear tetradentate ligands: syntheses, structures and bromoperoxidase activities

“…Haloperoxidases are capable of efficiently catalysing the halogenation of a variety of organic compounds in the presence of hydrogen peroxide and halides (Cl − , Br − and I − ) . Among halogenated organic compounds, brominated ones are of particular interest due to their extensive applications in the synthesis of flame retardants, pharmaceuticals, biocides and pesticides .…”

“…Among halogenated organic compounds, brominated ones are of particular interest due to their extensive applications in the synthesis of flame retardants, pharmaceuticals, biocides and pesticides . In recent times, because of its convenient and eco‐friendly nature, oxidative bromination with bromoperoxidases and their mimics has drawn considerable attention over traditional bromination using Br 2 . Vanadium(V)‐based bromoperoxidases are most widespread among all the naturally occurring bromoperoxidases .…”

“…In recent times, because of its convenient and eco‐friendly nature, oxidative bromination with bromoperoxidases and their mimics has drawn considerable attention over traditional bromination using Br 2 . Vanadium(V)‐based bromoperoxidases are most widespread among all the naturally occurring bromoperoxidases . As a result, complexes of oxovanadium(V) have been studied extensively as structural and functional models for bromoperoxidases .…”