Halogenases: a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation

Abstract

An overview of enzymatic tools for generation of carbon–halogen bonds and their use in enabling selective C–H functionalisation through combination of enzyme and chemo catalysis.

Directed evolution of nonheme iron enzymes to access abiological radical-relay C(sp 3 )−H azidation

“…This process mechanistically resembles the C(sp 3 )‒H halogenation reactions catalyzed by nonheme iron halogenases, in which an iron(IV)-oxo complex is used to activate substrates by means of HAT and an iron(III)halide/azide intermediate intercepts substrate radicals to form carbon‒halogen/azide bonds (Fig. 1B) ( 12 – 16 ). Enlightened by this mechanistic similarity, we proposed that a nonheme iron enzyme could mediate a radical relay process through an initial substrate activation at a Fe(II) center to generate a reactive amidyl radical for HAT and subsequent transfer of a Fe(III)-bound ligand to the carbon-centered radical (Fig.…”

Halogenation in Fungi: What Do We Know and What Remains to Be Discovered?

“…Nowadays, computational methods are the easiest way to detect potential halogenating proteins for example using genome-mining tools like antiSMASH or Blastp [ 24 , 44 ]. These genome-mining methods are very useful for the detection of enzymes present in biosynthetic gene clusters (mainly for FDHs) [ 45 , 46 , 47 ].…”

Constructing multi‐enzymatic cascade reactions for selective production of 6‐bromoindirubin from tryptophan in Escherichia coli

“…First, to overcome the difficulty in regiospecific bromination of the indole ring, flavin‐dependent tryptophan (Trp) halogenase was developed as an alternative to sustainable halogenation (Crowe et al, 2021; Latham et al, 2018). Flavin‐dependent Trp halogenases use FADH 2 and halide ion (X − ) for halogenation in the indole ring of Trp.…”

“…First, to overcome the difficulty in regiospecific bromination of the indole ring, flavin-dependent tryptophan (Trp) halogenase was developed as an alternative to sustainable halogenation (Crowe et al, 2021;Latham et al, 2018) ( Lee et al, 2020). Although they have relatively strict regiospecificity, their low activity and low solubility prevent their practical applications (Phintha et al, 2021).…”