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Mechanistic considerations of halogenating enzymes

Abstract

In nature, halogenation is a strategy used to increase the biological activity of secondary metabolites, compounds that are often effective as drugs. However, halides are not particularly reactive unless they are activated, typically by oxidation. The pace of discovery of new enzymes for halogenation is increasing, revealing new metalloenzymes, flavoenzymes, S-adenosyl-L-methionine (SAM)-dependent enzymes and others that catalyse halide oxidation using dioxygen, hydrogen peroxide and hydroperoxides, or that promote nucleophilic halide addition reactions.

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Figure 1: Halogenated natural products.
Figure 2: Biologically relevant halogenation reactions.
Figure 3: Structure of the active site of haem CPO from C. fumago, with a bound substrate, 1,3-cyclopentanedione25.
Figure 4: Proposed catalytic cycle for haem CPOs24,25,26,27.
Figure 5: Structure of the active site of V-CPO from C. inaequalis35.
Figure 6: Mechanistic considerations of V-HPOs.
Figure 7: Proposed biosynthesis of the napyradiomycins A80915A–A80915D30.
Figure 8: Bromination of 3-oxo-hexanoyl homoserine lactone and subsequent hydrolysis of the dibromo product60.
Figure 9: Structure of the active site of FeNH–αKG in SyrB2 from P. syringae45.
Figure 10: Proposed catalytic cycle of FeNH–αKG halogenases.
Figure 11: Examples of FeNH–αKG halogenase reactions.
Figure 12: Parallel assemblies in the biosynthesis of curacin A and jamaicamide A.

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Acknowledgements

A.B. greatly acknowledges US National Science Foundation Division of Chemistry award number 0719553 for support of her research.

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Correspondence should be addressed to A.B. (butler@chem.ucsb.edu).

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Butler, A., Sandy, M. Mechanistic considerations of halogenating enzymes. Nature 460, 848–854 (2009). https://doi.org/10.1038/nature08303

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