Halogenase Engineering for the Generation of New Natural Product Analogues

Brown, Stephanie; O’Connor, Sarah E.

doi:10.1002/cbic.201500338

Cited by 40 publications

(36 citation statements)

References 55 publications

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“…33,[249][250][251][252][253][254] Generation of natural product analogues via this method is significantly more efficient, and therefore economical and ecologicallyfriendly, than via laborious total synthesis. 255 A number of these reported examples rely upon the chlorination of tryptophan prior to incorporation into a biosynthetic pathway, thereby resulting in a natural product with a chlorinated tryptophan moiety.…”

Section: Integration Of Fl-hals Into Non-native Biosynthetic Pathwaysmentioning

confidence: 99%

“…[32][33][34]218,224,225 This is likely to be an artefact of these enzymes evolving as part of the biosynthetic pathways to non-essential secondary metabolites. Halogenases are not essential for the survival or growth of the native host, and hence there has been little evolutionary pressure for highly active halogenase enzymes.…”

Section: Engineering Fl-hals To Improve Activity and Stabilitymentioning

confidence: 99%

“…Elucidation of the biosynthetic pathways responsible for the production of these compounds has revealed a number of enzymes capable of halogenating both aliphatic and aromatic carbons on either protein-tethered or free-standing substrates. [32][33][34] These enzymes have received much interest since their first discoveries and now a number of fundamentally different classes of halogenases are known -categorised based upon the mechanism by which they generate and utilise activated halide.…”

Section: -28mentioning

confidence: 99%

“…[32][33][34] The first tryptophan Fl-Hal to be identified was PrnA which is required for the biosynthesis of pyrrolnitrin (25), a broad spectrum antifungal compound, produced by fluorescens. 127,137,138 In the pyrrolnitrin pathway, PrnA chlorinates the 7 second Fl-Hal, PrnC, chlorinates the pyrrolic intermediate halogenase RebH, with 55 % sequence identity to PrnA, was subsequent rebaccamycin biosynthetic pathway in of these two Fl-Hals were subsequently determined which, along with further biochemical studies, provided the basis of our understanding of the mechanism and reactivity of Fl…”

Section: Flavin-dependent Tryptophan Halogenasesmentioning

confidence: 99%

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Development of Halogenase Enzymes for Use in Synthesis

Latham

Brandenburger

Shepherd³

et al. 2017

Chem. Rev.

285

244

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Nature has evolved halogenase enzymes to regioselectively halogenate a diverse range of biosynthetic precursors, with the halogens introduced often having a profound effect on the biological activity of the resulting natural products. Synthetic endeavours to create non-natural bioactive small molecules for pharmaceutical and agrochemical applications have also arrived at a similar conclusion -halogens can dramatically improve the properties of organic molecules for selective modulation of biological targets in vivo. Consequently a high proportion of pharmaceuticals and agrochemicals on the market today possess halogens. Halogenated organic compounds are also common intermediates in synthesis and are particularly valuable in metal catalyzed cross-coupling reactions.Despite the potential utility of organohalogens, traditional non-enzymatic halogenation chemistry utilizes deleterious reagents and often lacks regiocontrol. Reliable, facile and cleaner methods for the regioselective halogenation of organic compounds are therefore essential in the development of economical and environmentally-friendly industrial processes. A potential avenue towards such methods is the use of halogenase enzymes, responsible for the biosynthesis of halogenated natural products, as biocatalysts. This review will discuss the advances towards this goal thus far, in addition to untapped potential sources of such biocatalysts and how further development of the enzymes may be focused in order to achieve the goal of industrial scale biohalogenation.

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Section: Integration Of Fl-hals Into Non-native Biosynthetic Pathwaysmentioning

confidence: 99%

Section: Engineering Fl-hals To Improve Activity and Stabilitymentioning

confidence: 99%

Section: -28mentioning

confidence: 99%

Section: Flavin-dependent Tryptophan Halogenasesmentioning

confidence: 99%

See 2 more Smart Citations

Development of Halogenase Enzymes for Use in Synthesis

Latham

Brandenburger

Shepherd³

et al. 2017

Chem. Rev.

285

244

View full text Add to dashboard Cite

show abstract

“…53 In other early work, rational design on the basis of structure-guided mutagenesis was applied to other FDHs with notable changes in site-selectivity in reactions of structurally different substrates, although a 100% shift in selectivity remains to be achieved. 54,55 Directed evolution of halogenases offers a more general and reliable solution to the problem of controlling the regioselectivity of halogenation. In one study the well-known tryptophan Scheme 13 Regioselective chlorination of (R)-or (S)-tryptophan (26) at three different sites catalyzed by different halogenases.…”

Section: Engineering Site-selectivity Of Halogenasesmentioning

confidence: 99%

Enzymatic site-selectivity enabled by structure-guided directed evolution

Wang

Reetz

2017

Chem. Commun.

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Biocatalytic site-selective (regioselective) organic transformations have been practiced for decades, but the traditional limitations of enzymes regarding narrow substrate acceptance and the often observed insufficient degree of selectivity have persisted until recently. With the advent of directed evolution, it is possible to engineer site-selectivity to suit the needs of organic chemists. This review features recent progress in this exciting research area, selected examples involving P450 monooxygenases, halogenases and Baeyer-Villiger monooxygenases being featured for illustrative purposes. The complementary nature of enzymes and man-made catalysts is emphasized.

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Functional Enzyme Mimics for Oxidative Halogenation Reactions that Combat Biofilm Formation

et al. 2018

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Transition-metal oxide nanoparticles and molecular coordination compounds are highlighted as functional mimics of halogenating enzymes. These enzymes are involved in halometabolite biosynthesis. Their activity is based upon the formation of hypohalous acids from halides and hydrogen peroxide or oxygen, which form bioactive secondary metabolites of microbial origin with strong antibacterial and antifungal activities in follow-up reactions. Therefore, enzyme mimics and halogenating enzymes may be valuable tools to combat biofilm formation. Here, halogenating enzyme models are briefly described, enzyme mimics are classified according to their catalytic functions, and current knowledge about the settlement chemistry and adhesion of fouling organisms is summarized. Enzyme mimics with the highest potential are showcased. They may find application in antifouling coatings, indoor and outdoor paints, polymer membranes for water desalination, or in aquacultures, but also on surfaces for food packaging, door handles, hand rails, push buttons, keyboards, and other elements made of plastic where biofilms are present. The use of natural compounds, formed in situ with nontoxic and abundant metal oxide enzyme mimics, represents a novel and efficient "green" strategy to emulate and utilize a natural defense system for preventing bacterial colonization and biofilm growth.

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Halogenase Engineering for the Generation of New Natural Product Analogues

Cited by 40 publications

References 55 publications

Development of Halogenase Enzymes for Use in Synthesis

Development of Halogenase Enzymes for Use in Synthesis

Enzymatic site-selectivity enabled by structure-guided directed evolution

Functional Enzyme Mimics for Oxidative Halogenation Reactions that Combat Biofilm Formation

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