Biocatalytic oxidative cross-coupling reactions for biaryl bond formation

Zetzsche, Lara; Yazarians, Jessica; Chakrabarty, Suman; Hinze, Meagan E.; Murray, Lauren A. M.; Lukowski, April L.; Joyce, Leo A.; Narayan, Alison R. H.

doi:10.1038/s41586-021-04365-7

Cited by 112 publications

(86 citation statements)

References 54 publications

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“…The known bacterial P450 enzymes involved in biaryl coupling can be classified into four types, including CYP158 enzymes for dimerization of naphthols [ 25 – 27 ], JulI/SetI/SptI clade for anthraquinones [ 3 ], HmtS/ClpS/LtzS clade for cyclopeptides [ 4 , 18 – 19 ], and Bmp7 clade for polybrominated substrates (Table S7 and Figure S1, Supporting Information File 1 ) [ 13 , 17 ]. These P450 enzymes tend to have broad substrate specificity and form a variety of biaryl products.…”

Section: Resultsmentioning

confidence: 99%

A Streptomyces P450 enzyme dimerizes isoflavones from plants

Liu

Chen

Zhang

2022

Beilstein J. Org. Chem.

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Dimerization is a widespread natural strategy that enables rapid structural diversification of natural products. However, our understanding of the dimerization enzymes involved in this biotransformation is still limited compared to the numerous reported dimeric natural products. Here, we report the characterization of three new isoflavone dimers from Streptomyces cattleya cultured on an isoflavone-containing agar plate. We further identified a cytochrome P450 monooxygenase, CYP158C1, which is able to catalyze the dimerization of isoflavones. CYP158C1 can also dimerize plant-derived polyketides, such as flavonoids and stilbenes. Our work represents a unique bacterial P450 that can dimerize plant polyphenols, which extends the insights into P450-mediated biaryl coupling reactions in biosynthesis.

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Section: Resultsmentioning

confidence: 99%

A Streptomyces P450 enzyme dimerizes isoflavones from plants

Liu

Chen

Zhang

2022

Beilstein J. Org. Chem.

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“…Auch in der Familie der Cytochrom-P450-Enzyme ist eine Untergruppe für nicht natürliche oxidative Kreuzkupplungen zur Biarylbindungsbildung nun besser untersucht. 12) Basierend auf der natürlichen Funktion des bekannten Enzyms, KtnC, entwickelte ein Forscherteam durch semirationales Proteindesign eine Enzymvariante, die die gewünschte Reaktivität, ortsspezifische Selektivität und Atroposelektivität für mehrere nicht natürliche Kreuzkupplungen besitzt. Zudem wurde mit einem SSN die natürliche Reaktivität nah verwandter Enzyme unter-sucht und kartiert.…”

Section: Cytochrom-p450 Und Halogenasen In Vitrounclassified

Trendbericht Biochemie 2022: Späte Funktionalisierung mit Biokatalysatoren aus Naturstoffsynthesen

Haslinger¹,

Schmidt²

2022

Nachr Chem

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“…Biocatalytic methods for atroposelective synthesis are dominated by hydrolysis or oxidation/reduction of functional groups on atropisomeric compounds 26 . Atroposelective lipasecatalyzed macrolactonization 27 and P450-catalyzed oxidative biaryl coupling have been developed, 28,29 but modest yields and/or selectivities have typically been observed for non-native substrates in the latter case to date 30 . Suitably engineered FDHs could therefore both improve the efficiency of electrophilic halogenation for atroposelective synthesis and expand the range of enzymes that catalyze atroposelective transformations via substrate elaboration.…”

Section: Introductionmentioning

confidence: 99%

Directed Evolution of Flavin-Dependent Halogenases for Atroposelective Halogenation of 3-Aryl-4(3H)-quinazolinones via Kinetic or Dynamic Kinetic Resolution

Snodgrass

Mondal

Lewis

2022

Preprint

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In this study, we engineer a variant of the flavin-dependent halogenase RebH that catalyzes site- and atroposelective halogenation of 3-aryl-4(3H)-quinazolinones via kinetic or dynamic kinetic resolution. The required directed evolution uses a combination of random and site-saturation mutagenesis, substrate walking using two probe substrates, and a two-tiered screening approach involving analysis of variant conversion and then enantioselectivity of improved variants. The resulting variant, 3-T, provides >99:1 e.r. for the (M)-atropisomer of the major brominated product, 25-fold improved conversion, and 91-fold improved site-selectivity relative to the parent enzyme on the probe substrate used in the final rounds of evolution. This high activity and selectivity translates well to several additional substrates with varied steric and electronic properties. Computational modeling and docking simulations are used to rationalize the effects of key mutations on substrate scope and site- and atroposelectivity. Given the range of substrates that have been used for atroposelective synthesis via electrophilic halogenation, these results suggest that FDHs could find many additional applications for atroposelective catalysis. More broadly, this study highlights how RebH can be engineered to accept structurally diverse substrates that enable its use for enantioselective catalysis.

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Biocatalytic oxidative cross-coupling reactions for biaryl bond formation

Cited by 112 publications

References 54 publications

A Streptomyces P450 enzyme dimerizes isoflavones from plants

A Streptomyces P450 enzyme dimerizes isoflavones from plants

Trendbericht Biochemie 2022: Späte Funktionalisierung mit Biokatalysatoren aus Naturstoffsynthesen

Directed Evolution of Flavin-Dependent Halogenases for Atroposelective Halogenation of 3-Aryl-4(3H)-quinazolinones via Kinetic or Dynamic Kinetic Resolution

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