Photobiocatalysis for Abiological Transformations

Harrison, Wesley; Huang, Xiaoqiang; Zhao, Huimin

doi:10.1021/acs.accounts.1c00719

Cited by 127 publications

(82 citation statements)

References 59 publications

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“…Thus, our evolved P450 atom-transfer radical cyclases provide a new means of taming radical intermediates for a synthetically valuable but underdeveloped class of asymmetric transformations. This metalloredox strategy is complementary to the elegant work of Hyster and Zhao on reductive C–C bond forming photoredox transformations using flavoenzymes, as the metallocofactor in our work allows redox-neutral atom-transfer reactions to proceed with excellent stereocontrol.…”

Section: Introductionmentioning

confidence: 90%

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Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity

Chen

et al. 2022

J. Am. Chem. Soc.

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New-to-nature radical biocatalysis has recently emerged as a powerful strategy to tame fleeting open-shell intermediates for stereoselective transformations. In 2021, we introduced a novel metalloredox biocatalysis strategy that leverages the innate redox properties of the heme cofactor of P450 enzymes, furnishing new-to-nature atom-transfer radical cyclases (ATRCases) with excellent activity and stereoselectivity. Herein, we report a combined computational and experimental study to shed light on the mechanism and origins of enantioselectivity for this system. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) calculations revealed an unexpected role of the key beneficial mutation I263Q. The glutamine residue serves as an essential hydrogen bond donor that engages with the carbonyl moiety of the substrate to promote bromine atom abstraction and enhance the enantioselectivity of radical cyclization. Therefore, the evolved ATRCase is a bifunctional biocatalyst, wherein the heme cofactor enables atom-transfer radical biocatalysis, while the hydrogen bond donor residue further enhances the activity and enantioselectivity. Unlike many enzymatic stereocontrol rationales based on a rigid substrate binding model, our computations demonstrate a high degree of rotational flexibility of the allyl moiety in an enzyme–substrate complex and succeeding intermediates. Therefore, the enantioselectivity is controlled by the radical cyclization transition states rather than the substrate orientation in ground-state complexes in the preceding steps. During radical cyclization, anchoring effects of the Q263 residue and steric interactions with the heme cofactor concurrently control the π-facial selectivity, allowing for highly enantioselective C–C bond formation. Our computational findings are corroborated by experiments with ATRCase mutants generated from site-directed mutagenesis.

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Section: Introductionmentioning

confidence: 90%

“…For a previous study using MM-GBSA calculations to analyze active site residue–substrate interactions, see: Ref .d.…”

mentioning

confidence: 99%

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity

Chen

et al. 2022

J. Am. Chem. Soc.

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“…Finally, the combined application of multiple methods or catalysts is similarly an effective way to solve the bottleneck of biocatalysis. Photoenzymatic catalysis 84 is a hot topic in recent years, and this approach to selective transformations using visible light can combine the advantages of biocatalysis and photocatalysis, including new reactivity, high stereoselectivity, green synthesis, and high yields. In addition, applications related to the combination of biocatalysis with electrocatalysis, i.e., bioelectrocatalysis, have been successively reported in recent years.…”

Section: Outlook and Conclusionmentioning

confidence: 99%

Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

Ding

Huang

et al. 2022

Pharmaceutical Fronts

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Multiple stereoisomers can be found when a substance contains chiral carbons in its chemical structure. To obtain the desired stereoisomers, asymmetric synthesis was proposed in the 1970s and developed rapidly at the beginning of this century. Stereodivergent synthesis, an extension of asymmetric synthesis in organic synthesis with the hope to produce all stereoisomers of chiral substances in high conversion and selectivity, enriches the variety of available products and serves as a reference suggestion for the synthesis of their derivatives and other compounds. Since biocatalysis has outstanding advantages of economy, environmental friendliness, high efficiency, and reaction at mild conditions, the biocatalytic reaction is regarded as an efficient strategy to perform stereodivergent synthesis. Thus, in this review, we summarize the stereodivergent synthesis catalyzed by enzymes or chemo-enzymes in cases where a compound contains two or three chiral carbons, i.e., at most four or eight stereoisomers are present. The types of reactions, including reduction of substituent ketones, cyclization reactions, olefin addition, and nonredox transesterification reactions, are also discussed for the understanding of the progress and application of biocatalysis in stereodivergent synthesis.

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“…[6][7][8][9][10][11][12][13] At the interface of these two fields of catalysis, photobiocatalysis arose, whereby either the enzyme itself requires light (naturally or by promiscuity) or photoinduced electrons are transferred to it. [14][15][16][17] The scope of photobiocatalytic transformations was significantly expanded following the discovery of fatty-acid photodecarboxylases in 2017. 18 This class of natural photoenzymes has subsequently shown great promise for the production of biofuels, [19][20][21][22] and apart from its natural substrates, fatty acids, the wild-type enzyme or its variants have been demonstrated to decarboxylate hydroxy-and amino-substituted fatty acids, 23,24 dicarboxylic acids, 25 α-substituted carboxylic acids 26 and the herbicide phosphinothricin.…”

Section: Introductionmentioning

confidence: 99%

Strategies for Transferring Photobiocatalysis to Continuous Flow Exemplified by the Photodecarboxylation of Fatty Acids

Simić

Jakštaitė

Huck

et al. 2022

Preprint

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The challenges of light-dependent biocatalytic transformations of lipophilic substrates in aqueous media are manifold. For instance, photolability of the catalyst as well as insufficient light penetration into the reaction vessel may be further exacerbated by a heterogeneously dispersed substrate. Light penetration may be addressed by performing the reaction in continuous flow, which allows two modes of applying the catalyst: (i) heterogenously, immobilized on a carrier, which requires light-permeable supports, or (ii) homogenously, dissolved in the reaction mixture. Taking the light-dependent photodecarboxylation of palmitic acid catalyzed by the fatty-acid photodecarboxylase from Chlorella variabilis (CvFAP) as a showcase, strategies for the transfer of a photoenzyme-catalyzed reaction into continuous flow were identified. A range of different supports was evaluated for the immobilization of CvFAP, whereby Eupergit C250 L was the carrier of choice. As the photostability of the catalyst was a limiting factor, a homogeneous system was preferred instead of employing the heterogenized enzyme. This implied that photolabile enzymes may preferably be applied in solution if repair mechanisms cannot be provided. Furthermore, when comparing different wavelengths and light intensities, extinction coefficients may be considered to ensure comparable absorption at each wavelength. Employing homogenous conditions in the CvFAP-catalyzed photodecarboxylation of palmitic acid afforded a space-time yield unsurpassed by any reported batch process (5.7 g/L·h, 26.9 mmol/L·h) for this reaction, demonstrating the advantage of continuous flow in attaining higher productivity of photobiocatalytic processes.

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Photobiocatalysis for Abiological Transformations

Abstract: This work applied photoexcitation of enzyme−substrate electron donor−acceptor complexes to expand the scope of abiological photobiocatalysis to intermolecular enantioselective transformations.

Cited by 127 publications

References 59 publications

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity

Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

Strategies for Transferring Photobiocatalysis to Continuous Flow Exemplified by the Photodecarboxylation of Fatty Acids

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