New catalytic reactions by enzyme engineering

Klaus, Cindy; Hammer, Stephan C.

doi:10.1016/j.trechm.2022.03.002

Cited by 18 publications

(9 citation statements)

References 13 publications

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“…In recent years, some efforts have been made to explore the specific properties of nanomaterials in regulating the original biological activity of enzymes to discover their different catalytic functions from those of native ones. [22][23][24][25][26][27] Therefore, we wondered whether a cell could be endowed with a new catalytic function under the mediation of intracellular bionic semiconducting nanoparticles. Here, bionic nanominerals can not only capture light and produce photoelectrons, but can also induce enzymes to catalyse new reactions.…”

Section: Introductionmentioning

confidence: 99%

Endowing cells with unnatural photocatalytic ability for sustainable chemicals production by bionic minerals-triggering

et al. 2023

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Section: Introductionmentioning

confidence: 99%

Endowing cells with unnatural photocatalytic ability for sustainable chemicals production by bionic minerals-triggering

et al. 2023

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“…Enzymes serve as exceptional catalysts for asymmetric synthesis, thanks to their remarkable ability to achieve precise stereocontrol in complex chemical reactions. Their applications range from small-scale synthesis to large-scale industrial manufacturing. − By repurposing naturally occurring enzymatic machinery, the utilization of non-natural chemistries holds the potential to broaden the range of reactions in biocatalysis. − …”

Section: Introductionmentioning

confidence: 99%

Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases

Capone,

Dell’Orletta,

Nicholls

et al. 2023

ACS Catal.

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We demonstrate here through molecular simulations and mutational studies the origin of the enantioselectivity in the photoinduced radical cyclization of α-chloroacetamides catalyzed by ene-reductases, in particular the Gluconobacter oxidans ene-reductase and the Old Yellow Enzyme 1, which show opposite enantioselectivity. Our results reveal that neither the π-facial selectivity model nor a protein-induced selective stabilization of the transition states is able to explain the enantioselectivity of the radical cyclization in the studied flavoenzymes. We propose a new enantioinduction scenario according to which enantioselectivity is indeed controlled by transition-state stability; however, the relative stability of the prochiral transition states is not determined by direct interaction with the protein but is rather dependent on an inherent degree of freedom within the substrate itself. This intrinsic degree of freedom, distinct from the traditional π-facial exposure mode, can be controlled by the substrate conformational selection upon binding to the enzyme.

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“…However, compared to the immensely diverse range of organic reactions discovered and optimized by synthetic chemists, only a small subset of these reactivity patterns is found in natural enzymology and is currently being utilized by biocatalysis practitioners, thus imposing a major limitation on the utility of contemporary enzyme technologies. The implementation of unnatural chemistries by repurposing naturally existing enzymatic machineries promises to expand the reaction space of biocatalysis, thereby significantly augmenting the synthetic chemist’s toolbox …”

Section: Introductionmentioning

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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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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New catalytic reactions by enzyme engineering

Cited by 18 publications

References 13 publications

Endowing cells with unnatural photocatalytic ability for sustainable chemicals production by bionic minerals-triggering

Endowing cells with unnatural photocatalytic ability for sustainable chemicals production by bionic minerals-triggering

Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases

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

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