2023
DOI: 10.1021/acscatal.3c02746
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Building Enzymes through Design and Evolution

Euan J. Hossack,
Florence J. Hardy,
Anthony P. Green

Abstract: Designing efficient enzymes is a formidable challenge at the forefront of modern biocatalysis. Here, we review recent developments in the field and illustrate how the interplay between computational design and advanced protein engineering has given rise to enzymes with diverse activities. Natural proteins have been re-engineered computationally to embed designed catalytic sites, affording active catalysts that can be optimized through laboratory evolution to enhance efficiency and selectivity. Computational de… Show more

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Cited by 24 publications
(7 citation statements)
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“…The challenging, multi-step nature of MBH reactions will undoubtedly provide a rigorous examination of computational design methods. However, given the remarkable accuracy and speed enabled by modern deep-learning based protein design tools, we are optimistic that the design of de novo enzymes that recapitulate the catalytic features of engineered enzymes such as BH MeHis 1.8 could be within reach 35 .…”
Section: Discussionmentioning
confidence: 99%
“…The challenging, multi-step nature of MBH reactions will undoubtedly provide a rigorous examination of computational design methods. However, given the remarkable accuracy and speed enabled by modern deep-learning based protein design tools, we are optimistic that the design of de novo enzymes that recapitulate the catalytic features of engineered enzymes such as BH MeHis 1.8 could be within reach 35 .…”
Section: Discussionmentioning
confidence: 99%
“…Naturally occurring enzymes are evolved to catalyze various chemical reactions of biological importance with enhanced rates compared to the corresponding uncatalyzed reactions. However, natural enzymes cannot catalyze many chemical reactions of relevance in organic synthesis and industrial applications. , In this case, the strategy of computational design followed by directed evolution of proteins is applicable. , Evolution often results in proteins with catalytic mechanisms that are distinct from those present in the original design model, highlighting the complexities of predicting and designing optimal active site arrangements for performing new chemistries. , …”
Section: Introductionmentioning
confidence: 99%
“…6,7 Evolution often results in proteins with catalytic mechanisms that are distinct from those present in the original design model, highlighting the complexities of predicting and designing optimal active site arrangements for performing new chemistries. 8,9 One of the important organic transformations catalyzed only by synthetic proteins is the Morita−Baylis−Hillman (MBH) reaction. 10−12 This reaction is useful for C−C bond formation between an activated alkene and a carbon electrophile promoted by small nucleophilic catalysts such as DABCO (triethylenediamine), DMAP(4-dimethylaminopyridine), DBU (diazabicycloundecene), and imidazole.…”
Section: ■ Introductionmentioning
confidence: 99%
“…Biocatalysis is a rapidly evolving research field. As a result, biocatalysts such as enzymes can now be efficiently designed using genetic engineering and applied to a variety of highly selective reactions in aqueous solutions ( 1 , 2 ). The use of enzymes for high-performance liquid chromatography (HPLC) derivatization reactions has also been reported ( 3 ).…”
Section: Introductionmentioning
confidence: 99%