Redesigning Enzymes for Biocatalysis: Exploiting Structural Understanding for Improved Selectivity DOI Creative Commons
Yaoyu Ding, Gustavo Pérez-Ortíz, Jessica Peate

et al.

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: July 22, 2022

The discovery of new enzymes, alongside the push to make chemical processes more sustainable, has resulted in increased industrial interest use biocatalytic produce high-value and chiral precursor chemicals. Huge strides protein engineering methodology silico tools have facilitated significant progress production enzymes for processes. However, there are gaps our knowledge relationship between enzyme structure function. This demonstrated need improved computational methods model mechanisms understand dynamics. Here, we explore efforts rationally modify toward changing aspects their catalyzed chemistry. We highlight examples where links function been made, thus enabling rational changes give predictable outcomes. look at future directions field could take technologies that will enable it.

Language: Английский

Biocatalysis DOI Open Access
Elizabeth L. Bell, William Finnigan, Scott P. France

et al.

Nature Reviews Methods Primers, Journal Year: 2021, Volume and Issue: 1(1)

Published: June 24, 2021

Language: Английский

Citations

439
Biocatalysis as Key to Sustainable Industrial Chemistry DOI
Andrés R. Alcántara, Pablo Domı́nguez de Marı́a, Jennifer A. Littlechild

et al.

ChemSusChem, Journal Year: 2022, Volume and Issue: 15(9)

Published: March 3, 2022

The role and power of biocatalysis in sustainable chemistry has been continuously brought forward step by to its present outstanding position. problem-solving capabilities have realized numerous substantial achievements biology, engineering. Advances breakthroughs the life sciences interdisciplinary cooperation with clearly accelerated implementation biocatalytic synthesis modern chemistry. Resource-efficient manufacturing processes already provided benefits as well customer-centric value creation pharmaceutical, food, flavor, fragrance, vitamin, agrochemical, polymer, specialty, fine chemical industries. Biocatalysis can make significant contributions not only processes, but also design completely new value-creation chains. now be considered a key enabling technology implement

Language: Английский

Citations

102
De novo metalloprotein design DOI
Matthew J. Chalkley, Samuel I. Mann, William F. DeGrado

et al.

Nature Reviews Chemistry, Journal Year: 2021, Volume and Issue: 6(1), P. 31 - 50

Published: Dec. 6, 2021

Language: Английский

Citations

84
Dual-function enzyme catalysis for enantioselective carbon–nitrogen bond formation DOI
Zhen Liu, Carla Calvó‐Tusell, Andrew Zhou

et al.

Nature Chemistry, Journal Year: 2021, Volume and Issue: 13(12), P. 1166 - 1172

Published: Oct. 18, 2021

Language: Английский

Citations

69
An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes DOI
Zhen Liu,

Ziyang Qin,

Ledong Zhu

et al.

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 144(1), P. 80 - 85

Published: Dec. 23, 2021

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp3)–H insertion. However, achieving this reaction good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform amination alkynes using a hydroxylamine derivative as precursor. Cytochrome P450 variant PA-G8 catalyzing transformation was identified after eight rounds directed evolution. A variety 1-aryl-2-alkyl accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process selective (up 2610 total turnover number (TTN) 96% ee) can performed on preparative scale.

Language: Английский

Citations

61
Enantioselective Synthesis of α-Trifluoromethyl Amines via Biocatalytic N–H Bond Insertion with Acceptor-Acceptor Carbene Donors DOI Creative Commons
Donggeon Nam, Antonio Tinoco, Zhuofan Shen

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(6), P. 2590 - 2602

Published: Feb. 2, 2022

The biocatalytic toolbox has recently been expanded to include enzyme-catalyzed carbene transfer reactions not occurring in Nature. Herein, we report the development of a strategy for synthesis enantioenriched α-trifluoromethyl amines through an asymmetric N-H insertion reaction catalyzed by engineered variants cytochrome c552 from Hydrogenobacter thermophilus. Using combination protein and substrate engineering, this metalloprotein scaffold was redesigned enable chiral amino esters with up >99% yield 95:5 er using benzyl 2-diazotrifluoropropanoate as donor. When diazo reagent varied, enantioselectivity enzyme could be inverted produce opposite enantiomers these products 99.5:0.5 er. This methodology is applicable broad range aryl amine substrates, it can leveraged obtain chemoenzymatic access β-trifluoromethyl-β-amino alcohols halides. Computational analyses provide insights into interplay protein- reagent-mediated control on reaction. work introduces first example carbenoid acceptor-acceptor donor, offers solution enantioselective α-trifluoromethylated valuable synthons medicinal chemistry bioactive molecules.

Language: Английский

Citations

54
Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement DOI
David C. Miller,

Ravi Lal,

Luca Marchetti

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(11), P. 4739 - 4745

Published: March 8, 2022

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity engineered "carbene transferase" enzymes. A laboratory-evolved variant cytochrome P450BM3, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over [1,2]-Stevens rearrangement but also overrides the inherent reactivity aziridinium ylides, cheletropic extrusion olefins, perform rearrangement. By controlling fate highly reactive ylide intermediates, these evolvable biocatalysts promote transformation which cannot currently be performed using other catalyst classes.

Language: Английский

Citations

53
Complete integration of carbene-transfer chemistry into biosynthesis DOI
Jing Huang, Andrew F. G. Quest, Pablo Cruz‐Morales

et al.

Nature, Journal Year: 2023, Volume and Issue: 617(7960), P. 403 - 408

Published: May 3, 2023

Language: Английский

Citations

34
Enlightening the Path to Protein Engineering: Chemoselective Turn-On Probes for High-Throughput Screening of Enzymatic Activity DOI Creative Commons
Sebastian Hecko, Astrid Schiefer, Christoffel P. S. Badenhorst

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(6), P. 2832 - 2901

Published: Feb. 28, 2023

Many successful stories in enzyme engineering are based on the creation of randomized diversity large mutant libraries, containing millions to billions variants. Methods that enabled their evaluation with high throughput dominated by spectroscopic techniques due speed and sensitivity. A proportion studies relies fluorogenic substrates mimic chemical properties target or coupled enzymatic assays an optical read-out assesses desired catalytic efficiency indirectly. The most reliable hits, however, achieved screening for conversions starting material product. For this purpose, functional group offer a general approach achieve fast, read-out. They use chemoselectivity, differences electronic steric various groups, reduce number false-positive results analytical noise stemming from background activities. This review summarizes developments probes chemoselective derivatizations, clear focus activity protein engineering.

Language: Английский

Citations

23
Multifunctional Biocatalysts for Organic Synthesis DOI Creative Commons
Thomas W. Thorpe, James R. Marshall, Nicholas J. Turner

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(12), P. 7876 - 7884

Published: March 15, 2024

Biocatalysis is becoming an indispensable tool in organic synthesis due to high enzymatic catalytic efficiency as well exquisite chemo- and stereoselectivity. Some biocatalysts display great promiscuity including a broad substrate scope the ability catalyze more than one type of transformation. These promiscuous activities have been applied individually efficiently access numerous valuable target molecules. However, systems which enzymes possessing multiple different are less developed. Such multifunctional (MFBs) would simplify chemical by reducing number operational steps enzyme count, simplifying sequence space that needs be engineered develop efficient biocatalyst. In this Perspective, we highlight recently reported MFBs focusing on their synthetic utility mechanism. We also offer insight into origin comment potential strategies for discovery engineering.

Language: Английский

Citations

10