The Impact of Metagenomics on Biocatalysis DOI Creative Commons
Bethany N. Hogg, Christian Schnepel, James Finnigan

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(21)

Published: March 18, 2024

Abstract In the ever‐growing demand for sustainable ways to produce high‐value small molecules, biocatalysis has come forefront of greener routes these chemicals. As such, need constantly find and optimise suitable biocatalysts specific transformations never been greater. Metagenome mining shown rapidly expand toolkit promiscuous enzymes needed new transformations, without requiring protein engineering steps. If is needed, metagenomic candidate can often provide a better starting point than previously discovered enzyme on open database or from literature, instance. this review, we highlight where metagenomics made substantial impact area in recent years. We review discovery unexplored ‘hidden’ sequence space, leading characterisation with enhanced properties that originate natural selection pressures native environments.

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

438
Recent trends in biocatalysis DOI Creative Commons
Dong Yi, Thomas Bayer, Christoffel P. S. Badenhorst

et al.

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(14), P. 8003 - 8049

Published: Jan. 1, 2021

Technological developments enable the discovery of novel enzymes, advancement enzyme cascade designs and pathway engineering, moving biocatalysis into an era technology integration, intelligent manufacturing enzymatic total synthesis.

Language: Английский

Citations

282
Late-Stage Diversification of Natural Products DOI Creative Commons

Benke Hong,

Tuoping Luo, Xiaoguang Lei

et al.

ACS Central Science, Journal Year: 2020, Volume and Issue: 6(5), P. 622 - 635

Published: April 22, 2020

Late-stage diversification of natural products is an efficient way to generate product derivatives for drug discovery and chemical biology. Benefiting from the development site-selective synthetic methodologies, late-stage has achieved notable success. This outlook will outline selected examples novel methodologies transformations reactive functional groups inert C–H bonds that enable complex products. Accordingly, provides opportunity rapidly access various modifying lead compounds, identifying cellular targets, probing protein–protein interactions, elucidating biosynthetic relationships.

Language: Английский

Citations

275
Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods DOI Creative Commons
Stefan Simić,

Erna Zukić,

Luca Schmermund

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 122(1), P. 1052 - 1126

Published: Nov. 30, 2021

Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in half last century exploited whole-cell microorganisms where specific enzyme at work was not known. In meantime, novel molecular biology methods, such efficient gene sequencing and triggered breakthroughs directed evolution rapid development process-stable with broad substrate scope good selectivities tailored substrates. To date, are employed to enable shorter, more efficient, sustainable alternative routes toward (established) small molecule APIs, additionally used perform standard reactions API efficiently. Herein, large-scale synthetic containing key steps >130 APIs approved drugs drug candidates compared corresponding chemical protocols (if available) regarding steps, reaction conditions, scale. review is structured according functional group formed reaction.

Language: Английский

Citations

177
Iron- and cobalt-catalyzed C(sp3)–H bond functionalization reactions and their application in organic synthesis DOI
Yungen Liu,

Tingjie You,

Hai‐Xu Wang

et al.

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(15), P. 5310 - 5358

Published: Jan. 1, 2020

This review highlights the developments in iron and cobalt catalyzed C(sp3)–H bond functionalization reactions with emphasis on their applications organic synthesis, i.e. natural products pharmaceuticals synthesis and/or modification.

Language: Английский

Citations

160
Enzymatic Late‐Stage Modifications: Better Late Than Never DOI Creative Commons
Elvira Romero, Bethan S. Jones, Bethany N. Hogg

et al.

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(31), P. 16824 - 16855

Published: Jan. 16, 2021

Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means bioinformatics and enzyme engineering opens up an immense variety selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven be useful direct introduction functional groups into complex scaffolds, as well rapid diversification compound libraries. Particularly important highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, amide bond formations due high prevalence these motifs pharmaceuticals. This Review gives overview strengths limitations enzymatic modifications using native engineered enzymes synthesis while focusing on examples drug development.

Language: Английский

Citations

116
Late-stage Functionalization for Improving Drug-like Molecular Properties DOI

Nathan J. Castellino,

Andrew P. Montgomery, Jonathan J. Danon

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(13), P. 8127 - 8153

Published: June 7, 2023

The development of late-stage functionalization (LSF) methodologies, particularly C–H functionalization, has revolutionized the field organic synthesis. Over past decade, medicinal chemists have begun to implement LSF strategies into their drug discovery programs, allowing for process become more efficient. Most reported applications drugs and drug-like molecules been rapidly diversify screening libraries explore structure–activity relationships. However, there a growing trend toward use methodologies as an efficient tool improving molecular properties promising candidates. In this review, we comprehensively reviewed recent progress in emerging area. Particular emphasis is placed on case studies where multiple techniques were implemented generate library novel analogues with improved properties. We critically analyzed current scope improve commented how believe can transform future. Overall, aim provide comprehensive survey tools efficiently properties, anticipating its continued uptake programs.

Language: Английский

Citations

99
Learning from Protein Engineering by Deconvolution of Multi‐Mutational Variants DOI Creative Commons
Frank Hollmann,

Joaquin Sanchis,

Manfred T. Reetz

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(36)

Published: June 17, 2024

Abstract This review analyzes a development in biochemistry, enzymology and biotechnology that originally came as surprise. Following the establishment of directed evolution stereoselective enzymes organic chemistry, concept partial or complete deconvolution selective multi‐mutational variants was introduced. Early experiments led to finding mutations can interact cooperatively antagonistically with one another, not just additively. During past decade, this phenomenon shown be general. In some studies, molecular dynamics (MD) quantum mechanics/molecular mechanics (QM/MM) computations were performed order shed light on origin non‐additivity at all stages an evolutionary upward climb. Data used construct unique multi‐dimensional rugged fitness pathway landscapes, which provide mechanistic insights different from traditional landscapes. Along related line, biochemists have long tested result introducing two point enzyme for reasons, followed by comparison respective double mutant so‐called cycles, showed only additive effects, but more recently also uncovered cooperative antagonistic non‐additive effects. We conclude suggestions future work, call unified overall picture epistasis.

Language: Английский

Citations

18
Natural Compounds as Pharmaceuticals: The Key Role of Cytochromes P450 Reactivity DOI
Giovanna Di Nardo, Gianfranco Gilardi

Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 45(6), P. 511 - 525

Published: April 5, 2020

Language: Английский

Citations

96
P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation DOI Creative Commons
Nico D. Fessner

ChemCatChem, Journal Year: 2019, Volume and Issue: 11(9), P. 2226 - 2242

Published: Jan. 24, 2019

The biological potency of natural products has been exploited for decades. Their inherent structural complexity and diversity might hold the key to efficiently address urgent need development novel pharmaceuticals. At same time, it is that very complexity, which impedes necessary chemical modifications such as diversification, improve effectiveness drug. For this purpose, Cytochrome P450 enzymes, possess unique abilities activate inert sp

Language: Английский

Citations

91