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Journal ArticleDOI

Peroxygenases en route to becoming dream catalysts. What are the opportunities and challenges

TL;DR: Peroxygenases are promising catalysts for preparative oxyfunctionalization chemistry as they combine the versatility of P450 monooxygenase with simplicity of cofactor-independent enzymes.
About: This article is published in Current Opinion in Chemical Biology.The article was published on 2017-04-01 and is currently open access. It has received 178 citations till now.
Citations
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Journal ArticleDOI
TL;DR: The most important recent developments in the field of biocatalytic oxidation chemistry are critically summarised and the most pressing bottlenecks as well as promising solutions are identified.
Abstract: Oxidation chemistry using enzymes is approaching maturity and practical applicability in organic synthesis. Oxidoreductases (enzymes catalysing redox reactions) enable chemists to perform highly selective and efficient transformations ranging from simple alcohol oxidations to stereoselective halogenations of non-activated C-H bonds. For many of these reactions, no "classical" chemical counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarise the most important recent developments in the field of biocatalytic oxidation chemistry and identify the most pressing bottlenecks as well as promising solutions.

302 citations

Journal ArticleDOI
20 Dec 2018
TL;DR: Significant advances in enzyme discovery, high-throughput screening and protein engineering have substantially expanded the available biocatalysts, and consequently, many more synthetic transformations are now possible, leading to greater predictability and confidence when scaling up these processes.
Abstract: The pharmaceutical industry, driven by an increasing need to deliver new and more effective medicines to patients, is increasingly turning to the use of engineered biocatalysts for both lead generation of active compounds and the sustainable manufacture of active pharmaceutical ingredients. Advances in enzyme discovery, high-throughput screening and protein engineering have substantially expanded the available biocatalysts, and consequently, many more synthetic transformations are now possible. Enzymes can be fine-tuned for practical applications with greater speed and likelihood of success than before, thereby leading to greater predictability and confidence when scaling up these processes. Coupled with a greater awareness of which reactions are suitable for biocatalysis (for example, biocatalytic retrosynthesis), new chemoenzymatic and multi-enzyme processes have been designed and applied to the synthesis of a range of important pharmaceutical target molecules. Increasingly, researchers are exploring opportunities for using immobilized biocatalysts in flow conditions. In this Review, we discuss some of the key drivers and scientific developments that are expanding the application of biocatalysis in the pharmaceutical industry and highlight potential future developments that likely will continue to increase the impact of biocatalysis in drug development. Engineered biocatalysts are increasingly being used for both the identification and manufacture of active pharmaceutical ingredients. Here, the authors review key developments that are expanding the use of biocatalysis in the pharmaceutical industry.

246 citations

Journal ArticleDOI
01 Jan 2018
TL;DR: It is shown that visible-light-driven, catalytic water oxidation can be used for in situ generation of H2O2 from water, rendering the peroxygenase catalytically active, allowing efficient oxyfunctionalization without stoichiometric reductants.
Abstract: Peroxygenases offer attractive means to address challenges in selective oxyfunctionalisation chemistry. Despite their attractiveness, the application of peroxygenases in synthetic chemistry remains challenging due to their facile inactivation by the stoichiometric oxidant (H2O2). Often atom inefficient peroxide generation systems are required, which show little potential for large scale implementation. Here we show that visible light-driven, catalytic water oxidation can be used for in situ generation of H2O2 from water, rendering the peroxygenase catalytically active. In this way the stereoselective oxyfunctionalisation of hydrocarbons can be achieved by simply using the catalytic system, water and visible light.

234 citations

Journal ArticleDOI
01 Aug 2021
TL;DR: In this paper, the authors provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of late-stage functionalization strategies to access new molecules of interest.
Abstract: Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

210 citations

Journal ArticleDOI
TL;DR: This Review is aimed at synthetic organic chemists who may be familiar with organometallic catalysis but have no experience with biocatalysis, and seeks to provide an answer to the perennial question: if it is so attractive, why wasn't it extensively used in the past?
Abstract: This Review is aimed at synthetic organic chemists who may be familiar with organometallic catalysis but have no experience with biocatalysis, and seeks to provide an answer to the perennial question: if it is so attractive, why wasn't it extensively used in the past? The development of biocatalysis in industrial organic synthesis is traced from the middle of the last century. Advances in molecular biology in the last two decades, in particular genome sequencing, gene synthesis and directed evolution of proteins, have enabled remarkable improvements in scope and substantially reduced biocatalyst development times and cost contributions. Additionally, improvements in biocatalyst recovery and reuse have been facilitated by developments in enzyme immobilization technologies. Biocatalysis has become eminently competitive with chemocatalysis and the biocatalytic production of important pharmaceutical intermediates, such as enantiopure alcohols and amines, has become mainstream organic synthesis. The synthetic space of biocatalysis has significantly expanded and is currently being extended even further to include new-to-nature biocatalytic reactions.

203 citations

References
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Journal ArticleDOI
10 May 2012-Nature
TL;DR: Applications of protein-engineered biocatalysts ranging from commodity chemicals to advanced pharmaceutical intermediates that use enzyme catalysis as a key step are discussed.
Abstract: Over the past ten years, scientific and technological advances have established biocatalysis as a practical and environmentally friendly alternative to traditional metallo- and organocatalysis in chemical synthesis, both in the laboratory and on an industrial scale. Key advances in DNA sequencing and gene synthesis are at the base of tremendous progress in tailoring biocatalysts by protein engineering and design, and the ability to reorganize enzymes into new biosynthetic pathways. To highlight these achievements, here we discuss applications of protein-engineered biocatalysts ranging from commodity chemicals to advanced pharmaceutical intermediates that use enzyme catalysis as a key step.

1,985 citations


"Peroxygenases en route to becoming ..." refers methods in this paper

  • ...We are convinced that applying the knowledge and techniques developed in this area during the past 20 years [62] will provide the chemist with selective and robust peroxygenases....

    [...]

Journal ArticleDOI
TL;DR: Various purification techniques for higher recovery of glucose oxidase are described here, and issues of enzyme kinetics, stability studies and characterization are addressed.

976 citations


"Peroxygenases en route to becoming ..." refers background in this paper

  • ...Today, the system glucose oxidase prevails due to its simplicity and the cheap, commercially available reagents [49]....

    [...]

Journal ArticleDOI
TL;DR: Emphasis is placed on the development of methods to make laboratory evolution faster and more efficient, thus providing chemists and biotechnologists with a rich and non-ending source of robust and selective catalysts for a variety of useful applications.
Abstract: Asymmetric catalysis plays a key role in modern synthetic organic chemistry, with synthetic catalysts and enzymes being the two available options. During the latter part of the last century the use of enzymes in organic chemistry and biotechnology experienced a period of rapid growth. However, these biocatalysts have traditionally suffered from several limitations, including in many cases limited substrate scope, poor enantioselectivity, insufficient stability, and sometimes product inhibition. During the last 15 years, the genetic technique of directed evolution has been developed to such an extent that all of these long-standing problems can be addressed and solved. It is based on repeated cycles of gene mutagenesis, expression, and screening (or selection). This Review focuses on the directed evolution of enantioselective enzymes, which constitutes a fundamentally new approach to asymmetric catalysis. Emphasis is placed on the development of methods to make laboratory evolution faster and more efficient, thus providing chemists and biotechnologists with a rich and non-ending source of robust and selective catalysts for a variety of useful applications.

468 citations


"Peroxygenases en route to becoming ..." refers background in this paper

  • ...However, to fully exploit its catalytic potential, access to mutants with tailored properties is mandatory [44,45]....

    [...]

Journal ArticleDOI
TL;DR: A short up-to-date overview of recent results on P450 engineering for technical applications including aspects of whole-cell biocatalysis with engineered recombinant enzymes and recently identified P450s with novel biotechnologically relevant properties are given.

441 citations

Journal ArticleDOI
TL;DR: It is seen that the fermentation yield in terms of final achievable cell concentration and expression level as well as the production scale are crucial for decreasing the total cost contribution of the biocatalyst.

395 citations