Enzyme immobilization has been developing since the 1960s and although many industrial biocatalytic processes use the technology to improve enzyme performance, still today we are far from full exploitation of the field. One clear reason is that many evaluate immobilization based on only a few experiments that are not always well-designed. In contrast to many other reviews on the subject, here we highlight the pitfalls of using incorrectly designed immobilization protocols and explain why in many cases sub-optimal results are obtained. We also describe solutions to overcome these challenges and come to the conclusion that recent developments in material science, bioprocess engineering and protein science continue to open new opportunities for the future. In this way, enzyme immobilization, far from being a mature discipline, remains as a subject of high interest and where intense research is still necessary to take full advantage of the possibilities.

Is enzyme immobilization a mature discipline? Some critical considerations to capitalize on the benefits of immobilization.

Biocatalysis harnesses enzymes to make valuable products. This green technology is used in countless applications from bench scale to industrial production and allows practitioners to access complex organic molecules, often with fewer synthetic steps and reduced waste. The last decade has seen an explosion in the development of experimental and computational tools to tailor enzymatic properties, equipping enzyme engineers with the ability to create biocatalysts that perform reactions not present in nature. By using (chemo)-enzymatic synthesis routes or orchestrating intricate enzyme cascades, scientists can synthesize elaborate targets ranging from DNA and complex pharmaceuticals to starch made in vitro from CO2-derived methanol. In addition, new chemistries have emerged through the combination of biocatalysis with transition metal catalysis, photocatalysis, and electrocatalysis. This review highlights recent key developments, identifies current limitations, and provides a future prospect for this rapidly developing technology. Description Editor’s summary As nature’s catalysts, enzymes are adaptable, specific, and interoperable. There have been important advances in the identification of transformations catalyzed by enzymes, and new methods have been developed for identifying, engineering, or creating de novo suitable enzymes for a wide range of applications. In a review, Buller et al. collect this recent progress in biocatalysis research and look ahead toward increasing the use of computational tools, accelerating design test cycles, and expanding chemistry beyond what is familiar in nature. Engineered enzymes provide a green chemistry solution to the synthesis of complex organic molecules and can be used in the degradation of waste plastic and chemicals. —Michael A. Funk Engineered enzymes provide a green chemistry solution for synthesis of complex molecules. BACKGROUND Biocatalysis is an approach to synthetic chemistry in which enzymes carry out chemical reactions. Historically, enzymes from natural sources have been used to break down oils and proteins in laundry detergents, produce semisynthetic antibiotics, and create simple chiral precursors for the pharmaceutical industry. In the past 5 years, the number of available protein sequences has increased by a staggering 20-fold, accelerating the discovery of enzymes with useful activities and properties. Directed evolution, the cornerstone of our ability to tailor enzymatic properties, is allowing researchers to tailor enzymes for the synthesis of complex molecules, the modification of biological therapeutics, and the breakdown of plastic waste. Machine learning–driven protein-structure prediction, coupled with advances in automation and high-throughput screening, is further advancing our ability to create enzymes with desired function. The ability to add nonbiological catalytic elements to enzymes means that enzyme engineers no longer have to rely solely on natural catalytic machinery. Scientists have thus gained the capacity to redesign, reimagine, and repurpose enzymes. Illustrative applications include enzyme cascades to manufacture the antivirals islatravir and molnupiravir, biocatalysts that can generate and control radicals, and enzymes that exploit photocatalysis to affect stereocontrolled C–C couplings, hydroaminations, or Diels-Alder reactions. ADVANCES The past 5 years have witnessed a surge in the development of data-driven tools enabling the accelerated discovery, engineering, and deployment of enzymes for applications in chemistry, medicine, and food technology. By leveraging enzymes’ ability to control the environment of a chemical reaction, scientists have developed successful platforms for the construction of complex small molecules from suitable starting materials or even CO2. In addition to their use in (chemo)-enzymatic cascade reactions, precisely tailored biocatalysts can manufacture new therapeutic modalities, such as antisense oligonucleotide therapeutics, and bioconjugates. DNA synthesis, which still relies on phosphoramidite chemistry, is being reinvented with template-independent deoxynucleotidyl transferases to make the process faster and cheaper. Machine learning, already dominating protein-structure prediction and design, is finding applications in enzyme engineering, including improvement of functions such as enantioselectivity, activity, and stability. OUTLOOK In the decade ahead, biocatalysis research and applications will continue to profit from advances in data mining, machine learning, and DNA reading and writing. The combinatorial design of enzymes and the ease with which new enzyme variants can be experimentally generated lends itself to train data-intense machine-learning algorithms. Ideally, the sequence-function data of variants screened in a directed-evolution campaign could be used to predict which variants to evaluate next. Machine learning works best with clean and reproducible data, mandating the standardization and reporting of data and the further development of experimental techniques, including molecular biology methods, automation, and high-throughput screening assays. The toolbox of drug discovery is expanding beyond traditional small molecules (molecular weights <500 g/mol) to include RNA therapeutics, protein degraders, cyclopeptides, antibody drug conjugates, and gene therapy. Consequently, the synthetic complexity of lead molecules and clinical candidates is increasing with a growing percentage of chiral and beyond-rule-of-5 molecules. Enzymatic synthesis will play a key role beyond its present impact in small-molecule drug discovery and development. The discovery of new enzyme families and the rational design of new enzyme functions will expand the toolbox of available biocatalysts. Development and deployment of retrosynthetic tools containing enzymatic reactions will be an important step toward democratizing biocatalysis and making it available to the nonexpert. Fueled by these innovations, nature’s catalysts will be profitably used to address current challenges, including the fight against diseases, provision of affordable clean energy, and reduction of industrial and consumer waste. The accelerating development of biocatalysis. In silico and experimental tools developed in the last decade allow the fast creation of tailored enzymes. In addition to the concise synthesis of complex small molecules in elegant (chemo)-enzymatic cascades, newly accessible applications include enzymatic DNA synthesis, the generation of therapeutic oligonucleotides, and up- and recycling of plastic waste. [Figure created with Canva]

From nature to industry: Harnessing enzymes for biocatalysis

The E Factor at 30: A Passion for Pollution Prevention

Invited for this month's cover is the Working Group Sustainable Chemistry of the European Society of Applied Biocatalysis (ESAB). The image shows the significant contributions of Biocatalysis to science, industry, society, and environment as a technology of first choice for Sustainable Chemistry in the 21st century. The Perspective itself is available at 10.1002/cssc.202102709.

Biocatalysis as Key to Sustainable Industrial Chemistry.

Molnupiravir (Lagevrio®) is an orally-administered antiviral prodrug that inhibits replication of RNA viruses through viral error induction. It is being developed by Merck and Ridgeback Biotherapeutics for the prevention and treatment of Coronavirus disease 2019 (COVID-19). Molnupiravir received its first approval on 4 November 2021 in the UK for the treatment of mild to moderate COVID-19 in adults with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic test and who have at least one risk factor for developing severe illness. Molnupiravir is filed for approval and has emergency use authorization for the treatment of COVID-19 in several countries, including the USA, Japan and those in the EU. This article summarizes the milestones in the development of molnupiravir leading to this first approval for COVID-19. 

/pdf/molnupiravir-first-approval-1y8odhqg.pdf

Molnupiravir: First Approval

Molnupiravir (MK-4482) is an investigational antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand and urgency for this compound, it was critical to develop a short and sustainable synthesis from simple raw materials that would minimize the time needed to manufacture and supply molnupiravir. The route reported here is enabled through the invention of a novel biocatalytic cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase. These engineered enzymes were deployed with a pyruvate-oxidase-enabled phosphate recycling strategy. Compared to the initial route, this synthesis of molnupiravir is 70% shorter and approximately 7-fold higher yielding. Looking forward, the biocatalytic approach to molnupiravir outlined here is anticipated to have broad applications for streamlining the synthesis of nucleosides in general. © 2021 The Authors. Published by American Chemical Society.

Engineered ribosyl-1-kinase enables concise synthesis of molnupiravir, an antiviral for covid-19

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Engineered ribosyl-1-kinase enables concise synthesis of molnupiravir, an antiviral for covid-19