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Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-07-15 , DOI: 10.1021/acs.oprd.2c00179 Carlos A. Martinez 1 , Nicholas J. Turner 2 , Zhi Li 3
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-07-15 , DOI: 10.1021/acs.oprd.2c00179 Carlos A. Martinez 1 , Nicholas J. Turner 2 , Zhi Li 3
Affiliation
This article is part of the Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering special issue. Notable developments continue in expanding the enzymatic toolbox available to synthetic chemists and in the widespread use of enzyme engineering to enable the development of highly active, selective, and stable biocatalysts. For example, biocatalysis was recognized through the 2018 Nobel Prize in Chemistry awarded to Frances Arnold for pioneering the development of directed evolution methods for engineering of enzymes. It has been 8 years since Organic Process Research & Development presented a special feature in this field, following earlier issues in 2014, 2011, 2006, and 2002. Therefore, we are pleased to introduce this Special Issue entitled Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering. The collection features an assortment of review and research articles prepared by distinguished experts from both industry and academia across the world. David Hughes has been publishing useful and informative periodic reviews of the biocatalysis patent literature during the past few years. In this issue’s edition of his Highlights of the Recent Patent Literature, he highlights recent applications of imine reductase/reductive aminases, aldolases, and cascade reactions, among others (DOI: 10.1021/acs.oprd.1c00417). Accessing this literature is not always easy, particularly for academic groups, and his articles provide fascinating insight into where biocatalysis is being applied in industry. Phelan et al. (DOI: 10.1021/acs.oprd.1c00467) review applications of underutilized biocatalysts for the synthesis of chiral amines, sulfoxides, carboxylic acids, and amino acid analogues. They highlight the use of enzyme engineering to complement process engineering and reaction optimization, underscoring the gaps that exist in enabling scalable processes and the role that industry–academy collaborations play in closing such gaps. The use of engineering approaches to enhance biocatalyst properties in batch and flow systems often aids in the development of biocatalytic processes. Rocha et al. (DOI: 10.1021/acs.oprd.1c00424) highlight key elements of enzyme and reaction design, retrosynthetic planning, continuous flow, and multistep enzyme systems to enable the synthesis of complex targets. Photobiocatalysis is an emerging theme in the field of biocatalysis, and during the past 5 years it has been used to generate new reaction pathways for asymmetric synthesis. Peng et al. (DOI: 10.1021/acs.oprd.1c00413) provide a timely review of this nascent field of research with a focus on cofactor regeneration, in situ production of hydrogen peroxide, and cascades that incorporate photobiocatalysis. They also discuss recent work on photoactivated cofactor-dependent enzymes. Dynamic kinetic resolution (DKR) allows theoretical 100% conversion of a racemic substrate to an enantiopure product and thus has received special attention from industry. Many methodologies for DKR have been developed in the past decade. Yang et al. (DOI: 10.1021/acs.oprd.1c00463) review such developments since 2010, summarize chemoenzymatic and biocatalytic DKRs, and provide a special focus on the syntheses of enantiopure active pharmaceutical ingredients, including alcohols, amines, and carbonyl compounds. Immobilization of enzymes could enhance enzyme stability and reduce enzyme cost via recycling. The advances in nanotechnology and materials science have provided new technologies for enzyme immobilization. T.sriwong and Matsuda (DOI: 10.1021/acs.oprd.1c00404) review recent progress on enzyme immobilization using nanotechnology, including immobilization technologies on different nanomaterials such as organic–inorganic nanocrystals, metal–organic frameworks, graphene-based nanomaterials, and functionalized solid surfaces. Multienzymatic cascade applications are of great importance in the development of high-complexity synthetic precursors. Choo and Li (DOI: 10.1021/acs.oprd.1c00473) review the enzyme styrene oxide isomerase (SOI) and its applications in cascade biocatalysis. This enzyme catalyzes the isomerization of substituted styrene oxides and related epoxides (e.g., indene epoxide) to the corresponding aldehydes/ketones. The authors discuss various aspects including enzyme discovery, mechanism, substrate scope, and synthetic applications. Darunavir is one of the main therapies used to treat HIV-infected patients, particularly in the developing world. As with many antivirals, reducing the cost of manufacture is a key to providing wider access of the drug to low-income economies. Riehl et al. (DOI: 10.1021/acs.oprd.2c00017) report a novel biocatalytic synthesis of a key intermediate for darunavir using a ketoreductase (KRED) identified from a metagenomic panel. The KRED catalyzes a highly stereoselective DKR of a β-keto lactone intermediate enroute to darunavir. Williams et al. (DOI:10.1021/acs.oprd.1c00383) report the large-scale production of (R)-tetrahydrothiophene-3-ol in both batch and continuous flow by the use of an engineered and immobilized KRED derived fromAcetobacter pasteurianus. Under flow conditions, they were able to obtain an impressive space-time yield (STY) of 729 g L–1 day–1 with 64 h of continuous usage. In both batch and flow, the enantiomeric purity of the alcohol product was >99%. Metal affinity KRED immobilization for batch and flow processes is also reported by Basso et al. (DOI: 10.1021/acs.oprd.1c00483), who used acetophenone as model substrate and demonstrated biocatalyst recycling in batch for up to 10 cycles and coimmobilization of glucose dehydrogenase. The synthesis of chiral amines by transaminases is highlighted in three elegant articles. Li et al. (DOI: 10.1021/acs.oprd.1c00408) report an efficient biocatalytic resolution of a wide range of amines and the synthesis of d-alanine and d-homoalanine through a native transaminase operating at substrate concentrations as high as 0.8 M. Cai et al. (DOI: 10.1021/acs.oprd.1c00409) report an impressive transaminase engineered through multiple rounds, to operate in nearly 100% organic media, and demonstrated the synthesis of (R)-1-phenylethylamine in a flow reaction system with a high STY of 168 g L–1 day–1. Using a combination of rational design, iterative saturation mutagenesis, and random mutagenesis, Ma et al. (DOI: 10.1021/acs.oprd.1c00376) developed a synthesis of an enantiopure bulky amine precursor for rimegepant starting from a transaminase that was originally unable to catalyze the desired reaction on the target substrate. Imine reductases (IREDs) are the focus of a paper by Bernhard et al. (DOI: 10.1021/acs.oprd.1c00471), who report the process development of an IRED-catalyzed asymmetric reduction of 2-arylpyrrolines to generate the corresponding pyrrolidines. The authors show that an IRED from Cupriavidus sp. expressed in Escherichia coli can operate at a substrate concentration of 18 g/L and afford the product with 99% conversion and 99% ee in a final isolated yield of 91%. Several important papers on enzymatic oxidations are also included. Fe(II)/α-ketoglutarate-dependent dioxygenases (αKGDs) are attractive for regio- and stereoselective C–H functionalization of unactivated sp3-hybridized carbons to produce chiral products for pharmaceutical applications. By the use of a genome mining approach, Tassano et al. (DOI: 10.1021/acs.oprd.1c00405) developed new α-KGDs for selective oxidation of l-proline to generate the 3,4-epoxide and 3,4-diol as new oxidation products, achieving 40-fold higher titer than recombinant P450-mediated hydroxylations and expanding the αKGD enzyme family. Baeyer–Villiger monooxygenases (BVMOs) are another type of useful green oxidation catalysts. Many methods have been developed for immobilization of BVMOs to allow enzyme reuse and reduce process costs. As a new example, Zhu et al. (DOI: 10.1021/acs.oprd.1c00382) report the coimmobilization of BVMOs and formate dehydrogenase by the use of cross-linked enzyme aggregate (CLEA) technology and demonstrated enhanced enzyme thermostability and reuse of the enzyme over 15 cycles. Alcohol dehydrogenases (ADHs) are useful for kinetic resolution of racemic secondary alcohols. Biermann et al. (DOI: 10.1021/acs.oprd.1c00415) report the pilot-scale production of (R)-undecavertol, a useful fragrance ingredient, at more than 200 g L–1 with 98.8% ee and 49.7% conversion, achieved by kinetic resolution using an S-selective ADH for the oxidation and an NAD(P)H oxidase for cofactor regeneration. More than 85 kg of (R)-undecavertol was produced in three pilot-plant batches, and the STY reached 14 g L–1 h–1. The advantages of connecting two continuously stirred tank reactors (CSTRs) for the conversion of d-glucose to d-glucono-δ-lactone are presented by Lindeque and Woodley (DOI: 10.1021/acs.oprd.1c00429). The system results in a 3-fold improvement in conversion relative to the use of a single CSTR and a lower-cost contribution of the enzyme in the overall process. The enantioselective hydroxylation of 3-arylpropanenitriles using an engineered P450 monooxygenase is discussed in a report by Deng et al. (DOI: 10.1021/acs.oprd.1c00444), who demonstrated a broad range of substitutions in the aromatic ring and high enantioselectivity for the synthesis of aryl-substituted β-hydroxy nitriles. Spöring et al. (DOI: 10.1021/acs.oprd.1c00433) report a one pot, two-step cascade enabling the conversion of butanal to (4S,5S)-octanediol with excellent selectivity. The reaction includes an enzymatic carboligation and a subsequent enzymatic carbonyl reduction that is coupled to a cofactor recycling reaction using the same enzyme. The optimized conditions include a biphasic system for in situ product removal, enabling high volumetric productivity and a low-cost process. Corrado et al. (DOI: 10.1021/acs.oprd.1c00490) report the use of an enzyme cascade for the synthesis of high-value aromatic 1,2-amino alcohols. Starting from engineered enzymes and l-phenylalanine as a renewable material, the authors developed a two-pot, four-step sequential biocatalytic cascade for the conversion to (R)- or (S)-1-phenylethane-1,2-diols, which were used as starting materials in two subsequent and distinct one-pot biocatalytic cascades for the synthesis of either optically pure 2-phenylglycinol or phenylethanolamine. We hope that this issue and its contributions reflect the advances in the field since OPR&D’s last biocatalysis special issue. Biocatalysis solutions in process chemistry will no doubt continue to grow, and with the help of enzyme engineering as a key enabling technology, many novel biocatalytic systems should continue to be implemented on the industrial scale, thus enhancing the value of this technology in the development of environmentally sustainable processes. 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更新日期：2022-07-15
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