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Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs
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Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs

A special issue of Catalysts (ISSN 2073-4344). This special issue belongs to the section "Biocatalysis".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 22271

Special Issue Editors

Prof. Dr. Frank Schulz

E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, Ruhr-Universität Bochum, Bochum, Germany
Interests: microbial biosynthetic pathways; selective derivatization of polyketides; microbial and chemoenzymatic synthesis of terpenoids; enzyme engineering; metabolomics
Dr. Katrin Rosenthal

E-Mail Website
Guest Editor
Department of Biochemical and Chemical Engineering, Chair for Bioprocess Engineering, TU Dortmund University, Dortmund, Germany
Interests: enzymatic reaction cascades; biocatalytic process development; cell-free protein synthesis (CFPS); biotransformations in microfluidic systems; enzyme immobilization

Special Issue Information

Dear Colleagues,

Natural products are a constant source of new chemical entities that have always inspired fundamental biological and chemical research as well as medical and technological applications. In recent years, it has become increasingly feasible to access natural products or their analogues by using biocatalytic cascades. This subject is studied in whole cells as well as in cell-free systems, and experiments have been inspired by progress made in the fields of enzyme engineering, immobilization of enzymes, and flow chemistry.

In this Special Issue, we would like to illustrate the interaction of these disciplines. One focus will be on multistage enzymatic cascades, both in vitro and in whole cells.

Prof. Dr. Frank Schulz
Dr. Katrin Rosenthal
Guest Editors

Manuscript Submission Information

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Keywords

  • Enzyme cascades
  • Enzyme cascades in flow systems
  • Enzyme engineering
  • Immobilized enzymes
  • In vitro reconstruction of biosynthetic pathways
  • Cell-free metabolic engineering
  • Fermentation processes
  • Natural product biosynthesis
  • Derivatization of natural products

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Published Papers (6 papers)

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Research

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15 pages, 3742 KiB  
Article
Immobilization of the Amidohydrolase MxcM and Its Application for Biocatalytic Flow Synthesis of Pseudochelin A
by Lea Winand, Stefanie Theisen, Stephan Lütz, Katrin Rosenthal and Markus Nett
Catalysts 2023, 13(2), 229; https://doi.org/10.3390/catal13020229 - 18 Jan 2023
Cited by 2 | Viewed by 2292
Abstract
The chemical synthesis of heterocycles typically requires elevated temperature and acid or base addition to form the desired product. Moreover, these reactions often involve hazardous reagents, which is why biocatalytic routes for heterocycle formation have gained increasing attention. In recent years, several enzymes [...] Read more.
The chemical synthesis of heterocycles typically requires elevated temperature and acid or base addition to form the desired product. Moreover, these reactions often involve hazardous reagents, which is why biocatalytic routes for heterocycle formation have gained increasing attention. In recent years, several enzymes belonging to the amidohydrolase superfamily have been identified to generate heterocycles via cyclocondensation reactions. Of particular interest is the amidohydrolase MxcM, which catalyzes the formation of an imidazoline moiety in the biosynthesis of the anti-inflammatory natural product pseudochelin A. In this study, we present a concept for the immobilization of this enzyme using a fused hexahistidine tag for fixation onto a solid, porous carrier. Notably, the immobilization improves the enzyme’s tolerance to organic solvents. The immobilized MxcM exhibits a residual activity of 169% in the polar solvent acetonitrile compared to the free enzyme, and the storage stability in the presence of 20 vol% acetonitrile was ameliorated. In addition, an immobilized enzyme reactor (IMER) was designed that can be operated under flow conditions. The MxcM-IMER retains its biocatalytic activity and mechanic stability over the tested operation time. These results provide important insights for the integration of heterocycle-forming amidohydrolases in chemical processes. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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19 pages, 3716 KiB  
Article
Heterologous Lignan Production in Stirred-Tank Reactors—Metabolomics-Assisted Bioprocess Development for an In Vivo Enzyme Cascade
by Andrea Steinmann, Maurice Finger, Christian Nowacki, Davide Decembrino, Georg Hubmann, Marco Girhard, Vlada B. Urlacher and Stephan Lütz
Catalysts 2022, 12(11), 1473; https://doi.org/10.3390/catal12111473 - 18 Nov 2022
Cited by 2 | Viewed by 1856
Abstract
Towards establishing a prospective industrial microbial lignan production process, we set up and investigated the biotransformation of coniferyl alcohol to secoisolariciresinol with recombinant Escherichia coli in a stirred-tank reactor (STR). Initially, we tested different cofactor concentrations and antifoam additions in shake flasks. Next, [...] Read more.
Towards establishing a prospective industrial microbial lignan production process, we set up and investigated the biotransformation of coniferyl alcohol to secoisolariciresinol with recombinant Escherichia coli in a stirred-tank reactor (STR). Initially, we tested different cofactor concentrations and antifoam additions in shake flasks. Next, we designed an STR batch bioprocess and tested aeration rates, pH regulation, and substrate-feeding strategies. Targeted metabolomics of phenylpropanoids and lignans assisted the bioprocess development by monitoring the lignan pathway activity. We found that the copper concentration and the substrate-feeding strategy had considerable impact on lignan production. Furthermore, time-resolved monitoring of pathway metabolites revealed two maximal intracellular lignan concentrations, the first shortly after induction of gene expression and the second after the cells entered the stationary growth phase. During STR cultivation, a maximal intracellular titer of 130.4 mg L−1 secoisolariciresinol was achieved, corresponding to a yield coefficient of 26.4 mg g−1 and a space–time yield of 2.6 mg L−1 h−1. We report for the first time the in-depth evaluation of microbially produced lignans in a well-controlled STR bioprocess. Monitoring of the lignan pathway activity showed that lignan accumulation is highly dynamic during the cultivation and points towards the need for a more efficient coniferyl alcohol dimerization system for optimal microbial production conditions. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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20 pages, 2997 KiB  
Article
From Enzyme to Preparative Cascade Reactions with Immobilized Enzymes: Tuning Fe(II)/α-Ketoglutarate-Dependent Lysine Hydroxylases for Application in Biotransformations
by Selina Seide, Lilia Arnold, Solange Wetzels, Mariela Bregu, Jochem Gätgens and Martina Pohl
Catalysts 2022, 12(4), 354; https://doi.org/10.3390/catal12040354 - 22 Mar 2022
Cited by 7 | Viewed by 2787
Abstract
Fe(II)/α-ketoglutarate-dependent dioxygenases (KDOs) catalyze a broad range of selective C–H oxidation reactions. However, the difficult production of KDOs in recombinant E. coli strains and their instability in purified form have so far limited their application in preparative biotransformations. Here, we investigated the immobilization [...] Read more.
Fe(II)/α-ketoglutarate-dependent dioxygenases (KDOs) catalyze a broad range of selective C–H oxidation reactions. However, the difficult production of KDOs in recombinant E. coli strains and their instability in purified form have so far limited their application in preparative biotransformations. Here, we investigated the immobilization of three KDOs (CaKDO, CpKDO, FjKDO) that catalyze the stereoselective hydroxylation of the L-lysine side chain using two one-step immobilization techniques (HaloTag®, EziG™). The HaloTag®-based immobilisates reached the best results with respect to residual activity and stability. In preparative lab-scale experiments, we achieved product titers of 16 g L−1 (3S)-hydroxy-L-lysine (CaKDO) and (4R)-hydroxy-L-lysine (FjKDO), respectively, starting from 100 mM L-lysine. Using a HaloTag®-immobilized lysine decarboxylase from Selenomonas ruminantium (SrLDC), the (3S)-hydroxy-L-lysine from the CaKDO-catalyzed reaction was successfully converted to (2S)-hydroxy-cadaverine without intermediate product purification, yielding a product titer of 11.6 g L−1 in a 15 mL consecutive batch reaction. We propose that covalent in situ immobilization is an appropriate tool to access the preparative potential of many other KDOs. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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12 pages, 2024 KiB  
Article
Regioselective Enzymatic Synthesis of Kojic Acid Monoesters
by Klaudia Karkeszová, Mária Mastihubová and Vladimír Mastihuba
Catalysts 2021, 11(12), 1430; https://doi.org/10.3390/catal11121430 - 24 Nov 2021
Cited by 2 | Viewed by 2544
Abstract
Kojic acid is a fungal metabolite and one of the strongest tyrosinase inhibitors. Its esters are used as lipid-compatible skin whitening components in cosmetic formulations. In this study, lipase PS, lipase AK, Lipolyve AN and pig pancreatic lipase catalyzed the acetylation of kojic [...] Read more.
Kojic acid is a fungal metabolite and one of the strongest tyrosinase inhibitors. Its esters are used as lipid-compatible skin whitening components in cosmetic formulations. In this study, lipase PS, lipase AK, Lipolyve AN and pig pancreatic lipase catalyzed the acetylation of kojic acid under selective formation of the same product, kojic 7-acetate. However, the enzymes differed in their regioselectivity when catalyzing the alcoholysis of kojic acid diacetate. While lipase PS and lipase AK produced mixtures of both monoacetate regioisomers (7-acetate and 5-acetate of kojic acid), the pancreatic lipase almost exclusively produced 5-acetate. The enzyme displayed the same regioselectivity in the palmitoylation of kojic acid and in the alcoholysis of kojic acid dipalmitate. Simple reaction engineering with PPL as a catalyst thus provides the complementary monoesters of kojic acid. Kojic 7-acetate, 5-acetate, 7-palmitate and 5-palmitate were prepared with yields after purification of 57.3%, 38.2%, 31.7% and 31.4%, respectively. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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11 pages, 2682 KiB  
Article
Characterization of a Solvent-Tolerant Amidohydrolase Involved in Natural Product Heterocycle Formation
by Lea Winand, Dustin Joshua Vollmann, Jacqueline Hentschel and Markus Nett
Catalysts 2021, 11(8), 892; https://doi.org/10.3390/catal11080892 - 24 Jul 2021
Cited by 4 | Viewed by 2354
Abstract
Heterocycles are important building blocks in pharmaceutical drugs and their enzymatic synthesis is attracting increasing interest. In recent years, various enzymes of the amidohydrolase superfamily were reported to catalyze heterocycle-forming condensation reactions. One of these enzymes, MxcM, is biochemically and kinetically characterized in [...] Read more.
Heterocycles are important building blocks in pharmaceutical drugs and their enzymatic synthesis is attracting increasing interest. In recent years, various enzymes of the amidohydrolase superfamily were reported to catalyze heterocycle-forming condensation reactions. One of these enzymes, MxcM, is biochemically and kinetically characterized in this study. MxcM generates an imidazoline moiety in the biosynthesis of the natural product pseudochelin A, which features potent anti-inflammatory properties. The enzyme shows maximal activity at 50 °C and pH 10 as well as a kcat/Km value of 22,932 s−1 M−1 at its temperature optimum. Experimental data suggest that the activity of MxcM does not depend on a catalytic metal ion, which is uncommon among amidohydrolases. MxcM is highly active in diverse organic solvents and concentrated salt solutions. Furthermore, we show that MxcM is also capable to introduce imidazoline rings into derivatives of its natural substrate myxochelin B. Overall, MxcM is a solvent-stable, halotolerant enzyme with promising biochemical and kinetic properties and, in future, might become a valuable biocatalyst for the manufacturing of pharmaceutical drugs. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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Review

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24 pages, 1807 KiB  
Review
Getting the Most Out of Enzyme Cascades: Strategies to Optimize In Vitro Multi-Enzymatic Reactions
by Regine Siedentop, Christiane Claaßen, Dörte Rother, Stephan Lütz and Katrin Rosenthal
Catalysts 2021, 11(10), 1183; https://doi.org/10.3390/catal11101183 - 28 Sep 2021
Cited by 50 | Viewed by 8972
Abstract
In vitro enzyme cascades possess great benefits, such as their synthetic capabilities for complex molecules, no need for intermediate isolation, and the shift of unfavorable equilibria towards the products. Their performance, however, can be impaired by, for example, destabilizing or inhibitory interactions between [...] Read more.
In vitro enzyme cascades possess great benefits, such as their synthetic capabilities for complex molecules, no need for intermediate isolation, and the shift of unfavorable equilibria towards the products. Their performance, however, can be impaired by, for example, destabilizing or inhibitory interactions between the cascade components or incongruous reaction conditions. The optimization of such systems is therefore often inevitable but not an easy task. Many parameters such as the design of the synthesis route, the choice of enzymes, reaction conditions, or process design can alter the performance of an in vitro enzymatic cascade. Many strategies to tackle this complex task exist, ranging from experimental to in silico approaches and combinations of both. This review collates examples of various optimization strategies and their success. The feasibility of optimization goals, the influence of certain parameters and the usage of algorithm-based optimizations are discussed. Full article
(This article belongs to the Special Issue Enzyme-Catalyzed Approaches towards Natural Products and Their Analogs)
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