Chemoenzymatic synthesis

Articles

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  H₂-driven biocatalysis for flavin-dependent ene-reduction in a continuous closed-loop flow system utilizing H₂ from water electrolysis

  Flavin-based biocatalysis using flavin mononucleotide (FMN) cofactor attracts significant attention for its application in asymmetric alkene reduction and various other reactions, however, the scale-up of flavin-based biocatalysis in flow remains unexplored. Here, the authors develop a closed-loop flow platform for H₂-driven regeneration of cofactor FMNH₂ and ene-reduction using immobilized Old Yellow Enzyme, achieving >99% conversion of ketoisophorone to levodione.

  • Guiyeoul Lim
  • Donato Calabrese
  • Lars Lauterbach

  ArticleOpen Access7 Sep 2024 Communications Chemistry
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  The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds

  Modular polyketide synthases (PKSs) play a vital role in the biosynthesis of complex natural products with pharmaceutically relevant properties, and their modular architecture makes them an attractive target for engineering to produce platform chemicals and drugs. In this study, the authors demonstrate that the promiscuous malonyl/acetyl-transferase domain (MAT) from murine fatty acid synthase serves as a highly versatile tool for the production of polyketide analogs.

  • Lynn Buyachuihan
  • Simon Reiners
  • Martin Grininger

  ArticleOpen Access24 Aug 2024 Communications Chemistry
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  Enzymatic synthesis of mono- and trifluorinated alanine enantiomers expands the scope of fluorine biocatalysis

  Establishing biotechnological alternatives to chemical syntheses requires the rational design of biosynthetic pathways and degradation routes either as enzymatic cascades in vitro or as part of living organisms. Here, the authors use alanine dehydrogenase from Vibrio proteolyticus and the diaminopimelate dehydrogenase from Symbiobacterium thermophilum for the in vitro production of (R) and (S)-3-fluoroalanine, reaching >85% yield with complete enantiomeric excess.

  • Manuel Nieto-Domínguez
  • Aboubakar Sako
  • Pablo I. Nikel

  ArticleOpen Access9 May 2024 Communications Chemistry
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  Design of a recombinant asparaginyl ligase for site-specific modification using efficient recognition and nucleophile motifs

  Asparaginyl ligases have been utilized as valuable tools for protein engineering, such as through site-specific bioconjugation or surface modification, however, their application is limited due to time-consuming preparation processes and unstable activities. Here, the authors develop a truncated protein ligase OaAEP1-C247A-aa55-351 from an OaAEP1-C247A mutant, which simplifies the preparation steps, tolerates a wider pH range, and enhances the catalytic activities by using efficient recognition and nucleophile motifs.

  • Jiabao Tang
  • Mengling Hao
  • Ningshao Xia

  ArticleOpen Access18 Apr 2024 Communications Chemistry
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  Combinatorial biosynthesis for the engineering of novel fungal natural products

  Combinatorial biosynthesis of natural products is a method to synthesize structurally diverse molecules with defined modifications. Here, the authors review the various approaches used for combinatorial biosynthesis of fungal natural products by engineering biosynthetic enzymes and pathways to generate novel molecules.

  • Elizabeth Skellam
  • Sanjeevan Rajendran
  • Lei Li

  Review ArticleOpen Access18 Apr 2024 Communications Chemistry
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  Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase

  Norcoclaurine synthase from Thalictrum flavum (TfNCS) has been demonstrated to display high stereospecificity and yield in catalyzing the Pictet-Spengler reaction of dopamine with chiral aldehydes, however, the mechanism and factors related to this high stereospecificity remain unclear. Here, the authors conduct quantum chemical calculations and reveal the rate-limiting step and differential energy barriers for the reactions of two enantiomers of α-methylphenylacetaldehyde, as well as key residues related to stereospecificity.

  • Shiqing Zhang
  • Chenghua Zhang
  • Xiang Sheng

  ArticleOpen Access27 Mar 2024 Communications Chemistry
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  Chemoenzymatic tandem cyclization for the facile synthesis of bicyclic peptides

  Bicyclic peptides exhibit improved metabolic stabilities, membrane permeabilities, and target specificities over their linear and mono-cyclic counterparts, however, efficient bicyclization remains challenging. Here, the authors develop a one-pot tandem chemoenzymatic bicyclization by combination of penicillin-binding protein-type thioesterase-mediated head-to-tail macrolactamization and copper(I)-catalyzed azide–alkyne cycloaddition.

  • Masakazu Kobayashi
  • Naho Onozawa
  • Toshiyuki Wakimoto

  ArticleOpen Access28 Mar 2024 Communications Chemistry
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  Transaminase-catalysis to produce trans-4-substituted cyclohexane-1-amines including a key intermediate towards cariprazine

  Stereoselective production of trans-4-substituted cyclohexane-1-amines—including a key intermediate in the synthesis of antipsychotic drug cariprazine—remains challenging. Here, the authors develop a process catalyzed by a single transaminase to produce trans-4-substituted cyclohexane-1-amines from the corresponding cis/trans-diastereomeric mixtures via a cis-deamination approach in continuous-flow, to achieve a dynamic cis-to-trans isomerization.

  • Emese Farkas
  • Péter Sátorhelyi
  • János Éles

  ArticleOpen Access18 Apr 2024 Communications Chemistry
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  Integrated preservation of water activity as key to intensified chemoenzymatic synthesis of bio-based styrene derivatives

  Lignin-derived phenolic acids can be upgraded to styrene derivatives through chemoenzymatic processes, however, the scale-up of such processes remains challenging. Here, the authors find that controlling the water activity during the decarboxylation of bio-based phenolic acids, including through the integration of a water reservoir, enables high conversions and efficient reaction times, that can be combined with a versatile acyl donor substrate scope.

  • Philipp Petermeier
  • Jan Philipp Bittner
  • Selin Kara

  ArticleOpen Access14 Mar 2024 Communications Chemistry
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  Effective engineering of a ketoreductase for the biocatalytic synthesis of an ipatasertib precursor

  Ipatasertib is a potent Akt (protein kinase B) inhibitor synthesized via a chemoenzymatic process. Here, the authors use mutational scanning and algorithm-aided enzyme engineering to optimize a ketoreductase from Sporidiobolus salmonicolor and generate a 10-amino acid substituted variant exhibiting a 64-fold higher k_cat and improved yield for the relevant alcohol intermediate, with ≥ 98% conversion and a diastereomeric excess of 99.7% (R,R-trans) from 100 g L⁻¹ ketone after 30 h.

  • Sumire Honda Malca
  • Nadine Duss
  • Rebecca Buller

  ArticleOpen Access28 Feb 2024 Communications Chemistry
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  Chemoenzymatic total synthesis of sorbicillactone A

  Sorbicillactone A is a nitrogen-containing sorbicillinoid that displays various bioactivities, identified from a sponge-derived Penicillium chrysogenum strain. The first and so far obly total synthesis of sorbicillactone A led to the racemate in 12 linear steps and a 0.13% overall yield. Here, the authors develop a chemoenzymatic stereoselective total synthesis of sorbicillactone A in 4 steps and 11% yield by using the enzyme SorbC for the enantioselective oxidative dearomatization of sorbillin to sorbicillinol followed by addition of an azlactone unit.

  • Jonas I. Müller
  • Tobias A. M. Gulder

  ArticleOpen Access24 Feb 2024 Communications Chemistry
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  A modular chemoenzymatic cascade strategy for the structure-customized assembly of ganglioside analogs

  Gangliosides are composed of oligosaccharide chains attached to ceramides and are employed as targeted drugs and diagnostic biomarkers, however, their industrially-relevant synthesis remains challenging. Here, the authors develop a modular chemoenzymatic cascade assembly strategy for the customized and large-scale synthesis of ganglioside analogues with various glycan and ceramide epitopes.

  • Xuefeng Jin
  • Hanchao Cheng
  • Guang-Yu Yang

  ArticleOpen Access18 Jan 2024 Communications Chemistry
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  Site-selective chlorination of pyrrolic heterocycles by flavin dependent enzyme PrnC

  Pyrroles are an important scaffold in medicinal chemistry with various bioactivities; however, the selective chemical halogenation of pyrroles remains challenging. Here, the authors develop an enzymatic site-selective chlorination of pyrrolic heterocycles by a flavin-dependent halogenase PrnC and apply it to the chemoenzymatic synthesis of a chlorinated analogue of the fungicide Fludioxonil.

  • GuangRong Peh
  • Terence Tay
  • Yee Hwee Lim

  ArticleOpen Access5 Jan 2024 Communications Chemistry
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  Enhancing the thermostability and activity of glycosyltransferase UGT76G1 via computational design

  Diterpene glycosyltransferase UGT76G1 is a key enzyme in the biosynthesis of rebaudioside A, a naturally sweet-tasting compound, however, its poor thermostability hinders its industrial application. Here, the authors use a computational design strategy to generate a mutant of UGT76G1 that exhibits improved thermostability and enzymatic activity.

  • Seong-Ryeong Go
  • Su-Jin Lee
  • Eui-Jeon Woo

  ArticleOpen Access6 Dec 2023 Communications Chemistry
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  Genome mining for macrolactam-encoding gene clusters allowed for the network-guided isolation of β-amino acid-containing cyclic derivatives and heterologous production of ciromicin A

  β-Amino acid-containing macrolactams are a known natural product family exhibiting structural and functional diversity, however, the natural chemical space of this family remains underexplored. Here, the authors use a targeted β-amino acid-specific homology-based multi-query search to identify their potential microbial producers, explore the variation of their biosynthetic gene clusters, heterologously produce ciromicin A, and identify new macrotermycin derivatives.

  • Elena Seibel
  • Soohyun Um
  • Christine Beemelmanns

  ArticleOpen Access20 Nov 2023 Communications Chemistry
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  Interdisciplinary development of an overall process concept from glucose to 4,5-dimethyl-1,3-dioxolane via 2,3-butanediol

  The bio-hybrid fuel 4,5-dimethyl-1,3-dioxolane can be produced from glucose via 2,3-butanediol (2,3-BDO), however, the separation of microbially produced 2,3-BDO remains costly. Here, the authors develop an alternative process route to 4,5-dimethyl-1,3-dioxolane via the enzymatic production of 2,3-BDO.

  • William Graf von Westarp
  • Jan Wiesenthal
  • Andreas Jupke

  ArticleOpen Access16 Nov 2023 Communications Chemistry
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  Biocatalytic characterization of an alcohol dehydrogenase variant deduced from Lactobacillus kefir in asymmetric hydrogen transfer

  Alcohol dehydrogenases (ADH) are known to be efficient and stereoselective biocatalysts for reducing prochiral carbonyl compounds to chiral alcohols; however, their catalytic performances remain limited for application. Here, the authors demonstrate the wide substrate scope of a L. kefir ADH variant with anti-Prelog specificity to generate (R)-alcohols.

  • Aleksandra Rudzka
  • Beata Zdun
  • Paweł Borowiecki

  ArticleOpen Access12 Oct 2023 Communications Chemistry
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  Structural and functional analysis of hyper-thermostable ancestral L-amino acid oxidase that can convert Trp derivatives to D-forms by chemoenzymatic reaction

  D-Amino acids are widely present in nature and display diverse physiological functions, however, their large-scale synthesis remains challenging for specific amino acids. Here, the authors design hyper-thermostable ancestral L-amino acid oxidases (HTAncLAAO2), catalyzing the chemoenzymatic synthesis of D-tryptophan from L-tryptophan at a preparative scale.

  • Yui Kawamura
  • Chiharu Ishida
  • Shogo Nakano

  ArticleOpen Access22 Sep 2023 Communications Chemistry
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  Chemo-enzymatic total synthesis of the spirosorbicillinols

  Spirosorbicillinols A–C are fungal natural products that display various biological properties, but their total synthesis has yet to be accomplished. Here, the authors report the total synthesis of spirosorbicillinols A–C based on a chemo-enzymatic transformation of sorbicillin into sorbicillinol, which is fused to synthetically prepared scytolide and isomers by a Diels-Alder cycloaddition reaction.

  • Tobias M. Milzarek
  • Tobias A. M. Gulder

  ArticleOpen Access6 Sep 2023 Communications Chemistry
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  Actinomycetes-derived imine reductases with a preference towards bulky amine substrates

  Imine reductases can catalyze reductive amination reactions to produce chiral amines, however, transformation of bulky amines has been challenging. Here, by using an increasing-molecule-volume-screening method, the authors identify a group of imine reductases that can accept bulky amines and achieve an efficient gram-scale synthesis of an API sensipar analogue.

  • Jun Zhang
  • Xin Li
  • Chengsen Cui

  ArticleOpen Access8 Oct 2022 Communications Chemistry
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  Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer camptothecin analogues

  Camptothecin derivatives are precursors of potent anticancer agents, but their biosynthesis remains largely unknown. Here two cytochrome P450 monooxygenases are shown to regiospecifically oxidize camptothecin, yielding 10- and 11- hydroxylated derivatives, which are subsequently used to produce a suite of known anticancer drugs and derivatives.

  • Tuan-Anh M. Nguyen
  • Trinh-Don Nguyen
  • Thu-Thuy T. Dang

  ArticleOpen Access16 Dec 2021 Communications Chemistry
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  Exo-selective intermolecular Diels–Alder reaction by PyrI4 and AbnU on non-natural substrates

  Diels-Alderases remain rare in nature, particularly those catalysing intermolecular reactions. Here two natural Diels-Alderases are shown to catalyse exo-selective intermolecular Diels-Alder reactions on non-natural substrates.

  • Rajnandani Kashyap
  • Naga Veera Yerra
  • Anthony Addlagatta

  ArticleOpen Access3 Aug 2021 Communications Chemistry
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  Chemoenzymatic synthesis of 3-ethyl-2,5-dimethylpyrazine by L-threonine 3-dehydrogenase and 2-amino-3-ketobutyrate CoA ligase/L-threonine aldolase

  Threonine is a biosynthetic precursor to dimethylpyrazine derivatives, but the pathway by which this occurs is not fully established. Here l-throenine-3-dehydrogenase and 2-amino-3-ketobutyrate CoA ligase together are shown to convert l-threonine to dimethylpyrazine derivatives as a byproduct of glycine metabolism.

  • Tomoharu Motoyama
  • Shogo Nakano
  • Sohei Ito

  ArticleOpen Access16 Jul 2021 Communications Chemistry
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  Ancestral L-amino acid oxidases for deracemization and stereoinversion of amino acids

  L-amino acid oxidases can convert racemic amino acids to D-isomers, but stable and structure-determined oxidases are scarce. Here, the authors report the structures, stabilities, and activities of two ancestral L-amino acid oxidases.

  • Shogo Nakano
  • Kohei Kozuka
  • Sohei Ito

  ArticleOpen Access4 Dec 2020 Communications Chemistry
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  Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

  The 1-aryl-tetrahydroisoquinoline moiety is a desirable synthetic target, but generating single enantiomers of THIQ products is synthetically challenging. Here the authors demonstrate that the M97V variant of enzyme norcoclaurine synthase catalyzes the synthesis of (1 S)-aryl-THIQs in high yields and enantiomeric excesses.

  • Rebecca Roddan
  • Altin Sula
  • Helen C. Hailes

  ArticleOpen Access13 Nov 2020 Communications Chemistry
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  Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium

  The merger of chemical and biocatalysis can offer powerful new options to synthetic chemists. Here a combination of a nickel-catalyzed Suzuki-Miyaura reaction and an enzymatic stereoselective reduction provides enantiomerically-enriched alcohols from amides in a single reaction vessel, in water.

  • Jacob E. Dander
  • Maude Giroud
  • Neil K. Garg

  ArticleOpen Access19 Jul 2019 Communications Chemistry