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Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-22606
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dc.contributor.authorMeyer, Fabian-
dc.contributor.authorFrey, Raphael-
dc.contributor.authorLigibel, Mathieu-
dc.contributor.authorSager, Emine-
dc.contributor.authorSchroer, Kirsten-
dc.contributor.authorSnajdrova, Radka-
dc.contributor.authorBuller, Rebecca-
dc.date.accessioned2021-06-10T09:46:47Z-
dc.date.available2021-06-10T09:46:47Z-
dc.date.issued2021-05-10-
dc.identifier.issn2155-5435de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/22606-
dc.description.abstractModification of aliphatic C–H bonds in a regio- and stereoselective manner can pose a formidable challenge in organic chemistry. In this context, the use of nonheme iron and α-ketoglutarate-dependent dioxygenases (αKGDs) represents an interesting tool for C–H activation as this enzyme family can catalyze a broad set of synthetically valuable reactions including hydroxylations, oxidations, and desaturations. The consensus reaction mechanism of αKGDs proceeds via the formation of a Fe(IV)-oxo complex capable of hydrogen atom transfer (HAT) from an sp3-hybridized substrate carbon center. The resulting substrate radical and Fe(III)–OH cofactor are considered to be the branch point toward the possible reaction outcomes which are determined by the enzyme’s active site architecture. To date, the modulation of the reaction fate in Fe(II)/α-ketoglutarate-dependent dioxygenases via enzyme engineering has been mainly elusive. In this study, we therefore set out to engineer the l-proline cis-4-hydroxylase SmP4H from Sinorhizobium meliloti for selective oxidative modifications of the nonproteinogenic amino acid l-homophenylalanine (l-hPhe) to produce pharmacological relevant small molecule intermediates. Using structure-guided directed evolution, we improved the total turnover number, the kcat, as well as the kcat/Km of the hydroxylation reaction yielding the desired γ-hydroxylation product by approximately 10-fold, >100-fold, and >300-fold, respectively. Notably, the exchange of only one amino acid in the active site (W40Y) allowed us to reprogram the natural hydroxylase to predominantly act as a desaturase, presumably through tyrosine’s capability to serve as a catalytic entity in the reaction mechanism. An investigation of the substrate scope revealed additional acceptance of the noncanonical amino acids l-homotyrosine and (S)-α-amino-3,4-dichlorobenzenebutanoic acid by SmP4H variants.de_CH
dc.language.isoende_CH
dc.publisherAmerican Chemical Societyde_CH
dc.relation.ispartofACS Catalysisde_CH
dc.rightsLicence according to publishing contractde_CH
dc.subject.ddc660.6: Biotechnologiede_CH
dc.titleModulating chemoselectivity in a Fe(II)/α-ketoglutarate-dependent dioxygenase for the oxidative modification of a non-proteinogenic amino acidde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
zhaw.organisationalunitInstitut für Chemie und Biotechnologie (ICBT)de_CH
dc.identifier.doi10.1021/acscatal.1c00678de_CH
dc.identifier.doi10.21256/zhaw-22606-
zhaw.funding.euNode_CH
zhaw.issue11de_CH
zhaw.originated.zhawYesde_CH
zhaw.publication.statusacceptedVersionde_CH
zhaw.volume2021de_CH
zhaw.embargo.end2022-05-10de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
zhaw.webfeedBiokatalysede_CH
zhaw.author.additionalNode_CH
zhaw.display.portraitYesde_CH
Appears in collections:Publikationen Life Sciences und Facility Management

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Meyer, F., Frey, R., Ligibel, M., Sager, E., Schroer, K., Snajdrova, R., & Buller, R. (2021). Modulating chemoselectivity in a Fe(II)/α-ketoglutarate-dependent dioxygenase for the oxidative modification of a non-proteinogenic amino acid. ACS Catalysis, 2021(11). https://doi.org/10.1021/acscatal.1c00678
Meyer, F. et al. (2021) ‘Modulating chemoselectivity in a Fe(II)/α-ketoglutarate-dependent dioxygenase for the oxidative modification of a non-proteinogenic amino acid’, ACS Catalysis, 2021(11). Available at: https://doi.org/10.1021/acscatal.1c00678.
F. Meyer et al., “Modulating chemoselectivity in a Fe(II)/α-ketoglutarate-dependent dioxygenase for the oxidative modification of a non-proteinogenic amino acid,” ACS Catalysis, vol. 2021, no. 11, May 2021, doi: 10.1021/acscatal.1c00678.
MEYER, Fabian, Raphael FREY, Mathieu LIGIBEL, Emine SAGER, Kirsten SCHROER, Radka SNAJDROVA und Rebecca BULLER, 2021. Modulating chemoselectivity in a Fe(II)/α-ketoglutarate-dependent dioxygenase for the oxidative modification of a non-proteinogenic amino acid. ACS Catalysis. 10 Mai 2021. Bd. 2021, Nr. 11. DOI 10.1021/acscatal.1c00678
Meyer, Fabian, Raphael Frey, Mathieu Ligibel, Emine Sager, Kirsten Schroer, Radka Snajdrova, and Rebecca Buller. 2021. “Modulating Chemoselectivity in a Fe(II)/α-Ketoglutarate-Dependent Dioxygenase for the Oxidative Modification of a Non-Proteinogenic Amino Acid.” ACS Catalysis 2021 (11). https://doi.org/10.1021/acscatal.1c00678.
Meyer, Fabian, et al. “Modulating Chemoselectivity in a Fe(II)/α-Ketoglutarate-Dependent Dioxygenase for the Oxidative Modification of a Non-Proteinogenic Amino Acid.” ACS Catalysis, vol. 2021, no. 11, May 2021, https://doi.org/10.1021/acscatal.1c00678.


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