Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H

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OriginalspracheEnglisch
Aufsatznummere202302590
Seitenumfang8
FachzeitschriftChemistry - a European journal
Jahrgang30
Ausgabenummer4
Frühes Online-Datum5 Nov. 2023
PublikationsstatusVeröffentlicht - 16 Jan. 2024

Abstract

Three central steps during the biosynthesis of cytochalasan precursors, including reductive release, Knoevenagel cyclisation and Diels Alder cyclisation are not yet understood at a detailed molecular level. In this work we investigated the reductive release step catalysed by a hybrid polyketide synthase non-ribosomal peptide synthetase (PKS-NRPS) from the pyrichalasin H pathway. Synthetic thiolesters were used as substrate mimics for in vitro studies with the isolated reduction (R) and holo-thiolation (T) domains of the PKS-NRPS hybrid PyiS. These assays demonstrate that the PyiS R-domain mainly catalyses an NADPH-dependent reductive release of an aldehyde intermediate that quickly undergoes spontaneous Knoevenagel cyclisation. The R-domain can only process substrates that are covalently bound to the phosphopantetheine thiol of the upstream T-domain, but it shows little selectivity for the polyketide.

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Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H. / Heinemann, Henrike; Zhang, Haili; Cox, Russell J.
in: Chemistry - a European journal, Jahrgang 30, Nr. 4, e202302590, 16.01.2024.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Heinemann H, Zhang H, Cox RJ. Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H. Chemistry - a European journal. 2024 Jan 16;30(4):e202302590. Epub 2023 Nov 5. doi: 10.1002/chem.202302590
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abstract = "Three central steps during the biosynthesis of cytochalasan precursors, including reductive release, Knoevenagel cyclisation and Diels Alder cyclisation are not yet understood at a detailed molecular level. In this work we investigated the reductive release step catalysed by a hybrid polyketide synthase non-ribosomal peptide synthetase (PKS-NRPS) from the pyrichalasin H pathway. Synthetic thiolesters were used as substrate mimics for in vitro studies with the isolated reduction (R) and holo-thiolation (T) domains of the PKS-NRPS hybrid PyiS. These assays demonstrate that the PyiS R-domain mainly catalyses an NADPH-dependent reductive release of an aldehyde intermediate that quickly undergoes spontaneous Knoevenagel cyclisation. The R-domain can only process substrates that are covalently bound to the phosphopantetheine thiol of the upstream T-domain, but it shows little selectivity for the polyketide.",
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note = "Funding Information: HH was funded by LUH. DFG Forschergruppe 5170 CytoLabs is also thanked for funding. H.Z. was funded by the China Scholarship Council (CSC 201506200065). Open Access funding enabled and organized by Projekt DEAL. ",
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AU - Cox, Russell J.

N1 - Funding Information: HH was funded by LUH. DFG Forschergruppe 5170 CytoLabs is also thanked for funding. H.Z. was funded by the China Scholarship Council (CSC 201506200065). Open Access funding enabled and organized by Projekt DEAL.

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N2 - Three central steps during the biosynthesis of cytochalasan precursors, including reductive release, Knoevenagel cyclisation and Diels Alder cyclisation are not yet understood at a detailed molecular level. In this work we investigated the reductive release step catalysed by a hybrid polyketide synthase non-ribosomal peptide synthetase (PKS-NRPS) from the pyrichalasin H pathway. Synthetic thiolesters were used as substrate mimics for in vitro studies with the isolated reduction (R) and holo-thiolation (T) domains of the PKS-NRPS hybrid PyiS. These assays demonstrate that the PyiS R-domain mainly catalyses an NADPH-dependent reductive release of an aldehyde intermediate that quickly undergoes spontaneous Knoevenagel cyclisation. The R-domain can only process substrates that are covalently bound to the phosphopantetheine thiol of the upstream T-domain, but it shows little selectivity for the polyketide.

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