Details
| Original language | English |
|---|---|
| Article number | e202302590 |
| Number of pages | 8 |
| Journal | Chemistry - a European journal |
| Volume | 30 |
| Issue number | 4 |
| Early online date | 5 Nov 2023 |
| Publication status | Published - 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.
Keywords
- cytochalasan, non-ribosomal peptide, polyketide, reductive release, SDR
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Chemistry(all)
- Organic Chemistry
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In: Chemistry - a European journal, Vol. 30, No. 4, e202302590, 16.01.2024.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H
AU - Heinemann, Henrike
AU - Zhang, Haili
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.
PY - 2024/1/16
Y1 - 2024/1/16
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.
AB - 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.
KW - cytochalasan
KW - non-ribosomal peptide
KW - polyketide
KW - reductive release
KW - SDR
UR - http://www.scopus.com/inward/record.url?scp=85178107839&partnerID=8YFLogxK
U2 - 10.1002/chem.202302590
DO - 10.1002/chem.202302590
M3 - Article
C2 - 37926691
AN - SCOPUS:85178107839
VL - 30
JO - Chemistry - a European journal
JF - Chemistry - a European journal
SN - 0947-6539
IS - 4
M1 - e202302590
ER -