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Total In Vitro Biosynthesis of the Thioamitide Thioholgamide and Investigation of the Pathway
Open accessPreprint — published as 10.1021/jacs.2c00402 · Paper page
Abstract
Thioholgamides are ribosomally synthesized and post-translationally modified peptides (RiPPs) with potent activity against cancerous cell lines and an unprecedented structure. Despite being one of the most structurally and chemically complex RiPPs, very few biosynthetic steps have been elucidated. Here, we report the complete in vitro reconstitution of the biosynthetic pathway. We demonstrate that thioamidation is the first step and acts as a gatekeeper for downstream processing. Thr dehydration follows thioamidation, and our studies reveal that both these modifications require the formation of protein complexes – ThoH/I and ThoC/D. Harnessing the power of AlphaFold we deduce that ThoD acts as a lyase and also propose putative catalytic residues. ThoF catalyzes the oxidative decarboxylation of the terminal Cys and the subsequent macrocyclization is facilitated by ThoE. This is followed by Ser dehydration, which is also carried out by ThoC/D. ThoG is responsible for histidine bis-N-methylation, which is a prerequisite for His β-hydroxylation – a modification carried out by ThoJ. The last step of the pathway is the removal of the leader peptide by ThoK to afford mature thioholgamide.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Sikandar, A., Lopatniuk, M., Luzhetskyy, A., Müller, R., & Koehnke, J.
- Affiliations
- Helmholtz Centre for Infection Research (DE)
- Saarland University (DE)
- German Center for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Corresponding author
- Müller, Rolf
- Koehnke, Jesko
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-01-11
- Volume
- 144
- Issue
- 11
- Pages
- 5136-5144
- ISSN
- 0002-7863 (ISSN-L)
- OpenAlex
- W4220717179
- Cited by
- 39
- References
- 1
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 6 · 2023: 13 · 2022: 5
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by-nc-sa)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/V016059/1)
- Topics
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- ribosomally synthesized and post-translationally modified peptides, biosynthetic pathway, dehydration
- MeSH terms
- Dehydration, Histidine, Humans, Peptides, Protein Processing, Post-Translational, Protein Sorting Signals
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