Details
| Original language | English |
|---|---|
| Pages (from-to) | 560-568 |
| Number of pages | 9 |
| Journal | Nature chemistry |
| Volume | 15 |
| Issue number | 4 |
| Early online date | 9 Mar 2023 |
| Publication status | Published - Apr 2023 |
| Externally published | Yes |
Abstract
Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids. [Figure not available: see fulltext.]
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Chemical Engineering(all)
- General Chemical Engineering
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In: Nature chemistry, Vol. 15, No. 4, 04.2023, p. 560-568.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Unusual peptide-binding proteins guide pyrroloindoline alkaloid formation in crocagin biosynthesis
AU - Adam, Sebastian
AU - Zheng, Dazhong
AU - Klein, Andreas
AU - Volz, Carsten
AU - Mullen, William
AU - Shirran, Sally L.
AU - Smith, Brian O.
AU - Kalinina, Olga V.
AU - Müller, Rolf
AU - Koehnke, Jesko
N1 - Funding Information: This work was supported by the European Research Council (Consolidator Grant 101002326 to J.K.). We are grateful for A. Heckmanns’s help with the knockout studies and to V. Olive at the Scottish Universities Environmental Research Centre for ICP-MS analysis. We acknowledge the College of Medical, Veterinary & Life Sciences Structural Biology and Biophysical Characterisation Facility, University of Glasgow, for the use of Microscale Thermophoresis. We thank J. Prunet and A. Jamieson for helpful discussions, M. Molinari for help running RiPPER and D. France and M. Groll for critical reading of the paper.
PY - 2023/4
Y1 - 2023/4
N2 - Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids. [Figure not available: see fulltext.]
AB - Ribosomally synthesized and post-translationally modified peptide natural products have provided many highly unusual scaffolds. This includes the intriguing alkaloids crocagins, which possess a tetracyclic core structure and whose biosynthesis has remained enigmatic. Here we use in vitro experiments to demonstrate that three proteins, CgnB, CgnC and CgnE, are sufficient for the production of the hallmark tetracyclic crocagin core from the precursor peptide CgnA. The crystal structures of the homologues CgnB and CgnE reveal them to be the founding members of a peptide-binding protein family and allow us to rationalize their distinct functions. We further show that the hydrolase CgnD liberates the crocagin core scaffold, which is subsequently N-methylated by CgnL. These insights allow us to propose a biosynthetic scheme for crocagins. Bioinformatic analyses based on these data led to the discovery of related biosynthetic pathways that may provide access to a structurally diverse family of peptide-derived pyrroloindoline alkaloids. [Figure not available: see fulltext.]
UR - http://www.scopus.com/inward/record.url?scp=85149459257&partnerID=8YFLogxK
U2 - 10.1038/s41557-023-01153-w
DO - 10.1038/s41557-023-01153-w
M3 - Article
C2 - 36894702
AN - SCOPUS:85149459257
VL - 15
SP - 560
EP - 568
JO - Nature chemistry
JF - Nature chemistry
SN - 1755-4330
IS - 4
ER -