Details
| Original language | English |
|---|---|
| Article number | 1529 |
| Journal | Nature Communications |
| Volume | 8 |
| Publication status | Published - 16 Nov 2017 |
| Externally published | Yes |
Abstract
The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- General Biochemistry,Genetics and Molecular Biology
- Physics and Astronomy(all)
- General Physics and Astronomy
Sustainable Development Goals
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Nature Communications, Vol. 8, 1529, 16.11.2017.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD
AU - Fu, Chengzhang
AU - Sikandar, Asfandyar
AU - Donner, Jannik
AU - Zaburannyi, Nestor
AU - Herrmann, Jennifer
AU - Reck, Michael
AU - Wagner-Döbler, Irene
AU - Koehnke, Jesko
AU - Müller, Rolf
N1 - Funding Information: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the program e:bio (grant number 031 A299). We acknowledge use of the ESRF (beamline ID30A) and SLS (beamline X06DA) synchrotrons. J.K. thanks the Deutsche Forschungsgemeinschaft for an Emmy Noether fellowship (KO4116/3–1).
PY - 2017/11/16
Y1 - 2017/11/16
N2 - The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.
AB - The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.
UR - http://www.scopus.com/inward/record.url?scp=85034419121&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01671-5
DO - 10.1038/s41467-017-01671-5
M3 - Article
C2 - 29142318
AN - SCOPUS:85034419121
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1529
ER -