The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD

Fu, C., Sikandar, A., Donner, J., Zaburannyi, N., Herrmann, J., Reck, M., Wagner-Döbler, I., Koehnke, J. and Müller, R. (2017) The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. Nature Communications, 8, 1529. (doi: 10.1038/s41467-017-01671-5) (PMID:29142318) (PMCID:PMC5688156)

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.

• Item Type: Articles
• Additional Information: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the program e:bio (grant number 031 A299).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Koehnke, Professor Jesko
• Authors: Fu, C., Sikandar, A., Donner, J., Zaburannyi, N., Herrmann, J., Reck, M., Wagner-Döbler, I., Koehnke, J., and Müller, R.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2017
• First Published: First published in Nature Communications 8(1):1529
• Publisher Policy: Reproduced under a Creative Commons license