5o22
E. coli FolD in complex with carolacton
Structural highlights
FunctionFOLD_ECOLI Catalyzes the oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate. This enzyme is specific for NADP.[1] Publication Abstract from PubMedThe 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. 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-Dobler I, Koehnke J, Muller R Nat Commun. 2017 Nov 16;8(1):1529. doi: 10.1038/s41467-017-01671-5. PMID:29142318[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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