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dc.contributor.authorFu, Chengzhang
dc.contributor.authorSikandar, Asfandyar
dc.contributor.authorDonner, Jannik
dc.contributor.authorZaburannyi, Nestor
dc.contributor.authorHerrmann, Jennifer
dc.contributor.authorReck, Michael
dc.contributor.authorWagner-Döbler, Irene
dc.contributor.authorKoehnke, Jesko
dc.contributor.authorMüller, Rolf
dc.date.accessioned2017-12-01T10:57:05Z
dc.date.available2017-12-01T10:57:05Z
dc.date.issued2017-11-16
dc.identifier.citationThe natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. 2017, 8 (1):1529 Nat Communen
dc.identifier.issn2041-1723
dc.identifier.pmid29142318
dc.identifier.doi10.1038/s41467-017-01671-5
dc.identifier.urihttp://hdl.handle.net/10033/621190
dc.description.abstractThe 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.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleThe natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124Braunschweig, Germany.en
dc.identifier.journalNature communicationsen
refterms.dateFOA2018-06-13T21:25:50Z
html.description.abstractThe 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.


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