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

Author

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  • Chengzhang Fu

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1)

  • Asfandyar Sikandar

    (Helmholtz Institute for Pharmaceutical Research Saarland, Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Centre for Infection Research, Saarland University, Campus E8.1)

  • Jannik Donner

    (Helmholtz Center for Infection Research (HZI), Group Microbial Communication)

  • Nestor Zaburannyi

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1)

  • Jennifer Herrmann

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1
    German Centre for Infection Research (DZIF), Partner Site Hannover)

  • Michael Reck

    (Helmholtz Center for Infection Research (HZI), Group Microbial Communication)

  • Irene Wagner-Döbler

    (Helmholtz Center for Infection Research (HZI), Group Microbial Communication)

  • Jesko Koehnke

    (Helmholtz Institute for Pharmaceutical Research Saarland, Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Centre for Infection Research, Saarland University, Campus E8.1)

  • Rolf Müller

    (Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1
    German Centre for Infection Research (DZIF), Partner Site Hannover)

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.

Suggested Citation

  • Chengzhang Fu & Asfandyar Sikandar & Jannik Donner & Nestor Zaburannyi & Jennifer Herrmann & Michael Reck & Irene Wagner-Döbler & Jesko Koehnke & Rolf Müller, 2017. "The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01671-5
    DOI: 10.1038/s41467-017-01671-5
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    Cited by:

    1. Xiaochen Wang & Rongxin Yang & Binbing Zhu & Yuxiu Liu & Hongjian Song & Jianyang Dong & Qingmin Wang, 2023. "Direct allylic acylation via cross-coupling involving cooperative N‑heterocyclic carbene, hydrogen atom transfer, and photoredox catalysis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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