Department of Microbial Natural Products, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland, Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Centre for Infection Research, Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.
Nat Commun. 2017 Nov 16;8(1):1529. doi: 10.1038/s41467-017-01671-5.
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.
天然产物卡罗他汀是由粘细菌 Sorangium cellulosum 产生的大环酮羧酸，最初被描述为一种具有抗菌作用的化合物。在这里，我们表明卡罗他汀靶向 FolD，一种依赖叶酸的 C1 代谢中的关键酶。我们从生物物理、结构和生化方面对细菌 FolD 和卡罗他汀之间的相互作用进行了表征。卡罗他汀以纳摩尔亲和力结合 FolD，卡罗他汀-FolD 复合物的晶体结构揭示了结合模式。我们表明，人类 FolD 同源物 MTHFD1 和 MTHFD2 也以低纳摩尔范围被抑制，并且微摩尔浓度的卡罗他汀抑制癌细胞系的生长。由于线粒体 MTHFD2 已知在癌细胞中上调，因此可能可以使用卡罗他汀作为抑制剂工具化合物来评估 MTHFD2 作为抗癌靶标。
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