Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 17, Pages 13656-13665Publisher
ELSEVIER
DOI: 10.1074/jbc.M111.318170
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Funding
- Sonnenfeld Stiftung
- Roland and Elfriede Schauer Stiftung
- DFG [Sonderforschungsbereich 449]
- Bundesministerium fur Bildung und Forschung
- German-Israeli Foundation for Research and Development
- Helmholtz Zentrum Berlin fur Materialien and Energie
- Freie Universitat Berlin
- Humboldt-Universitat zu Berlin
- Max-Delbruck Centrum
- Leibniz-Institut fur Molekulare Pharmakologie
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Sialic acids are essential components of membrane glycoconjugates. They are responsible for the interaction, structure, and functionality of all deuterostome cells and have major functions in cellular processes in health and diseases. The key enzyme of the biosynthesis of sialic acid is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase that transforms UDP-N-acetylglucosamine to N-acetylmannosamine (ManNAc) followed by its phosphorylation to ManNAc 6-phosphate and has a direct impact on the sialylation of cell surface components. Here, we present the crystal structures of the human N-acetylmannosamine kinase (MNK) domain of UDP-N-acetylglucosamine- 2-epimerase/N-acetylmannosamine kinase in complexes with ManNAc at 1.64 angstrom resolution, MNK.ManNAc.ADP (1.82 angstrom) and MNK.ManNAc 6-phosphate.ADP (2.10 angstrom). Our findings offer detailed insights in the active center of MNK and serve as a structural basis to design inhibitors. We synthesized a novel inhibitor, 6-O-acetyl-ManNAc, which is more potent than those previously tested. Specific inhibitors of sialic acid biosynthesis may serve to further study biological functions of sialic acid.
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