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Long range molecular dynamics study of regulation of eukaryotic glucosamine-6-phosphate synthase activity by UDP-GlcNAc
Abstract
Glucosamine-6-phosphate (GlcN-6-P) synthase catalyses the first and practically irreversible step in hexosamine metabolism. The final product of this pathway, uridine 5' diphospho N-acetyl-D-glucosamine (UDPGlcNAc), is an essential substrate for assembly of bacterialand fungal cell walls. Moreover, the enzyme is involved in phenomenon of hexosamine induced insulin resistance in type II diabetes, which makes it a potential target for antifungal, antibacterial and antidiabetic therapy. The crystal structure of the isomerase domain of GlcN-6-P synthase from human pathogenic fungus Candida albicans,in complex with UDP-GlcNAc has been solved recently but it has not revealed the molecular mechanism of inhibition taking place under UDP-GlcNAc influence, the unique feature of the eukaryotic enzyme. UDP-GlcNAc is a physiological inhibitor of GlcN-6-P synthase, binding about 1 nm away from the active site of the enzyme. In the present work, comparative molecular dynamics simulations of the free and UDP-GlcNAc-bounded structures of GlcN-6-P synthase have been performed. The aim was to complete static X-ray structural data and detect possible changes in the dynamics of the two structures. Results ofthe simulation studies demonstrated higher mobility of the free structure when compared to the liganded one.Several amino acid residues were identified, flexibility of which is strongly affected upon UDP-GlcNAc binding. Importantly, the most fixed residues are those related to the inhibitor binding process and to the catalytic reaction.The obtained results constitute an important step toward understanding of mechanism of GlcN-6-P synthase inhibition by UDP-GlcNAc molecule.
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- DOI:
- Digital Object Identifier (open in new tab) 10.1007/s00894-011-1003-x
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
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JOURNAL OF MOLECULAR MODELING
no. 17,
pages 3103 - 3115,
ISSN: 1610-2940 - Language:
- English
- Publication year:
- 2011
- Bibliographic description:
- Miszkiel A., Wojciechowski M., Milewski S.: Long range molecular dynamics study of regulation of eukaryotic glucosamine-6-phosphate synthase activity by UDP-GlcNAc// JOURNAL OF MOLECULAR MODELING. -Vol. 17, nr. 12 (2011), s.3103-3115
- DOI:
- Digital Object Identifier (open in new tab) 10.1007/s00894-011-1003-x
- Verified by:
- Gdańsk University of Technology
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