NDLI: Long range molecular dynamics study of regulation of eukaryotic glucosamine-6-phosphate synthase activity by UDP-GlcNAc

Content Provider	Springer Nature Link
Author	Miszkiel, Aleksandra Wojciechowski, Marek Milewski, Sławomir
Copyright Year	2011
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 (UDP-GlcNAc), is an essential substrate for assembly of bacterial and 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 of the 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.
Starting Page	3103
Ending Page	3115
Page Count	13
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	17
Issue Number	12
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2011-03-02
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cosine content Glucosamine-6-phosphate synthase Molecular dynamics Principal component analysis UDP-GlcNAc Health Informatics Life Sciences Molecular Medicine Biomedicine general Computer Applications in Chemistry Computer Application in Life Sciences
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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