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Author(s): Bearne SL; Blouin C
Title: Inhibition of Escherichia coli glucosamine-6 phosphate synthase by reactive intermediate analogues - The role of the 2-amino function in catalysis
Source: JOURNAL OF BIOLOGICAL CHEMISTRY 275 (1): 135-140
Date: 2000 JAN 7
Document Type: Journal : Article
DOI:
Language: English
Comment:
Address: Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H 4H7, Canada.
Reprint: Bearne, SL, Dalhousie Univ, Dept Biochem & Mol Biol, Halifax, NS B3H
4H7, Canada. E-mail:
Abstract: Glucosamine-6-phosphate synthase (GlmS) catalyzes the formation of D-glucosamine 6-phosphate from D-fructose 6-phosphate using L-glutamine as the ammonia source. Because N-acetylglucosamine is an essential building block of both bacterial cell walls and fungal cell wall chitin, the enzyme is a potential target for antibacterial and antifungal agents. The most potent carbohydrate-based inhibitor of GlmS reported to date is 2-amino-2-deoxy-D-glucitol 6-phosphate, an analogue of the putative cis-enolamine intermediate formed during catalysis. The interaction of a series of structurally related cis-enolamine intermediate analogues with GlmS is described. Although arabinose oxime 6-phosphate is identified as a good competitive inhibitor of GlmS with an inhibition constant equal to 1.2 (+/-0.3) mM, the presence of the amino function at the 2-position is shown to be important for potent inhibition. Comparison of the binding affinities of 2-deoxy-D-glucitol 6-phosphate and 2-amino-2-deoxy-D-glucitol 6-phosphate indicates that the amino function contributes -4.1 (+/-0.1) kcal/mol to the free energy of inhibitor binding. Similarly, comparison of the binding affinities of 2-deoxy-D-glucose 6-phosphate and D-glucosamine 6-phosphate indicates that the amino function contributes -3.0 (+/-0.1) kcal/mol to the free energy of product binding. Interactions between GlmS and the 2-amino function of its ligands contribute to the uniform binding of the product and the cis-enolamine intermediate as evidenced by the similar contribution of the amino group to the free energy of binding of D-glucosamine 6-phosphate and 2-amino-2-deoxy-D-glucitol 6-phosphate, respectively.
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