Structural analogues of reactive intermediates as inhibitors of glucosamine-6-phosphate synthase and phosphoglucose isomerase

Archives of Biochemistry and Biophysics
Sławomir MilewskiMarek Wojciechowski

Abstract

The active centers of phosphoglucose isomerase (PGI) and the hexose phosphate isomerase domain (HPI) of glucosamine-6-P (GlcN-6-P) synthase demonstrate apparent similarity in spatial arrangement of critical amino acid residues, except Arg272 of the former and Lys603 and Lys485 of the latter. Ten derivatives of d-hexitol-6-P, 5-phosphoarabinoate, or 6-phosphogluconate, structural analogues of putative cis-enolamine or cis-enolate intermediates, were tested as inhibitors of fungal GlcN-6-P synthase and PGI. None of the investigated compounds demonstrated equally high inhibitory potential against both enzymes. 2-Amino-2-deoxy-D-mannitol 6-P was found to be the strongest GlcN-6-P synthase inhibitor in the series, with an inhibition constant equal to 9.0 (+/-1.0) x 10(-6)M. On the contrary, 5-phosphoarabinoate (5PA) exhibited specificity for PGI, with K(i)=2.2 (+/-0.1) x 10(-6) M. N-acetylation substantially lowered the GlcN-6-P synthase inhibitory potential of 2-amino-2-deoxy-D-glucitol-6-P but strongly enhanced inhibitory potential of this compound towards PGI. Molecular modeling studies revealed that interactions of the C1-C2 part of transition state analogue inhibitors with the respective areas demonstrating different distributi...Continue Reading

References

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Citations

Aug 8, 2007·Journal of Molecular Biology·Joanna RaczynskaWojciech Rypniewski
Jun 20, 2017·Carbohydrate Research·Kornelia SkarbekMaria J Milewska
Sep 22, 2018·ACS Chemical Biology·Yi-Fan XuJoshua D Rabinowitz
Sep 21, 2007·Analytical Biochemistry·Yanyan LiMarie-Ange Badet-Denisot
Oct 9, 2007·Bioorganic & Medicinal Chemistry Letters·Anna MelcerSławomir Milewski
Feb 19, 2008·Archives of Biochemistry and Biophysics·Philippe DurandMarie-Ange Badet-Denisot

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