HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Synthesis and evaluation of non-hydrolyzable D-mannose 6-phosphate surrogates reveal 6-deoxy-6-dicarboxymethyl-D-mannose as a new strong inhibitor of phosphomannose isomerases.

Abstract
Non-hydrolyzable d-mannose 6-phosphate analogues in which the phosphate group was replaced by a phosphonomethyl, a dicarboxymethyl, or a carboxymethyl group were synthesized and kinetically evaluated as substrate analogues acting as potential inhibitors of type I phosphomannose isomerases (PMIs) from Saccharomyces cerevisiae and Escherichia coli. While 6-deoxy-6-phosphonomethyl-d-mannose and 6-deoxy-6-carboxymethyl-D-mannose did not inhibit the enzymes significantly, 6-deoxy-6-dicarboxymethyl-D-mannose appeared as a new strong competitive inhibitor of both S. cerevisiae and E. coli PMIs with K(m)/K(i) ratios of 28 and 8, respectively. We thus report the first malonate-based inhibitor of an aldose-ketose isomerase to date. Phosphonomethyl mimics of the 1,2-cis-enediolate high-energy intermediate postulated for the isomerization reaction catalyzed by PMIs were also synthesized but behave as poor inhibitors of PMIs. A polarizable molecular mechanics (SIBFA) study was performed on the complexes of d-mannose 6-phosphate and two of its analogues with PMI from Candida albicans, an enzyme involved in yeast infection homologous to S. cerevisiae and E. coli PMIs. It shows that effective binding to the catalytic site occurs with retention of the Zn(II)-bound water molecule. Thus the binding of the hydroxyl group on C1 of the ligand to Zn(II) should be water-mediated. The kinetic study reported here also suggests the dianionic character of the phosphate surrogate as a likely essential parameter for strong binding of the inhibitor to the enzyme active site.
AuthorsJohanna Foret, Benoit de Courcy, Nohad Gresh, Jean-Philip Piquemal, Laurent Salmon
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 17 Issue 20 Pg. 7100-7 (Oct 15 2009) ISSN: 1464-3391 [Electronic] England
PMID19783448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 6-deoxy-6-dicarboxymethylmannose
  • Enzyme Inhibitors
  • Mannosephosphates
  • Uronic Acids
  • mannose-6-phosphate
  • Mannose-6-Phosphate Isomerase
Topics
  • Chromatography, Ion Exchange
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors (chemical synthesis, pharmacology)
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Mannose-6-Phosphate Isomerase (antagonists & inhibitors, chemistry, metabolism)
  • Mannosephosphates (chemical synthesis, pharmacology)
  • Models, Molecular
  • Saccharomyces cerevisiae (enzymology)
  • Spectrometry, Mass, Electrospray Ionization
  • Substrate Specificity
  • Uronic Acids (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: