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Synthesis and kinetic evaluation of 4-deoxy-4-phosphonomethyl-d-erythronate, the first hydrolytically stable and potent competitive inhibitor of ribose-5-phosphate isomerase

Authors
Journal
Tetrahedron Letters
0040-4039
Publisher
Elsevier
Publication Date
Volume
45
Issue
17
Identifiers
DOI: 10.1016/j.tetlet.2004.03.004
Keywords
  • Enzyme Inhibitor
  • Phosphonate
  • Ribose-5-Phosphate Isomerase
Disciplines
  • Biology

Abstract

Abstract 4-deoxy-4-Phosphonomethyl- d-erythronate, an isosteric and hydrolytically stable analogue of the known ribose-5-phosphate isomerase inhibitor 4-deoxy-4-phospho- d-erythronate, was obtained by a 14-step synthesis from d-arabinose through an highly improved synthesis of the precursor 5-deoxy-5-phosphonomethyl- d-arabinose. The title compound appears as the first stable and potent competitive inhibitor of the enzyme catalyzed isomerization of ribose-5-phosphate to d-ribulose-5-phosphate ( K i=74 μM, K m/ K i=100), exhibiting only a 3-fold weaker inhibitory activity than its phosphate analogue.

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