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

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 (Ki=74 μM, Km/Ki=100), exhibiting only a 3-fold weaker inhibitory activity than its phosphate analogue.