Inhibition of fructose bisphosphatase and stimulation of phosphofructokinase by a stable isosteric phosphonate analog of fructose 2,6-bisphosphate.
We describe the synthesis of a mixture of D-manno- and D-gluco-2,5-anhydro-1-deoxy-1-phosphonohexitol 6-phosphate via a Horner-Emmons reaction of 2,3,5-tri-O-benzyl-beta-D-arabinofuranose followed by phosphorylation of the equivalent 6-position and subsequent deprotection. This mixture inhibits fructose-1,6-bisphosphatase; the concentration required for half-maximal effect in the presence of 25 microM AMP is approximately 6 microM. The mixture of analogs also stimulates 6-phosphofructo-1-kinase from rabbit liver; the concentration required to reach one-half Vmax was found to be ca. 25 microM at 0.25 mM fructose 6-phosphate and 50 microM AMP. These analogs have replaced the labile anomeric phosphate of fructose 2,6-bisphosphate with a stable methylenephosphonate, and could be of great interest due to their appropriate physiological effects and their chemical stability.
D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D005635:Fructosediphosphates / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D011817:Rabbits; D013403:Sugar Phosphates / Q000138:chemical synthesis / Q000494:pharmacology*
D005635:Fructosediphosphates; D013403:Sugar Phosphates; C047880:2,5-anhydro-1-deoxy-1-phosphonohexitol-6-phosphate; D000249:Adenosine Monophosphate; C027652:fructose 2,6-diphosphate; D010732:Phosphofructokinase-1; D006597:Fructose-Bisphosphatase