Conversion of UMP, an allosteric inhibitor of carbamyl phosphate synthetase, to an activator by modification of the UMP ribose moiety.
UMP is known to be an allosteric inhibitor of carbamyl phosphate synthetase, whereas IMP activates the enzyme. Surprisingly, dialdehyde UMP (prepared by periodate oxidation of UMP) was found to be a potent activator of the enzyme. Dialdehyde IMP, like IMP, produced activation. The corresponding dialcohol analogs of UMP and IMP (prepared by borohydride reduction of the dialdehyde analogs) had no effect on activity. These nucleotide interactions were further characterized by sedimentation velocity studies and by examination of the effects of inorganic phosphate on enzymatic activity. Although UMP promotes formation of an enzyme dimer, and IMP promotes formation of a tetramer (Powers, S. G., Meister, A., and Haschemeyer, R. H. (1980) J. Biol. Chem. 255, 1554-1558), the dialdehyde analogs of UMP and IMP both promote formation of mixed species. Low levels (less than 10 mM) of inorganic phosphate decrease the extent of activation by IMP, dialdehyde IMP, and dialdehyde UMP, but increase the extent of inhibition by UMP. The marked activation observed with dialdehyde UMP, and other considerations, suggest that the binding sites on the enzyme for IMP and UMP may overlap substantially. The findings also suggest that physiological levels of inorganic phosphate function in the modulation of the allosteric regulation of this enzyme by nucleotides.
D000494:Allosteric Regulation; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004789:Enzyme Activation / Q000187:drug effects; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism*; D046911:Macromolecular Substances; D010710:Phosphates / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000494:pharmacology*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology*
D046911:Macromolecular Substances; D010710:Phosphates; D014500:Uracil Nucleotides; D007291:Inosine Monophosphate; C030362:UMP dialdehyde; C030361:IMP dialdehyde; D014542:Uridine Monophosphate; D008025:Ligases; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)