title: Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate.
abstract: Blockade of a metabolic pathway by interaction of a drug with a particular 'target enzyme' results in depletion of essential end-products of the pathway and accumulation of intermediates prior to the blockade. Metabolic resistance to a particular drug can arise if the substrate of the inhibited enzyme accumulates to levels sufficiently high to compete effectively with the inhibitor, leading to restoration of full activity of the metabolic pathway after a transitory delay. Such resistance has recently been demonstrated in vitro for the interaction of the tight-binding inhibitor N-phosphonacetyl-L-aspartate (PAcAsp) with the aspartate transcarbamoylase activity of the trifunctional protein which initiates pyrimidine biosynthesis in mammals [Christopherson, R. I. and Jones, M. E. (1980) J. Biol. Chem. 255, 11381-11395]. Carbamoyl phosphate, the product of the carbamoyl phosphate synthetase activity of this trifunctional protein, accumulates to a sufficiently high concentration that the inhibitory effect of PAcAsp is effectively abolished. We have developed a theoretical model for metabolic resistance which quantitatively accounts for these experimental data. This model has been used to simulate the interaction between the following potential or proven anti-cancer drugs and their target enzyme, under conditions similar to those which would occur in vivo: PAcAsp with aspartate transcarbamoylase; various OMP analogues [the 5'-monophosphates of 6-azauridine, pyrazofurin and 1-(beta-D-ribofuranosyl)-barbituric acid] with OMP decarboxylase; 5-fluorodeoxyUMP with thymidylate synthase; methotrexate with dihydrofolate reductase; and deoxycoformycin with adenosine deaminase.
mesh_terms: D001221:Aspartate Carbamoyltransferase / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002221:Carbamyl Phosphate / Q000378:metabolism; D004351:Drug Resistance; D008956:Models, Chemical; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000378:metabolism; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D001224:Aspartic Acid; D002221:Carbamyl Phosphate; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase; D010746:Phosphonoacetic Acid