Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate. 687 66

Antimetabolic anticancer agents possess their own target enzymes: that of methotrexate is dihydrofolate reductase; 5-fluorouracil and ZD1604, thymidylate synthase; hydroxyurea, ribonucleotide reductase; 2'-deoxycoformycin, adenosine deaminase; N-(phosphonacetyl)-L-aspartate, aspartate transcarbamylase. Overproduction of each target enzyme has been observed with various animal and human cell lines which acquired resistance to all these agents. These facts suggest that this is a common mechanism for resistance to these agents. Most of these resistant cells showed amplification of the corresponding genes in double minute chromosome or homogeneously stained region of the chromosome. The relation between the degree of resistance and those of enzyme overproduction, the expression and amplification of the gene coding for each enzyme protein in various resistant cell lines are demonstrated and discussed.
 ...
PMID:[Acquisition of resistance to anticancer agents by overproduction of target enzymes]. 915 48