Adenosine monophosphate deaminase inhibition

MTX also has several effects on the purine synthetic pathway. MTXPGs inhibit the enzyme aminoimidazole carboxamide ribonucleotide (AlCAR) transformylase, which in turn causes intracellular accumulation of AICAR. AICAR and its metabolites can then inhibit two enzymes in the adenosine pathway adenosine deaminase and adenosine monophosphate (AMP) deaminase, which leads to intracellnlar accumulation of adenosine and adenine nucleotides. Subsequent dephosphorylation of these nucleotides results in increased extracellular concentrations of adenosine, which is a powerful anti-inflammatory agent (11). 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

Coformycin (4.11) is a transition state analogue that competitively inhibits the enzyme adenosine monophosphate (AMP) deaminase (Scheme 4.12). AMP deaminase... 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Adenosine uptake may involve a membrane-bound kinase enzyme which releases adenosine as its monophosphate within the cell.2 Dipyridamole inhibits this membranal kinase in guinea pigs to a greater degree than soluble intracellular adenosine deaminase or kinase enzymes. Dipyridamole, in rats, does not prevent uptake or potentiate the vasodilator effects of adenosine due to a lack of the membranal kinase transport mechanism. Thus, species variation in adenosine uptake mechanism may tend to confuse studies in mechanisms of action with vasodilators interfering with adenosine. 

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