Adenosine monophosphate deaminase

Figure 3. Compartmentalization of the purine salvage pathway of Leishmania. Abbreviations are as follows AAH, adenine aminohydrolase XPRT, xanthine phosphoribosyltransferase HGPRT, hypoxanthine-guaninephosphoribosyltransferase ADSS, adenylosuccinate synthetase ASL, adenylosuccinate lyase IMPDH, inosine monophosphate dehydrogenase GMPS, gua-nosine monophosphate synthase GDA, guanine deaminase AMPDA, adenosine monophosphate deaminase GMPR, guanosine monophosphate reductase APRT, adenine phosphoribosyltransferase AK, adenosine kinase. Enzymes that have been localized are shown in black and those that are predicted to be in the denoted locations are depicted in gray.

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). 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Pharmacokinetics Rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. Extensively distributed and rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Ralf-life 10 sec. 

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. 

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

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

Myoadenylate deaminase deficiency is a recessive disorder that affects approximately 1 -2% of populations of European descent, but appears considerably rarer in Asian populations. Myoadenylate deaminase, also called adenosine monophosphate (AMP) deaminase, is an enzyme that converts AMP to inosine monophosphate (IMP). Its deficiency results in excess AMP, which is lost by excretion with disturbances in energy generation. Symptoms of severe fatigue and muscle pain can result. 

Pennington (PI) and Uberti (U1) first introduced the technique of liquid chromatographic enzyme assays by using the ion-exchange mode of HPLC in their analyses of 3, 5 -cyclic adenosine monophosphate phosphodiesterase and adenosine deaminase, respectively. Since that time, a number of liquid chromatographic enzyme assays have been developed. 

Roth, E., Jr., Ogasawara, N., and Schulman, S. (1989). The deamination of adenosine and adenosine monophosphate in Plasmodium falciparu m-i n fee ted human erythrocytes In vitro use of 2 deoxycoformycin and AMP deaminase-deficient red cells. Blood 74, 1121-1125. 

Fig. 173. Interconversion of inosine, adenosine and guanosine monophosphates 1 Inosine monophosphate dehydrogenase 2 guanosine monophosphate synthase 3 guanosine monophosphate reductase 4 adenylosuccinate synthetase 5 adenylosuccinate lyase 6 adenosine (phosphate) deaminase...

Adenosine deaminase converts adenosine monophosphate back to inosine monophosphate, liberating ammonia. This sequence of reactions thus provides a pathway for the deamination of a variety of amino acids, linked to transamination, similar to those shown in Figure 9.9 for transamination linked to glutamate dehydrogenase or glycine oxidase. 

CoMFA, CoMSIA and docking studies of N3-substituted coformycin aglycon analogs as potent adenosine 5 -monophosphate deaminase (AMPDA) inhibitors... 

Adenosine is formed from ATP via a phosphatase cascade that sequentially involves the diphosphate, ADP, and the monophosphate, AMP. The actions of adenosine are terminated by uptake and rephosphorylation via adenosine kinase to AMP or by cataboHsm via adenosine deaminase to inosine and hypoxanthine. 

Answer C. The child most likely has severe combined immunodeficiency caused by adenosine deaminase defidency. This enzyme deaminates adenosine (a nudeoside) to form inosine (another nucleoside). Hypoxanthine and xanthine are both purine bases, and the monophosphates are nucleotides. 

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