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Role of the Adenylate Deaminase Reaction in Regulation of Adenine Nucleotide Metabolism in Ehrlich Ascites Tumor Cells1

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Role of the Adenylate Deaminase Reaction in Regulation of Adenine Nucleotide Metabolism in Ehrlich Ascites Tumor Cells1 [CANCER RESEARCH 36, 1144-1 150, March 1976] Role of the Adenylate Deaminase Reaction in Regulation of Adenine Nucleotide Metabolism in Ehrlich Ascites Tumor Cells1 Astrid G. Chapman, Arnold L. Miller,2 and Daniel E. Atkinson Biochemistry Division, Department of Chemistry, University of California, Los Angeles, California 90024 SUMMARY ing cell by regulating the rates of ATP-utilizing and ATP regenerating sequences have been discussed (1-3) and are The regulatory properties of adenylate deaminase (EC implicit in the subsequent discussion. 3.5.4.6) from Ehnlich ascites tumor cells suggest that the It has been known for a number of years that upon the reaction catalyzed by this enzyme serves to protect the cell addition of glucose on 2-deoxyglucose to incubated ascites against sharp decreases in the adenylate energy charge by cells there is a rapid and eventually reversible decrease in removing adenosine 5'-monophosphate generated when both the concentration of ATP and the total adenine nucleo the rate of utilization of adenosine tniphosphate is suddenly tide concentration of the cells (13, 15, 16, 21, 22, 25, 35). In increased. The enzyme is effectively inhibited under normal Chart 1, the analytical results of Overgaard-Hansen (25) are physiological conditions of high energy change (0.9) and 4 plotted, together with the calculated values of the adenylate to 5 mM adenine nucleotide pool size. The reaction is energy charge. Conversion of AMP to inosine has recently sharply activated by a decrease in the energy change in the been shown to occur mainly via the AMP deaminase neac physiological range (0.9 to 0.6). At low energy change (0.6), tion, followed by a dephosphorylation of IMP (22). decrease in the size of the pool causes a marked and non The utilization of ATP and the subsequent transient in linear decrease in the rate of the deaminase reaction. This crease in AMP can, of course, be explained in terms of the effect presumably serves to prevent excessive depletion of sudden high rate of hexokinase-mediated phosphorylation the adenine nucleotide pool. Calculations based on the of the added carbohydrate, followed by a rapid conversion kinetic data obtained in this study show that the AMP deam of the ADP produced to AMP and ATP through the action of inase reaction can account for the well-established altena adenylate kinase, but it has remained unclean why there tion of adenine nucleotide metabolism that is observed should be a concomitant decrease in the level of the total following addition of glucose on 2-deoxyglucose to intact adenylate pool. This question is compounded by the fact ascites cells. that AMP deaminase from ascites cells, as from other sources, has been shown to be activated by ATP (4, 35), but the increase in the rate of the reaction following glucose INTRODUCTION addition to the cells coincides with a decrease in the level of the activator ATP. Adenine nucleotide metabolism in Ehnlich ascites cells It has been suggested that the depletion of the adenylate has been studied extensively, partly in search of a clue to pool is caused by a release of the known phosphate inhibi the high rate of aerobic glycolysis in these tumor cells. The tion of AMP deaminase as the intracellular phosphate level total concentration of the adenine nucleotides rn ascites decreases (35). This undoubtedly contributes to the negula cells is normally maintained at a steady level (in the range tion of the enzyme, but the drop in the adenylate pool is 3.5 to 5 p@moles/mlof cells) under different conditions of observed even when the concentration of phosphate in the growth and incubation by keeping the rates of synthesis and medium is very high (25) and a smaller decrease in the utilization of the adenine nucleotides in balance (12, 17, 18, intracellular phosphate concentration would be expected. 20-22, 24, 25, 33, 35). Within the adenylate pool there is an We have recently suggested that a very similar fructose extremely rapid interconversion of the 3 adenine nucleo induced adenylate depletion in liver serves to stabilize the tides, yet the adenylate energy charge (ATP + 0.5 ADP)/ adenylate energy charge (8). When the energy demand on (ATP + ADP + AMP) (1) is maintained at a value of about the cell is suddenly increased, the AMP that would tend to 0.90 in ascites cells (12, 17, 18, 20-22, 24, 25, 27, 33, 35) as accumulate is rapidly removed by the AMP deaminase neac well as in most tissues and organisms studied (9). The need tion, thereby restoring the energy charge to control values. for a closely controlled energy charge value and the role of This response is then followed by a much slower replenish thisparameterinmaintaininghomeostasisina metaboliz ing of the adenine nucleotide pool. I This work was supported in part by Research Grant AM09863 from the The energy change values shown in Chart 1 suggest that National Institute of Arthritis, Metabolism, and Digestive Diseases. this proposal can be extended to ascites tumor cells. This 2 Recipient of Postdoctoral Fellowship 5 FO2-CA-28,649 from the National paper reports experiments on AMP deaminase from ascites Cancer Institute. Present address: Department of Neurosciences, University of California, San Diego, La Jolla, Calif. 92037. cells. The results are consistent with the prediction that the Received December 13, 1974; accepted December 3. 1975. regulatory properties of this enzyme contribute to the ob 1144 CANCERRESEARCHVOL. 36 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1976 American Association for Cancer Research. Ascites Adenylate Deaminase was dissolved in Tnis-glycerol buffer (3 ml) and stored at 5 i0 — 1 5°. The enzyme was purified only about 1 2- to 1 5-fold 4 La 2 with a 40 to 50% yield, but the preparation was free of 0 adenylate kinase and ATPase activities. In this form, the 2e c@It°@;@ 4 n I enzyme was stable for 10 to 15 days at —15°.However the U.! ‘4 0 response of the enzyme to ATP activation decreased toward z@ 7, \ .2 the end of this period, and consequently the kinetic studies were carried out within 1 week of the enzyme purification. 0 2 4 6'1E 3@ 50 TIME (minI Freezing, which was prevented at —15°bythe presence of Chart 1. Changes in concentrations of ATP, total adenine nucleotides (@ glycerol, caused a 20 to 50% inactivation of the enzyme Ad.N.), inosine, and adenylate energy charge (E.C.) values in Ehrllch ascites activity. tumor cells following addition of 5 m@ glucose at zero time. Tumor cell Assays for AMP Deamlnase Activity. The glutamate de volume was 7.8% and the cells were suspended in 55 m@@iphosphate-Locke's solution (pH 7.35) at 37°.From the data of Overgaard-Hansen (25). hydnogenase-coupled determination of the ammonium gen erated (8) was routinely used in the kinetic studies. A stand served glucose-induced variations in the adenylate concen and assay mixture for measuring optimal enzyme activity trations in the intact cell. contains: 100 mM imidazole chloride, pH 6.8, 100 mM KCI, 4 mM AMP, 2 mM ATP, 4 mM MgSO4, 4 mM a-ketoglutarate, 0.26 mM DPNH, and 0.5 mg of commercial glutamate dehy MATERIALS AND METHODS drogenase (Boehninger enzyme in 50% glycerol). The assay mixture, including glutamate dehydrogenase, Ascites Cells. Ehrlich ascites cells were grown in 10- to was preincubated at 37°for10 to 15 mm before the reaction 12-week-old Swiss female mice and collected on the 8th day was initiated by the addition of 10 to 50 @gof partially following a 0.25-mI i.p. inoculation. The average yield was purified AMP deaminase. The reaction was followed at 340 about 4 to 6 ml of packed cells pen animal. After the cells nm by means of a Vanian Model 135 spectrophotometen with were collected in a beaker containing hepanin, they were recorder. washed twice with 0.9% NaCI solution to remove erythro During the purification, the AMP deaminase activity was cytes. Following a subsequent wash in 50 mM Tnis-CI, pH measured by the microdiffusion method (28). The amount of 7.4, 5 mM /3-mercaptoethanol, and 20% glycerol (Tnis-glyc ammonia generated in 30 mm at 37°wasdetermined colon erol buffer), the cells were suspended in the initial volume of metrically at 420 nm after reaction with Nessler's reagent. @ the same Tris-glycerol buffer. In order to determine a possibleeffect of or DPNH on The cells were broken by sonic disruption (Bronson sonic the AMP deaminase reaction, the conversion of AMP to IMP oscillator at 8 amp) for a total of 2 to 2.5 mm (in 20-sec was followed directly at 285 nm (19). Because of the high periods interspersed with 1-mm cooling periods). The cell extinction coefficient of the adenine nucleotides at 285 nm, debris was removed by 60 mm of centnifugation at 40,000 x the assay can be used only when the total adenylate con g, and the cell extract was stored frozen at —20°. centration is less than about 4 mM, which corresponds to an Partial Purification of AMP Deaminase. The AMP deami absorbance of 2.8 at 285 nm. nase activity from ascites cells was completely stable for 2 Calculation of Total Mg2@Concentration Corresponding years when the crude cell extract was stored at —20°.How to I m@Free [email protected] the amount of Mg2@thatis even, subsequent purification led to a fairly rapid inactiva complexed by the different components in the assay mix tion of the enzyme. tune, the following stability constants, quoted by Blair (6), AMP deaminase from ascites cells was purified by a pro were used: MgATP2, 73300 N' ; MgHATP, 600 M'; cedure similar to that used for the liver enzyme (8).
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