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Mathematical model of metabolic systems: application and validation by metabolome
Author(s) -
Suematsu Makoto,
Kinoshita Ayako Yachie
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.995.3
Subject(s) - glycolysis , adenylate kinase , adenosine , adenosine triphosphate , hypoxia (environmental) , biochemistry , extracellular , metabolism , biology , energy charge , chemistry , microbiology and biotechnology , enzyme , oxygen , organic chemistry
ATP maintenance costs large energy for erythrocytes that mostly depend on glycolysis, although mechanisms for balancing its consumption and synthesis remain unknown. The large‐scale mathematical model of erythrocyte metabolism predicted that uptake of extracellular adenosine into the cells to supply the substrate for ATP synthesis constitutes a major fraction of the consumption: this process causes a decrease in the basal ATP amounts in the cell under normoxia, but not under hypoxia, since the hemoglobin‐dependent O 2 sensing activates glycolysis. A shortage of ATP during the adenosine uptake was predicted to be compensated by the hypoxia‐induced glycolytic activation until 20 min after the onset of hypoxia, whereas further lengths of hypoxia did not compensate it. Such a prediction was consistent with the data indicating temporal ATP measurements in human erythrocytes in the presence of adenosine under hypoxia. Based on the model prediction that adenosine kinase and adenylate kinase constitute the major fraction of ATP consumption during the adenosine adsorption, we conducted experiments under the 15 N‐labeled adenosine incubation, measuring the mass‐labeled AMP, ADP and ATP in the cells. Results indicated that hypoxia stimulated the uptake of the mass‐labeled adenosine to synthesize the high‐energy adenosine phosphates. When pretreated with CO that inhibits the hypoxia‐induced glycolytic activation, erythrocytes decelerated the salvage of the mass‐labeled adenosine. These results predicted by biosimulation and demonstrated by measurements suggest that hypoxia‐triggered glycolytic activation plays a crucial role in compensating cellular energetics for maintaining adenylate pool through salvaging extracellular adenosine.