Metabolie Regulation in Enzyme-Deficient Red Cells

Ha, Buc; Jp, Leroux; Garreau, Hervé; Jc, Marchand; Cartier, P

doi:10.1159/000459411

“…Calculated range of disease Properties of deficient enzymes Number of References diseased minimum range of minimum enzyme unstable kinetic change in persons survival chronic normal activity variants change isoenzyme activity disease activity ? - Tanaka, 1990;Valentine, 1983;Board, 1978;Rijksen, 1983;Miwa, 1985;Paglia, 1981;Necheles, 1970Tanka, 1990Paglia, 1974;Zanella, 1980;Neubauer, 1990;Arnold, 1973Tanka, 1990Vora, 1983;Valentine, 1984 ;Fogelfeld, 1990Kishi, 1987Miwa, 1981 ;Valentine, 1984Eber, 1979Valentine, 1984;Rosa, 1985 ;Zanella, 1985Waller, 1974Tanaka, 1990Maeda, 1991 ;Fujii, 1980Fujii, , 1992Valentine, 1984Schroter, 1965Rosa, 1973Rosa, , 1978Buc, 1974;Rosa, 1989;Tanaka, 1990 Syllm- Rapoport, 1965…”

Section: Enzymementioning

confidence: 99%

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

Schuster

¹

,

Holzhütter

²

1995

European Journal of Biochemistry

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There are numerous examples showing that the metabolism of cells can be severely impaired if the activity of only one of the participating enzymes undergoes large-scale alterations, resulting, for example, from spontaneous mutations (inherited or aquired enzymopathies), the administration of toxic drugs or self-inactivation of enzymes during cell aging. However, a quantitative relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction is very difficult to establish by experimental means. An alternative is to tackle this problem by mathematical modelling. Our approach is based on a comprehensive mathematical model of the energy and redox metabolism for human erythrocytes. We calculate stationary states of the cell metabolism, varying the activity of each of the participating enzymes by several orders of magnitude. The metabolic states are then evaluated in terms of a performance function which relates the metabolic variables to the overall functional fitness of the cell. The performance function for the erythrocyte takes into account the homeostasis of three essential metabolic variables : the energetic state (ATP), the reductive capacity (reduced glutathione), and the osmotic state. Based on the behaviour of the performance function at varying enzyme activities, we estimate those ranges of enzyme activities, in which the metabolic alterations should be either tolerable, associated with non-chronic or chronic diseases, or letal. For most enzymopathies, the experimental and clinical observations can be satisfactorily rationalized by the computational results. Moreover, a surprisingly high correlation is found between the range of the activity range where disease is predicted by the model and the observed number of diseased probands.Another objective of our study was to contribute to the theory of metabolic control. The well-elaborated concept of the metabolic control theory is restricted to (infinitely) small activity alterations. In order to quantify the metabolic effect of finite (large-scale) changes in the activity of an enzyme, we propose, as a control measure, the effective activity Em, defined as the relative activity of an enzyme (with respect to the activity in a reference state) required to bring about a change in the stationary value of a metabolic variable by the (finite) factor a. We demonstrate that none of the existing extrapolation methods using the conventional control coefficient is capable to provide reliable predictions of the effective activities for all enzymes of erythrocyte metabolism.

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“…Calculated range of disease Properties of deficient enzymes Number of References diseased minimum range of minimum enzyme unstable kinetic change in persons survival chronic normal activity variants change isoenzyme activity disease activity Tanaka, 1990;Valentine, 1983;Board, 1978;Rijksen, 1983;Miwa, 1985;Paglia, 1981;Necheles, 1970Tanka, 1990Paglia, 1974;Zanella, 1980;Neubauer, 1990;Arnold, 1973Tanka, 1990Vora, 1983;Valentine, 1984 ;Fogelfeld, 1990Kishi, 1987Miwa, 1981 ;Valentine, 1984Eber, 1979Valentine, 1984;Rosa, 1985 ;Zanella, 1985Waller, 1974Tanaka, 1990Maeda, 1991 ;Fujii, 1980Fujii, , 1992Valentine, 1984Schroter, 1965Rosa, 1973Rosa, , 1978Buc, 1974;Rosa, 1989;Tanaka, 1990 Syllm- Rapoport, 1965…”

Section: Enzymementioning

confidence: 99%

Use of Mathematical Models for Predicting the Metabolic Effect of Large-Scale Enzyme Activity Alterations. Application to Enzyme Deficiencies of Red Blood Cells

Schuster

¹

,

Holzhütter

²

1995

View full text Add to dashboard Cite

There are numerous examples showing that the metabolism of cells can be severely impaired if the activity of only one of the participating enzymes undergoes large-scale alterations, resulting, for example, from spontaneous mutations (inherited or aquired enzymopathies), the administration of toxic drugs or self-inactivation of enzymes during cell aging. However, a quantitative relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction is very difficult to establish by experimental means. An alternative is to tackle this problem by mathematical modelling. Our approach is based on a comprehensive mathematical model of the energy and redox metabolism for human erythrocytes. We calculate stationary states of the cell metabolism, varying the activity of each of the participating enzymes by several orders of magnitude. The metabolic states are then evaluated in terms of a performance function which relates the metabolic variables to the overall functional fitness of the cell. The performance function for the erythrocyte takes into account the homeostasis of three essential metabolic variables : the energetic state (ATP), the reductive capacity (reduced glutathione), and the osmotic state. Based on the behaviour of the performance function at varying enzyme activities, we estimate those ranges of enzyme activities, in which the metabolic alterations should be either tolerable, associated with non-chronic or chronic diseases, or letal. For most enzymopathies, the experimental and clinical observations can be satisfactorily rationalized by the computational results. Moreover, a surprisingly high correlation is found between the range of the activity range where disease is predicted by the model and the observed number of diseased probands.Another objective of our study was to contribute to the theory of metabolic control. The well-elaborated concept of the metabolic control theory is restricted to (infinitely) small activity alterations. In order to quantify the metabolic effect of finite (large-scale) changes in the activity of an enzyme, we propose, as a control measure, the effective activity Em, defined as the relative activity of an enzyme (with respect to the activity in a reference state) required to bring about a change in the stationary value of a metabolic variable by the (finite) factor a. We demonstrate that none of the existing extrapolation methods using the conventional control coefficient is capable to provide reliable predictions of the effective activities for all enzymes of erythrocyte metabolism.

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“…Interpretation ofthe data on the contents ofglycolytic intermediates is rather complicated because of the high reticulocytosis. In normal reticulocytes and young erythrocytes, the contents of glc-6-P, fructose-6-phosphate, and fructose-1,6-diphosphate are increased because of the high activity of hexokinase (24,25). Furthermore, the levels of ATP and 2,3-diphosphoglycerate are elevated in reticulocytes (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…In normal reticulocytes and young erythrocytes, the contents of glc-6-P, fructose-6-phosphate, and fructose-1,6-diphosphate are increased because of the high activity of hexokinase (24,25). Furthermore, the levels of ATP and 2,3-diphosphoglycerate are elevated in reticulocytes (24,25). With this in mind we conclude that with respect to the reticulocytosis, the levels of glc-6-P, fructose-6-phosphate, ATP, and 2,3-diphosphoglycerate are decreased in our patient, reflecting a block at the hexokinase level with consequent impairment of glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Human erythrocyte hexokinase deficiency. Characterization of a mutant enzyme with abnormal regulatory properties.

Rijksen¹,

Staal²

1978

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A B S T R A C T In the erythrocytes of a patient with hereditary nonspherocytic hemolytic anemia, a homozygous expression of hexokinase deficiency was detected. The mutant enzyme was characterized by normal kinetic parameters with respect to its substrates, glucose and MgATP2-, normal pH optimum, normal heat stability at 40°C, but abnormal behavior with respect to its regulation by glucose-1,6-diphosphate and inorganic phosphate, and an altered electrophoretic pattern. Interpretation of the results revealed the presence of two different hexokinases type I in normal human erythrocytes: one enzyme with a high affinity for glucose-1,6-diphosphate, the inhibition of which is regulated by inorganic phosphate; and another enzyme with a lower affinity for the inhibitor, not regulated by inorganic phosphate. The former enzyme was not detectable in the erythrocytes of the patient, whereas the presence of the latter enzyme could be demonstrated.

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Metabolie Regulation in Enzyme-Deficient Red Cells

Cited by 15 publications

References 14 publications

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

Use of Mathematical Models for Predicting the Metabolic Effect of Large-Scale Enzyme Activity Alterations. Application to Enzyme Deficiencies of Red Blood Cells

Human erythrocyte hexokinase deficiency. Characterization of a mutant enzyme with abnormal regulatory properties.

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