Interrelations between glycolysis and the hexose monophosphate shunt in erythrocytes as studied on the basis of a mathematical model

Schuster, R.; Holzhütter, Hermann‐Georg; Jacobasch, G

doi:10.1016/0303-2647(88)90047-0

Cited by 47 publications

(47 citation statements)

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“…In these and other physiological and pathological processes, GSH is oxidized to form GSSG. It was beyond the scope of the present model to include all of these individual reactions, so following the example of Schuster et al (21), individual reactions leading to the oxidation of GSH were not specified. Instead the overall process was described by a non-enzymatic rate equation with a second-order rate constant (k GSHox ) (see "Supplemental Information" online).…”

Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

“…Comprehensive models of erythrocyte glycolysis, the pentose phosphate pathway, 2,3-bisphosphoglycerate metabolism (12,(15)(16)(17), and the regulation of erythrocyte volume, pH, and transmembrane electrolyte distribution (18 -20) have all been developed and used to provide insights into various biophysical and biochemical mechanisms and the regulation of erythrocyte function. Although models used to simulate certain aspects of glutathione function have been developed (21,22), until now there have been no detailed and comprehensive models of glutathione metabolism based on realistic enzyme mechanisms and estimates of steady-state kinetic parameters.An understanding of glutathione metabolism in the erythrocyte has been developed from information gained by investigating the kinetics of isolated enzymes. Such information allows the prediction that increased activity of the ␥-glutamatecysteine ligase (GCL), increased substrate availability, and decreased GSH concentrations in the cell should all increase the rate of glutathione synthesis; but it is not possible to predict the magnitude of the increases or the interactions that produce a particular steady-state concentration without a comprehensive mathematical model (23).…”

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Glutathione Synthesis and Turnover in the Human Erythrocyte

Raftos

Whillier

Kuchel

2010

Journal of Biological Chemistry

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The erythrocyte is exposed to reactive oxygen species in the circulation and also to those produced by autoxidation of hemoglobin. Consequently, erythrocytes depend on protection by the antioxidant glutathione. Mathematical models based on realistic kinetic data have provided valuable insights into the regulation of biochemical pathways within the erythrocyte but none have satisfactorily accounted for glutathione metabolism. In the current model, rate equations were derived for the enzyme-catalyzed reactions, and for each equation the nonlinear algebraic relationship between the steady-state kinetic parameters and the unitary rate constants was derived. The model also includes the transport processes that supply the amino acid constituents of glutathione and the export of oxidized glutathione. Values of the kinetic parameters for the individual reactions were measured predominately using isolated enzymes under conditions that differed from the intracellular environment. By comparing the experimental and simulated results, the values of the enzyme-kinetic parameters of the model were refined to yield conformity between model simulations and experimental data. Model output accurately represented the steady-state concentrations of metabolites in erythrocytes suspended in plasma and the changing glutathione concentrations in whole and hemolyzed erythrocytes under specific experimental conditions. Analysis indicated that feedback inhibition of ␥-glutamate-cysteine ligase by glutathione had a limited effect on steady-state glutathione concentrations and was not sufficiently potent to return glutathione concentrations to normal levels in erythrocytes exposed to sustained increases in oxidative load.Erythrocyte glutathione plays a vital role in mitigating the damaging effects of reactive oxygen species (ROS) 4 encountered in the circulation (1) and produced by continuous oxidation of hemoglobin within the cytosol of the erythrocyte (2, 3). Reduced glutathione (GSH) reacts with superoxide reaction products, and via specific enzymes, it degrades hydrogen peroxide and lipid peroxides (glutathione peroxidase, EC 1.11.1.9), and covalently modifies toxic xenobiotics and endogenous electrophiles (glutathione S-transferase, EC 2.5.1.18) to form water-soluble conjugates that are exported from the erythrocyte for excretion (4). In diseases associated with increased production of ROS that results in GSH depletion, restoration of the normal erythrocyte GSH concentration has been shown to have positive therapeutic effects (5, 6).Experimental studies have provided a wealth of information on the individual reactions that together underlie the metabolic processes of the human erythrocyte (7)(8)(9)(10)(11)(12)(13)(14). This information has been used to develop mathematical models to analyze and then predict the way in which the kinetic characteristics and control mechanisms for each reaction combine to regulate particular metabolic processes. Comprehensive models of erythrocyte glycolysis, the pentose phosphate pathway, 2,3-bisphosphogl...

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Section: Refinement Of Parameter Values-experimentally Measured Steadmentioning

confidence: 99%

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confidence: 99%

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Glutathione Synthesis and Turnover in the Human Erythrocyte

Raftos

Whillier

Kuchel

2010

Journal of Biological Chemistry

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“…Normally, 5-10 % of the total glucose consumption in RBC passes through the HMS, and the flux is limited by the GóPD reaction which ope rates at less than 1 % of its capacity at physiological levels of NADPH. Thus, glycolysis and HMS are controlled by the energetic and oxidative loads, res pectively (Schuster et al, 1988). Under conditions of oxidative stress, i.e., high levels of GSSG, more than 80 % of the 2-fold increased glucose consumption passes through the HMS.…”

Section: Interrelationships Between Glycolysis and The Hexose Monophomentioning

confidence: 99%

“…Under conditions of oxidative stress, i.e., high levels of GSSG, more than 80 % of the 2-fold increased glucose consumption passes through the HMS. In this case the velocity of GSSG reduction is rate-limited by the activity of hexokinase rather than by G6PD (Thorburn & Kuchel, 1985), indicating that both glycolysis and HMS are tightly coupled (Schuster et al, 1988). This would mean that the tolerable oxidative load is severely res tricted by an increasing energetic load, and vice versa.…”

Section: Interrelationships Between Glycolysis and The Hexose Monophomentioning

confidence: 99%

The redox status of malaria-infected erythrocytes: an overview with an emphasis on unresolved problems

Ginsburg

Atamna

1994

Parasite

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Summary :The various mechanisms involved in the redox defence of norma erythrocytes are adequately known. They are herein briefly reviewed, outlining the principal enzymes and metabolic pathways, such as superoxide dismutase, catalase, glutathione peroxidase and reductase, the hexose monophosphate shunt (HMS) and glutathione synthesis and turnover. The intraerythrocytic malaria parasite is imposing an oxidative stress on its host cell. Malaria-infected cells produce O 2 -, H 2 O 2 , enhance lipide peroxidation and activate host cell HMS. This stress is produced during the digestion of host cell hemoglobin by the parasite. Hence, both parasite and host cell must be able to confront this stress. The antioxidant defence systems of the parasite and the response of those systems in the infected host cell are reviewed, underscoring unresolved problems. Nothing is virtually known on the parasite's glutathione metabolism, and on possible interactions between host cell and parasite antioxidant defence systems. The postulate that 1. host cell activated HMS in conjunction with purine salvage can provide purine nucleotides to the parasite, and 2. that glutathione transferase can participate in parasite resistance to antimalarial drugs, are also discussed.T he redox status of malaria infected erythrocytes has been the subject of intense investigations and reviews in past years (Vennerstrom & Eaton, 1988 ; Golenser & Chevion, 1989 ; Hunt & Stocker, 1990). It is generally accepted that the intraerythrocytic malaria parasite exerts an oxidative stress on its host erythrocyte ; that externally applied oxidative stress is antagonistic to survival and propagation of the malaria parasite, and that pro-oxidant agents are effective inhibitors of parasite growth in vitro and in vivo. The host's response to malaria involves, among others, oxidative attack on intraerythrocytic parasites by activated macrophages. This perception is based mostly on phenomenological observations, but relatively little is known on the redox metabolism of the parasite itself, or how the latter may affect that of the host cell. In this essay we shall briefly review our present knowledge and underscore those problems Rice-Evans, 1991), and therefore RBC are exquisitely well equipped to counteract the damage that can be produced by these radicals (Stern, 1985).Superoxide anions (O2 -) produced during the spontaneous oxidation of hemoglobin to methemoglobin are dismutated to H 2 C>2 by superoxide dismutase (SOD).

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Modeling and Simulating Metabolic Networks

Schuster¹,

Fell²

2007

Bioinformatics‐From Genomes to Therapies

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Interrelations between glycolysis and the hexose monophosphate shunt in erythrocytes as studied on the basis of a mathematical model

Cited by 47 publications

References 27 publications

Glutathione Synthesis and Turnover in the Human Erythrocyte

Glutathione Synthesis and Turnover in the Human Erythrocyte

The redox status of malaria-infected erythrocytes: an overview with an emphasis on unresolved problems

Modeling and Simulating Metabolic Networks

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