In silico study of peculiarities of metabolism of erythrocytes with glucosephosphate isomerase deficiency

Abstract

Glucose phosphate isomerase (GPI) deficiency, the third most common cause of hereditary nonspherocytic hemolytic anemia, is associated with the mutation of the GPI gene. The results of the GPI deficiency are premature aging of erythrocytes, macrocytosis, reticulocytosis, minor splenomegaly, hyperbilirubinemia and hyperferritinemia, and hemolytic crisis under the influence of exogenous oxidants such as infections or drugs. Regarding the the lack of GPI correction drugs, the theoretical substantiation of supportive therapy based on system biology approaches that would allow the analysis of the relationships between numerical metabolic processes in a cell would be beneficial. The stoichiometric model of erythrocytes’ steady state metabolism, including the pathways of Embden-Meyerhof and pentose phosphate (PPP), purine metabolism cycles and glutathione synthesis, has been developed. To predict the redistribution of metabolic flows in erythrocytes under conditions of GPI deficiency, we used the flux balance analysis (FBA). In this approach, calculations of the elementary flux modes (EFMs) and the control-effective flux (CEF) have been performed. Using the CEF evaluation approach, effective profiles of enzymatic reactions depending on the degree of enzyme deficiency were obtained. It has been shown that these relationships can be the basis for future experimental studies. Analysis of the profiles of enzymatic reactions of metabolic networks suggests that erythrocytes are capable of metabolizing other substrates that contribute to overcoming the effects of energy stress in the case of enzymopathies. So, it is shown that erythrocytes can effectively use SAM and adenosine as alternative energy sources. It has been established that the GPI enzymopathy results in a decrease in the flow through the glycolysis and pentose phosphate pathway, resulting in a decrease in the content of such reducing agents as NADPH and GSH, ATP. The processes of the GSH synthesis from amino acids in the cell are shown to be suppressed. Decreased content of NADPH and GSH cause the premature aging of erythrocytes. The target therapeutic approaches that influence the behaviour of the metabolic network of erythrocytes are discussed.

Keywords

• stoichiometric modeling; elementary flux modes; control-effective flux; system biology; flux balance analysis method; metabolic networks of erythrocytes; enzyme deficiencies.