Triosephosphate Isomerase Deficiency: Predictions and Facts

Abstract

Deficiencies in around 20 enzymes, associated with widely different degrees of severity and complexity, have been identified for human erythrocytes. The fact that glycolysis is crucial for erythrocyte function is reflected by the large number of inherited glycolytic enzymopathies. Triosephosphate isomerase (TPI) deficiency, a rare autosomal disease, is usually associated with nonspherocytic hemolytic anemia, progressive neurologic dysfunction, and death in childhood. The two affected Hungarian brothers studied by us have less than 3% TPI activity and enormously (30–50-fold) increased dihydroxyacetone phosphate (DHAP) concentration in their erythrocytes. The well-established concept of the metabolic control theory was used to test the contribution of TPI and some related enzymes to the control of a relevant segment of the glycolytic pathway in normal and deficient cells. Deviation indices, D E J = (Δ J/Δ E) E r/ J r, which give a good estimation of flux control coefficients using a single large change in enzyme activity, were determined from the fluxes in the absence and presence of exogenous enzymes. We found that PFK and aldolase are the enzymes that predominantly control the flux, however, the quantitative values depend extensively on the pH: D E J values are 0.85 and 0.14 at pH 8.0 and 0.33 and 0.67 at pH 7.2 for aldolase and PFK, respectively. Neither the flux rates nor the capacities of the enzymes seem to be significantly different in normal and TPI deficient cells. There is a discrepancy between DHAP levels and TPI activities in the deficient cells. In contrast to the experimental data the theoretical calculations predict elevation in DHAP level at lower than 0.1% of the normal value of TPI activity. Several possibilities suggested fail to explain this discrepancy. Specific associations of glycolytic enzymes to band-3 membrane proteins with their concomitant inactivation have been demonstrated. We propose that the microcompartmentation of TPI that could further decrease the reduced isomerase activity of the deficient cells is responsible for the high DHAP level.