Oxygen-linked modulation of erythrocyte metabolism: state of the art.

About fifteen years ago a number of experimental data on the specific interaction of haemoglobin (Hb) and various enzymes of the glycolytic pathway with the cytoplasmatic domain of band 3 protein emerged13. These data induced our research group to formulate the hypothesis of a modulation of the erythrocyte (RBC) metabolism driven by the free energy connected to the R to T Hb transition4. The general scheme of this simple model is reported in figure 1. In this model band 3 protein plays a pivotal role: when the erythrocyte is at high oxygenation state (HOS) band 3 interacts with some glycolytic enzymes (inhibiting their activity) and more glucose is addressed towards the pentose phosphate pathway (PPP). When the erythrocyte is at low oxygenation state (LOS) the high affinity of deoxy-Hb for the N-terminal cytoplasmatic domain of band 3 induces the release of glycolytic enzymes, and thus glucose flux towards the glycolytic pathway increases. Some recent results obtained by our and other groups are in agreement with this simple model, even though they indicate, that other factors might play a significant role in this erythrocyte modulation. The aim of this brief review is to offer to the reader a critical examination of the significance of these recent results in light of the model framework. Figure 1 Simplified scheme representing the modulation of erythrocyte metabolism by the O2 transition of Hb and its competition with glycolytic enzymes (mainly phosphofructokinase, PFK) for the cytoplasmic domain of band 3 (CDB3). Band 3 protein Band 3 is a transmembrane protein that accounts for about 25% of the total RBC membrane proteins. It is characterized by three distinct functional domains: (1) the membrane spanning domain, which transverses 12 times the bilayer and serves to catalyze the exchange of anions (mainly Cl− and HCO3−) across the membrane5; (2) the short C-terminal cytoplasmatic domain that binds carbonic anhydrase II6,7, and (3) the N-terminal cytoplasmatic domain (CDB3) that binds a variety of proteins8 and anchors the RBC membrane to the underlying cytoskeleton via ankyrin and protein 4.29.