Modulating hemoglobin nitrite reductase activity through allostery: A mathematical model

The production of nitric oxide by hemoglobin (Hb) has been proposed to play a major role in the control of blood flow. Because of the allosteric nature of hemoglobin, the nitrite reductase activity is a complex function of oxygen partial pressure P<inf>O2</inf>. We have previous developed a model to obtain the micro rate constants for nitrite reduction by R state (k<inf>R</inf>) and T state (k<inf>T</inf>) hemoglobin in terms of the experimental maximal macro rate constant k<inf>Nmax</inf> and the corresponding oxygen concentration P<inf>O2max</inf>. However, because of the intrinsic difficulty in obtaining accurate macro rate constant k<inf>N</inf>, from available experiments, we have developed an alternative method to determine the micro reaction rate constants (k<inf>R</inf> and k<inf>T</inf>) by fitting the simulated macro reaction rate curve (k<inf>N</inf> versus P<inf>O2</inf>) to the experimental data. We then use our model to analyze the effect of pH (Bohr Effect) and blood ageing on the nitrite reductase activity, showing that the fall of bisphosphoglycerate (BPG) during red cell storage leads to increase NO production. Our model can have useful predictive and explanatory power. For example, the previously described enhanced nitrite reductase activity of ovine fetal Hb, in comparison to the adult protein, may be understood in terms of a weaker interaction with BPG and an increase in the value of k<inf>T</inf> from 0.0087 M^-1s ^-1 to 0.083 M^-1s^-1. © 2013 Elsevier Inc. All rights reserved.