Hemoglobin catalyzes ATP-synthesis in human erythrocytes: a murburn model

Blood hemoglobin (Hb), known to transport oxygen, is the most abundant globular protein in humans. Erythrocytes have similar to 10(-3) M concentration of ATP in steady-state and we estimate that this high amounts cannot be formed from 10(-4) - 10(-7) M levels of precursors via substrate-level phosphorylation of glycolysis. To account for this discrepancy, we propose that Hb serves as a `murzyme' (a redox enzyme working along the principles of murburn concept), catalyzing the synthesis of the major amounts of ATP found in erythrocytes. This proposal is along the lines of our earlier works demonstrating DROS (diffusible reactive oxygen species) mediated ATP-synthesis as a thermodynamically and kinetically viable mechanism for physiological oxidative phosphorylation. We support the new hypothesis for Hb with theoretical arguments, experimental findings of reputed peers and in silico explorations. Using in silico methods, we demonstrate that adenosine nucleotide and 2,3-bisphosphoglycerate (2,3-BPG) binding sites are located suitably on the monomer/tetramer, thereby availing facile access to the superoxide emanating from the heme center. Our proposal explains earlier reported in situ experimental findings/suggestions of 2,3-BPG and ADP binding at the same locus on Hb. The binding energy is in the order of 2,3-BPG > NADH > ATP > ADP > AMP and agrees with earlier reports, potentially explaining the bioenergetic physiology of erythrocytes. Also, the newly discovered site for 2,3-BPG shows lower affinity in fetal Hb (as compared to adults) explaining oxygen transfer from mother to embryo. The findings pose significant implications in routine physiology and pathologies like sickle cell anemia and thalassemia.

Automated summary

The high ATP concentration in erythrocytes may be catalyzed by hemoglobin serving as a ‘murzyme’, explaining discrepancies in previous findings. Adenosine nucleotide and 2,3-bisphosphoglycerate binding sites on Hb allow interaction with superoxide, potentially providing a new mechanism for ATP synthesis. The new hypothesis for Hb binding affinities and lower affinity for 2,3-BPG in fetal Hb compared to adults may have significant implications in physiology and pathologies like sickle cell anemia and thalassemia.