Abstract
Hemoglobin dissociation is of great interest in protein process and clinical medicine as well as in artificial blood research. However, the pathway and mechanisms of pH-dependent human Hb dissociation are not clear, whether Hb would really dissociate into monomers is still a question. Therefore, we have conducted a multi-technique investigation on the structure and function of human Hb versus pH. Here we demonstrate that tetramer hemoglobin can easily dissociate into dimer in abnormal pH and the tetramer → dimer dissociation is reversible if pH returns to normal physiological value. When the environmental pH becomes more acidic (<6.5) or alkaline (>8.0), Hb can further dissociate from dimer to monomer. The proportion of monomers increases while the fraction of dimers decreases as pH declines from 6.2 to 5.4. The dimer → monomer dissociation is accompanied with series changes of protein structure thus it is an irreversible process. The structural changes in the dissociated Hbs result in some loss of their functions. Both the Hb dimer and monomer cannot adequately carry and release oxygen to the tissues in circulation. These findings provide a comprehensive understanding on the pH-dependent protein transitions of human Hb, give guideline to explain complex protein processes and the means to control protein dissociation or re-association reaction. They are also of practical value in clinical medicine, blood preservation and blood substitute development.
Highlights
In certain abnormal metabolism and respiration conditions, especially in some pathological situations such as acidosis or alkalosis, the pH value of human blood would fall outside of the normal physiological range of 7.35-7.45
We have conducted a multi-technique systematic study on the effect of pH on the structure and function of human hemoglobin, and demonstrated with direct and convincing evidences that when the environmental pH is away from normal physiological value, the tetramer hemoglobin would dissociate into dimer by having electrostatic free energy advantage
The tetramer → dimer dissociation is a α2β2 → 2αβ process and it is reversible if the environmental pH returns to neutral value
Summary
In certain abnormal metabolism and respiration conditions, especially in some pathological situations such as acidosis or alkalosis, the pH value of human blood would fall outside of the normal physiological range of 7.35-7.45. It was reported that under abnormal pH condition, human tetramer hemoglobin would dissociate into dimers[3,4,5,6,7,8,9]. The dissociation of tetrameric hemoglobin is a very important issue in clinic and blood substitute research because dissociated Hb in body circulation would induce some side effects such as renal tubular damage and toxicity[10], and be cleared rapidly from circulation[11]. Whether the Hb dimer would further dissociate into monomers is a question for lack of solid evidence, several hypotheses have been made
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