The further understanding of hemoglobin structure, function, and stability is paramount in the search for therapies directed towards highly morbid or fatal hemoglobinopathies (diseases that arise from mutant hemoglobins) that continue to be a world-wide health problem.
A recent focus of our laboratory is the hemoglobinopathy HbE (β26 Glu →Lys) and its related diseases. HbE is the most common hemoglobin mutant world-wide and is predominantly found in Southeast Asia. With the increasing wave of immigration to North America, HbE is now the second most common hemoglobinopathy found in the USA, second to sickle cell hemoglobin. The consequence of this mutation is very different from that of the β6 mutants. In vitro, HbE is highly unstable. Surprisingly, HbE homozygous individuals present a benign clinical picture, while double heterozygotes such as HbE/β-thalassemia present severe clinical symptoms in this life-threatening disease. The mechanistic role of HbE as the origin of the pathophysiology remains an enigma. We have established transgenic mouse models producing soley human HbE. recently, we have recently discovered the first reported functional differerence for HbE: HbE generates less bioactive nitric oxide, a compound critical for the cardiovasculature - in that HbE is reduced in function as a nitrite reductase and altered as a nitrite anhydrase. These findings serve as the basis for a project, with our collaborators from Thailand, to develop potential therapeutics to ameliorate this grave and morbid disease.
The β6 mutants give rise to hemoglobin instability with ensuing red blood cell (RBC) consequences, unique to the particular hemoglobinopathy. β6 hemoglobin mutants form aggregates in the RBC: Why does oxy HbC (β6 Glu → Lys) form crystals in the red blood cell in contrast to deoxy sickle cell hemoglobin [HbS, β6 Glu → Val] that forms polymers?
Interactions of hemoglobin with natural or synthetic allosteric effectors and RBC components are providing key information about (1) intramolecular pathways of communication in hemoglobin; and (2) critical regions imparting unique stability to hemoglobin molecules important for the development of hemoglobin based oxygen carriers (i.e., blood substitutes). Unique hemoglobins with unusual stability, such as the giant hemoglobin (a dodecamer, 3.8 x 106 Da) found in the earthworm, Lumbricus terrestris provide insight into some of these questions. Hemoglobin conformational alterations that lead to instability are pursued by biophysical approaches: site-specific steady-state and time-resolved spectroscopy, crystallography, molecular dynamics, and crystal growth studies.
NCBI PubMed search of "R.E. Hirsch"
CJ Roche, MB Cassera, DD Dantsker, RE Hirsch, JM Friedman. “Generating S-nitrosothiols from Hemoglobin: Mechanisms, Conformational Dependence and Physiological Relevance.” Journal of Biological Chemistry 288:22408-22425 (2013)
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