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J Biol Chem, Vol. 273, Issue 32, 20323-20333, August 7, 1998

Electron Paramagnetic Resonance and Oxygen Binding Studies of -Nitrosyl Hemoglobin
A NOVEL OXYGEN CARRIER HAVING NO-ASSISTED ALLOSTERIC FUNCTIONS

From the Department of Biochemistry and Biophysics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19194-6089

-Nitrosyl hemoglobin, (Fe-NO)₂(Fe)₂, which is frequently observed upon reaction of deoxy hemoglobin with limited quantities of NO in vitro as well as in vivo, has been synthetically prepared, and its reaction with O₂ has been investigation by EPR and thermodynamic equilibrium measurements. -Nitrosyl hemoglobin is relatively stable under aerobic conditions and undergoes reversible O₂ binding at the heme sites of its -subunits. Its O₂ binding is coupled to the structural/functional transition between T- (low affinity extreme) and R- (high affinity) states. This transition is linked to the reversible cleavage of the heme Fe-proximal His bonds in the (Fe-NO) subunits and is sensitive to allosteric effectors, such as protons, 2,3-biphosphoglycerate, and inositol hexaphosphate. In fact, (Fe-NO)₂(Fe)₂ is exceptionally sensitive to protons, as it exhibits a highly enhanced Bohr effect. The total Bohr effect of -nitrosyl hemoglobin is comparable to that of normal hemoglobin, despite the fact that the oxygenation process involves only two ligation steps. All of these structural and functional evidences have been further confirmed by examining the reactivity of the sulfhydryl group of the Cys⁹³ toward 4,4'-dipyridyl disulfide of several -nitrosyl hemoglobin derivatives over a wide pH range, as a probe for quaternary structure. Despite the halved O₂-carrying capacity, -nitrosyl hemoglobin is fully functional (cooperative and allosterically sensitive) and could represent a versatile low affinity O₂ carrier with improved features that could deliver O₂ to tissues effectively even after NO is sequestered at the heme sites of the -subunits. It is concluded that the NO bound to the heme sites of the -subunits of hemoglobin acts as a negative allosteric effector of Hb and thus might play a role in O₂/CO₂ transport in the blood under physiological conditions.

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