Mechanisms of nitric oxide reactions with globins using mammalian myoglobin as a model system.

Globins play a key role in regulating nitric oxide (NO) levels in all forms of life. Five key reactions of NO with mammalian muscle myoglobin (Mb) and red blood cell hemoglobin (Hb) have been examined: (1) reversible NO binding to Fe(II) forms; (2) reversible NO binding to Fe(III) forms; (3) NO dioxygenation by Fe(II)O complexes; (4) autoxidation of Fe(II)NO complexes in the presence of O; and (5) autoreduction of Fe(III)NO complexes. NO reacts rapidly and almost irreversibly with deoxyMb(FeII) in the absence of O, whereas it reacts much more slowly and weakly with metMb(FeIII). The reaction of NO with Mb(FeII)O is very rapid and results in oxidation of the iron atom and dioxygenation of NO to nitrate. Autoxidation of Mb(FeII)NO in air is determined by the slow rate of NO dissociation from the Fe(II)NO complex, which is followed by rapid O binding to the newly formed deoxyMb(FeII) and dioxygenation of the displaced NO to generate NO and metMb(FeIII). MetMb(FeIII)NO autoreduces slowly by addition of a hydroxide ion to bound NO to generate nitrous acid and reduced deoxyMb(FeII), which immediately binds another NO to generate Mb(FeII)NO as the final product. The reverse of this process involves nitrite reduction to NO by deoxyMb(FeII), which can occur on physiological time scales when the globin concentration is in the millimolar range. The relevance of these processes to the regulation of NO metabolism by hemoglobins and myoglobins in humans and other organisms is discussed.