A microscopic study of the deoxyhemoglobin-catalyzed generation of nitric oxide from nitrite anion

Title	A microscopic study of the deoxyhemoglobin-catalyzed generation of nitric oxide from nitrite anion
Publication Type	Journal Article
Year of Publication	2008
Authors	Perissinotti, LL, Marti MA, Doctorovich F, Luque FJ, Estrin DA
Journal	Biochemistry
Volume	47
Issue	37
Pagination	9793 - 9802
Date Published	2008/09/16/
Keywords	Anions/chemistry/metabolism; Binding Sites; Catalysis; Hemoglobins/chemistry/metabolism; Histidine/chemistry/metabolism; Humans; Ligands; Models, Molecular; Nitric Oxide/chemistry/metabolism; Nitrite Reductases/chemistry/metabolism; Nitrites/chemistry/metabolism; Protein Conformation
Abstract	There is recent evidence suggesting that nitrite anion (NO 2 ⊖) represents the major intravascular NO storage molecule whose transduction to NO is facilitated by a reduction mechanism catalyzed by deoxygenated hemoglobin (deoxy-Hb). In this work, we provide a detailed microscopic study of deoxy-Hb nitrite reductase (NIR) activity by combining classical molecular dynamics and hybrid quantum mechanical-molecular mechanical simulations. Our results point out that two alternative mechanisms could be operative and suggest that the most energetic barriers should stem from either reprotonation of the distal histidine or NO dissociation from the ferric heme. In the first proposed mechanism, which is similar to that proposed for bacterial NIRs, nitrite anion or nitrous acid coordinates to the heme through the N atom. This pathway involves HisE7 in a one or two proton transfer process, depending on whether the active species is nitrite anion or nitrous acid, to yield an intermediate Fe(III)NO species which eventually dissociates leading to NO and methemoglobin. In the second mechanism, the nitrite anion coordinates to the heme through the O atom. This pathway requires only one proton transfer from HisE7 and leads directly to the formation of a hydroxo Fe(III) complex and NO.

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