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

L.L. PERISSINOTTI; M. A. MARTI; F. DOCTOROVICH; F.J. LUQUE; D.A. ESTRIN

BIOCHEMISTRY

American Chemical Society

Año: 2008 vol. 47 p. 9793 - 9802

0006-2960

ABSTRACT:There is recent evidence suggesting that nitrite anion (NO2-) 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 mechanismscould 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 issimilar 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 whetherthe 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 tothe 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.