A theoretical study of myoglobin working as a nitric oxide scavenger

Abstract

The mechanism for the reaction between nitric oxide (NO) and O(2) bound to the heme iron of myoglobin (Mb), including the following isomerization to nitrate, has been investigated using hybrid density functional theory (B3LYP). Myoglobin working as a NO scavenger could be of importance, since NO reversibly inhibits the terminal enzyme in the respiration chain, cytochrome c oxidase. The concentration of NO in the cell will thus affect the respiration and thereby the synthesis of ATP. The calculations show that the reaction between NO and the heme-bound O(2) gives a peroxynitrite intermediate whose O-O bond undergoes a homolytic cleavage, forming a NO(2) radical and myoglobin in the oxo-ferryl state. The NO(2) radical then recombines with the oxo-ferryl, forming heme-bound nitrate. Nine different models have been used in the present study to examine the effect on the reaction both by the presence and the protonation state of the distal His64, and by the surroundings of the proximal His93. The barriers going from the oxy-Mb and nitric oxide reactant to the peroxynitrite intermediate and further to the oxo-ferryl and NO(2) radical are around 10 and 7 kcal/mol, respectively. Forming the product, nitrate bound to the heme iron has a barrier of less than approximately 7 kcal/mol. The overall reaction going from a free nitric oxide and oxy-Mb to the heme bound nitrate is exergonic by more than 30 kcal/mol.

Elucidating the mechanism for the reduction of nitrite by copper nitrite reductase—A contribution from quantum chemical studies

“…The entropy effect on the transition state has not been estimated. However, previous studies 27 indicate that this effect is very small, as already mentioned above.…”

“…It should be noted that even if the product of this step is expected to gain up to 10 kcal/mol in free energy, due to the increased entropy on releasing the NO molecule, previous calculations on similar reactions show that the corresponding entropy increase in the transition state region is negligible. 27 Therefore, the transition state is estimated to be higher than 20 kcal/mol, and this route was considered too unfavorable energetically to be a viable reaction pathway, and it appears unlikely that the hydroxyl-bound H-state would be an intermediate. Thus the R → H → O pathway in Figure 3 is unlikely to be the main reaction path.…”

Nuclear Quantum Tunneling in the Light-activated Enzyme Protochlorophyllide Oxidoreductase

“…We have assumed a starting reactant complex (R) that involves Pchlide forming a long range complex with NADPH and the phenol group of the Tyr proton donor. Full geometry optimizations were performed in a dielectric constant of magnitude ⑀ ϭ 5.7, which has been shown to correctly predict the values of an enzyme-mimicked environment (35,36). The overall reaction mechanism is endothermic (63.9 kJ mol Ϫ1 ) and involves hydride transfer from NADPH to the C-17 atom of Pchlide to give an intermediate (I) via transition state TS1, followed by the subsequent proton transfer reaction to form the product complex (P) via barrier TS2.…”

Reaction Intermediates and Molecular Mechanism of Peroxynitrite Activation by NO Synthases

“…Indeed, this reaction is believed to lead to a heme-bound PN complex, which will eventually undergo a homolytic cleavage, leading to the formation of a [Cpd-II/NO 2 ] cage pair. This step would be followed by a direct recombination of NO 2 on the oxoferryl complex, resulting in the isomerization of PN and the release of nitrate (57) (Fig. 1, green arrow).…”