Nitric oxide transfer

Methylhydroxyurea (28, Fig. 7.5) oxidizes oxyHb to metHb and reduces metHb to deoxyHb but neither of these reactions produces HbNO, further supporting the mechanism depicted in Scheme 7.16 for the formation of NO and HbNO from the reactions of hydroxyurea and hemoglobin [115]. The O-methyl group of 27 prevents the association and further reaction of 27 with the heme iron [115]. Scheme 7.16 predicts the redox chemistry observed during the reaction of 28 with hemoglobin and the failure to detect HbNO shows the inability of 28 or any derivative radicals to transfer NO during these reactions [115]. These results indicate that nitric oxide transfer in these reactions of hydroxyurea requires an unsubstituted acylhydroxylamine (-NHOH) group. 

Factors That Control the Reactivity of Cobalt(III)-Nitrosyl Complexes in Nitric Oxide Transfer and Dioxygenation Reactions... 

Ueno T, Suzuki Y et al (2002) In vivo nitric oxide transfer of a physiological NO caniCT, dinitrosyl dithiolato iron complex, to target complex. Biochem Pharmacol 63 485-493... 

C.-Y. Chiang and M. Y. Darensbourg. Iron nitrosyl complexes as models for biological nitric oxide transfer reagents. J. Biol. Inorg. Chem. 11, 2006, 359-370. 

Reactions 8 and 9 are important steps for the Hquid-phase nitration of paraffins. The nitric oxide which is produced is oxidized with nitric acid to reform nitrogen dioxide, which continues the reaction. The process is compHcated by the presence of two Hquid phases consequentiy, the nitrogen oxides must transfer from one phase to another. A large interfacial area is needed between the two phases. 

This statement does not mean, however, that the mechanism of diazotization was completely elucidated with that breakthrough. More recently it was possible to test the hypothesis that, in the reaction between the nitrosyl ion and an aromatic amine, a radical cation and the nitric oxide radical (NO ) are first formed by a one-electron transfer from the amine to NO+. Stability considerations imply that such a primary step is feasible, because NO is a stable radical and an aromatic amine will form a radical cation relatively easily, especially if electron-donating substituents are present. As discussed briefly in Section 2.6, Morkovnik et al. (1988) found that the radical cations of 4-dimethylamino- and 4-7V-morpholinoaniline form the corresponding diazonium ions with the nitric oxide radical (Scheme 2-39). 

Productive bimolecular reactions of the ion radicals in the contact ion pair can effectively compete with the back electron transfer if either the cation radical or the anion radical undergoes a rapid reaction with an additive that is present during electron-transfer activation. For example, the [D, A] complex of an arene donor with nitrosonium cation exists in the equilibrium with a low steady-state concentration of the radical pair, which persists indefinitely. However, the introduction of oxygen rapidly oxidizes even small amounts of nitric oxide to compete with back electron transfer and thus successfully effects aromatic nitration80 (Scheme 16). 

Importantly, the purple color is completely restored upon recooling the solution. Thus, the thermal electron-transfer equilibrium depicted in equation (35) is completely reversible over multiple cooling/warming cycles. On the other hand, the isolation of the pure cation-radical salt in quantitative yield is readily achieved by in vacuo removal of the gaseous nitric oxide and precipitation of the MA+ BF4 salt with diethyl ether. This methodology has been employed for the isolation of a variety of organic cation radicals from aromatic, olefinic and heteroatom-centered donors.174 However, competitive donor/acceptor complexation complicates the isolation process in some cases.175... 

In contrast to superoxide, which participates in one-electron transfer reactions as a reductant, nitric oxide is apparently able to oxidize various transition metal-containing proteins and enzymes. The study of NO reaction with hemoglobin has been started many years ago when... 

At present, new developments challenge previous ideas concerning the role of nitric oxide in oxidative processes. The capacity of nitric oxide to oxidize substrates by a one-electron transfer mechanism was supported by the suggestion that its reduction potential is positive and relatively high. However, recent determinations based on the combination of quantum mechanical calculations, cyclic voltammetry, and chemical experiments suggest that °(NO/ NO-) = —0.8 0.2 V [56]. This new value of the NO reduction potential apparently denies the possibility for NO to react as a one-electron oxidant with biomolecules. However, it should be noted that such reactions are described in several studies. Thus, Sharpe and Cooper [57] showed that nitric oxide oxidized ferrocytochrome c to ferricytochrome c to form nitroxyl anion. These authors also proposed that the nitroxyl anion formed subsequently reacted with dioxygen, yielding peroxynitrite. If it is true, then Reactions (24) and (25) may represent a new pathway of peroxynitrite formation in mitochondria without the participation of superoxide. 

Furthermore, Laranjinha and Cadenas [58] have recently showed that nitric oxide oxidizes 3,4-dihydroxyphenylacetic acid (DOPAC) to form nitrosyl anion and the DOPAC semiqui-none supposedly by one-electron transfer mechanism. 

In addition to nitric oxide, superoxide, and peroxynitrite, NO synthases are able to generate secondary free radicals because similar to cytochrome P-450 reductase, the reductase domain can transfer an electron from the heme to a xenobiotic. Thus it has been found [158,159] that neuronal NO synthase NOS I catalyzed the formation of CH3CH(OH) radical from ethanol. It was suggested that the perferryl complex of NOS I is responsible for the formation of such secondary radicals. Miller [160] also demonstrated that 1,3-dinitrobenzene mediated the formation of superoxide by nNOS. It was proposed that the enhancement of superoxide production in the presence of 1,3-dinitrobenzene converted nNOS into peroxynitrite-produced synthase and may be a mechanism of neurotoxicity of certain nitro compounds. 

Peroxyl radicals are not only ones, which are able to react with ubihydroquinones. Poderoso et al. [245] showed that the short-chain ubihydroquinones Q0 and Q2 are oxidized by nitric oxide with the rate constants of 0.49 x 104 and 1.6x 1041 mol-1 s 1, respectively. The reaction apparently proceeded by one-electron transfer mechanism because the formation of intermediate semiquinone radicals has been registered. 

The NO/NO+ and NO/NO- self-exchange rates are quite slow (42). Therefore, the kinetics of nitric oxide electron transfer reactions are strongly affected by transition metal complexes, particularly by those that are labile and redox active which can serve to promote these reactions. Although iron is the most important metal target for nitric oxide in mammalian biology, other metal centers might also react with NO. For example, both cobalt (in the form of cobalamin) (43,44) and copper (in the form of different types of copper proteins) (45) have been identified as potential NO targets. In addition, a substantial fraction of the bacterial nitrite reductases (which catalyze reduction of NO2 to NO) are copper enzymes (46). The interactions of NO with such metal centers continue to be rich for further exploration. 

Zai, A., Rudd, M. A., Scribner, A. W., Loscalzo, J., Cell-surface protein disulfide isomerase catalyzes transnitrosation and regulates intracellular transfer of nitric oxide, J. Clin. Invest. 103 (1999), p. 393-399... 

SN P spontaneously releases N O both thermally and photochemically [61-65], but is quite stable in the dark and in aqueous in vitro physiological media [66]. This implies that absorption of heat and light energy induces electron transfer from the Fe2+ center to the N 0+ ligand, resulting in weakening of the Fe-N O bond and subsequent release of NO [65]. SNP also decomposes in an aqueous environment in the presence of biological reductants [65, 66] and some transition metal ions to produce nitric oxide. 

Siddhanta U., Presta, A., Fan, B., Wolan, D., Rousseau, D. L., Stuehr, D.)., Domain swapping in inducible nitric-oxide synthase. Electron transfer occurs between flavin and heme groups located on adjacent subunits in the dimmer, J. Biol. Chem. 273 (1998), p. 18950-18958... 

Despite intense study of the chemical reactivity of the inorganic NO donor SNP with a number of electrophiles and nucleophiles (in particular thiols), the mechanism of NO release from this drug also remains incompletely understood. In biological systems, both enzymatic and non-enzymatic pathways appear to be involved [28]. Nitric oxide release is thought to be preceded by a one-electron reduction step followed by release of cyanide, and an inner-sphere charge transfer reaction between the ni-trosonium ion (NO+) and the ferrous iron (Fe2+). Upon addition of SNP to tissues, formation of iron nitrosyl complexes, which are in equilibrium with S-nitrosothiols, has been observed. A membrane-bound enzyme may be involved in the generation of NO from SNP in vascular tissue [35], but the exact nature of this reducing activity is unknown. 

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