Nitrosated heme

Iron bioavailability may be increased in the presence of meat (Politz and Clydesdale 1988). This is the so-called meat factor. The exact mechanism of this effect is not known, but it has been suggested that amino acids or polypeptides that result from digestion are able to chelate nonheme iron. These complexes would facilitate the absorption of iron. In nitrite-cured meats some factors promote iron bioavailability (the meat factor), particularly heme iron and ascorbic acid or erythor-bic acid. Negative factors may in-clude nitrite and nitrosated heme (Lee and Greger 1983). 

The fact that nitrite reacts with the iron of the heme compound was described earlier. Because such a large number of metal ions are present in meat, and because some occur in relatively high concentration, there has been considerable interest in them. For the most part, studies have dealt with how metal ions influence reactions of nitrite. The role of sodium chloride (which is used extensively in meat processing) must also be recognized both in terms of its functional role in making reactants in the meat more or less available, and in terms of reports that it directly influences nitrosation reactions (50). Ando (51) studied the effect of several metal ions on decomposition of nitrite, and in the absence of ascorbate, only Fe++ caused a loss of nitrite but in its presence, the effect of Fe " was more pronounced and Fe+++, Mg++, Ca++ and Zn++ showed similar effects. Lee e al. 

The wealth of data on HbSNO formation has given rise to two broad interpretations that either support the hypothesis that the S-nitrosation of Hb-Cys 93 is redox catalyzed by the heme and is under allosteric control or that it is N2 03 or N02 -mediated without the involvement of the hemes. 

The dissimilatory nitrite reductase (cytochrome cdlt see below) catalyzes the nitrosation of several nucleophiles by nitrite.1531 This may occur through a heme-nitrosyl in which an NO+ group is present. Coordinated nitrite in simple metal complexes such as [Run(NH3)5(N02)]+... 

The direct interactions between metals and ONOO- can catalyze modifications. For example, the metals in Cu,Zn SOD and FeEDTA (EDTA = ethyl-enediaminetetraacetic acid) enhance nitration reactions (229). Heme-containing enzymes such as myeloperoxidase (6 x 106A/-1 s-1) and lactoperoxidase (3.3 x 105M-1s-1) also react with ONOO- (230) such that compound II [FeIV(P+)0] is formed. In contrast, horseradish peroxidase (3.2 x 106M-1 s-1) is converted to compound I (FevO) by ONOO-. Floris et al. (230) proposed an interesting mechanism by which compound I is initially produced and then rapidly oxidizes NO-f to N02. In the presence of NO, a number of nitrosation reactions would subsequently be facilitated by subsequent formation of N2O3 (Eq. 32). 

Hoshino M, Maeda M, Konishi R, Seki H, Ford PC. Studies on the reaction mechanism for reductive nitrosylation of ferrihemopro-teins in buffer solutions. J. Am. Chem. Soc. 1996 118 5702-5707. Weichsel A, Maes EM, Andersen JF, Valenzuela JG, Shokhireva T, Walker FA, Montfort WR. Heme-assisted S-nitrosation of a proximal thiolate in a nitric oxide transport protein. Proc. Natl. Acad. Sci. U. S. A. 2005 102 594-599. 

The above chemistry can be described as reductive nitrosation. That is, the reduction of the metal by bound NO results in bound NO formation. The NO complex can then nitrosate a nucleophile such as a thiol (to give a nitrosothiol) or H2O (to give nitrite). Significantly, the reduction of metal salts (nonheme bound) by NO has also been observed (Gwost and Caulton, 1973), and therefore this chemistry may not be limited to heme proteins. 

Low et al. (2004) have proposed a model to explain thioacetamide-induced hepatotox-icity and cirrhosis in rat livers. The pathways of thioacetamide-induced liver fibrosis were found to be initiated by thioacetamide S-oxide derived from the biotransformation of thioacetamide by the microsomal flavin-adenine nucleotide containing monooxygenase and cytochrome P450 systems and involve oxidative stress and depletion of succinyl-CoA, thus affecting heme and iron metabolism. Karabay et al. (2005) observed such hepatic damage in rats with elevation of total nitrite level in livers and decrease in arginase activity. The authors have reported that nitrosative stress was essentially the critical factor in thioacetamide-induced hepatic failure in rats. 

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