Oxidative heme-mediated

Traylor, T. G., Duprat, A. F., and Sharma, V. S. (1993). Nitric oxide-triggered heme-mediated hydrolysis A possible model for biological reactions of NO. J. Am. Chem. Soc. 115, 810-811. 

Heme d,6 another isobacteriochlorin, occurs as one of two cofactors in the reductase cytochrome cdj which mediates the nitrite reduction to nitrogen monoxide (NO) and from there to dinitrogen oxide (N20) in denitrifying bacteria.7... 

Several factors affect drug-mediated derepression of ALASl in liver—eg, the administration of glucose can prevent it, as can the administration of hematin (an oxidized form of heme). 

Minteer and co-workers have also exploited the broad substrate specificity of PQQ-dependent alcohol dehydrogenase and aldehyde dehydrogenase from Gluconobacter species trapped within Nahon to oxidize either ethanol or glycerol at a fuel cell anode [Arechederra et al., 2007]. Although the alcohol dehydrogenase incorporates a series of heme electron transfer centers, it is unlikely that many enzyme molecules trapped within the mediator-free Nahon polymer are electronically engaged at the electrode. 

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. 

Sulfite oxidase is a dimetallic enzyme that mediates the two-electron oxidation of sulfite by the one-electron reduction of cytochrome c. This reaction is physiologically essential as the terminal step in oxidative degradation of sulfur compounds. The enzyme contains a heme cofactor in the 10 kDa N-terminal domain and a molybdenum center in the 42 kDa C-terminal domain. The catalytic cycle is depicted in Fig. 9. 

Given that hydroxylamine reacts rapidly with heme proteins and other oxidants to produce NO [53], the hydrolysis of hydroxyurea to hydroxylamine also provides an alternative mechanism of NO formation from hydroxyurea, potentially compatible with the observed clinical increases in NO metabolites during hydroxyurea therapy. Incubation of hydroxyurea with human blood in the presence of urease results in the formation of HbNO [122]. This reaction also produces metHb and the NO metabolites nitrite and nitrate and time course studies show that the HbNO forms quickly and reaches a peak after 15 min [122]. Consistent with earlier reports, the incubation ofhy-droxyurea (10 mM) and blood in the absence of urease or with heat-denatured urease fails to produce HbNO over 2 h and suggests that HbNO formation occurs through the reactions of hemoglobin and hydroxylamine, formed by the urease-mediated hydrolysis of hydroxyurea [122]. Significantly, these results confirm that the kinetics of HbNO formation from the direct reactions of hydroxyurea with any blood component occur too slowly to account for the observed in vivo increase in HbNO and focus future work on the hydrolytic metabolism of hydroxyurea. 

The first electrochemical studies of Mb were reported for the horse heart protein in 1942 (94) and subsequently for sperm whale Mb (e.g., 95) through use of potentiometric titrations employing a mediator to achieve efficient equilibriation of the protein with the electrode (96). More recently, spectroelectrochemical measurements have also been employed (97, 98). The alternative methods of direct electrochemistry (99-102) that are used widely for other heme proteins (e.g., cytochrome c, cytochrome bs) have not been as readily applied to the study of myoglobin because coupling the oxidation-reduction eqiulibrium of this protein to a modified working electrode surface has been more difficult to achieve. As a result, most published electrochemical studies of wild-type and variant myoglobins have involved measurements at eqiulibrium rather than dynamic techniques. 

Fig. 1. Overview of intravascular heme catabolism. Hemoglobin, myoglobin, and other heme proteins are released into the circulation upon cellular destruction, and the heme moiety is oxidized by O2 to the ferric form (e.g., methemoglobin and metmyoglobin). Haptoglobin can bind a substantial amount of hemoglobin, but is readily depleted. Ferric heme dissociates from globin and can be bound by albumin or more avidly by hemopexin. Hemopexin removes heme from the circulation by a receptor-mediated transport mechanism, and once inside the ceU heme is transported to heme oxygenase for catabolism.

The expression of several genes is induced or repressed by hemopexin-mediated heme transport. Most of these are simple responses of the cell to the increased heme (or iron derived from heme) in the cell. For example, HO-1 is induced (15, 88), ferritin levels rise (14, 61, 89), the transferrin receptor is down-regulated (15), and hemopexin mRNA itself is induced (A. Smith, unpublished). However, MT-1 is also induced, apparently to prepare the cell for oxidative stress thus, in addition to sequestering heme in a low-spin, non-oxidatively active form, hemopexin also indirectly exerts antioxidant effects by inducing MT-1 (16, 61, 90). 

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