Inhibition iron coordination

A molecule that binds iron through coordinating moieties (e.g., carboxylates or amines). They are used to inhibit iron-catalyzed free radical reactions or to treat iron overload conditions. Desferrioxamine and defer-iprone are two widely used iron chelators. 

The high specificity of siderophore iron coordination has been extensively explored in iron-chelation therapy for various medical applications, including iron overload diseases, control of iron in specific brain tissues , arresting the growth and proliferation of malaria parasite within their host , as well as arresting the proliferation of cancer cells . Other directions for metal ligation involve enzyme inhibition, which have been demonstrated by the inhibition of urease by coordination of hydroxamate ligand to nickel ions and zinc coordination in matrix metalloprotease (MMP) inhibition by primary hydroxamates. ... 

In the presence of adenosine triphosphate, flavenoids were observed to inhibit hydroxyl radical formation [63]. These contrasting results further emphasize that the effect of iron chelators is highly dependent on the other species present. The relative efficiencies of the chelators for hydroxyl radical formation will determine whether the added chelator will have a positive or negative effect on radical formation. Furthermore, increased radical formation is not always correlated with improved pollutant degradation. Catechol groups and 4-keto,5-hydroxyl benzene groups are believed to be important iron coordination sites for flavenoids [63]. 

The low reactivity of both Cyt111 and Cyt11 toward NO can be attributed to occupation of the heme iron axial coordination sites by an imidazole nitrogen and by a methionine sulfur of the protein (28). Thus, unlike other heme proteins where one axial site is empty or occupied by H20, formation of the nitrosyl complex not only involves ligand displacement but also significant protein conformational changes which inhibit the reaction with NO. However, the protein does not always inhibit reactivity given that Cat and nNOS are more reactive toward NO than is the model complex Fem(TPPS)(H20)2 (Table II). Conversely, the koS values... 

Figure 3.5. Continued. The H2-NAD reaction is inhibited neither in air nor in the presence of CO. C,The possible reactions of hydrogen with the Fe-Fe site of active [Fe]-hydrogenases. In the oxidized state, the bimetallic center shows a S = 1/2 EPR signal, presumably due to an Fe -Fe pair (an Fe -Fe pair cannot be excluded). Whether the unpaired spin is localized on iron (Pierik et al. 1998a) or elsewhere (Popescu and Mtlnck 1999) is not known. Hydrogen is presumably reacting at the vacant coordination site on Fe2 (Fig. 3.1C). After the heterolytic splitting, the two reducing equivalents from the hydride are rapidly taken up by the Fe-Fe site (one electron) and the attached proximal cluster (one electron). Subsequently, the electron is transferred from the proximal cluster to the other Fe-S clusters in the enzyme. Under equilibrium conditions, the proximal cluster in the active enzyme appears to be always in the oxidized [4Fe-4S] state (Popescu and Mtlnck 1999). Protons are not shown.

A large number of iron-containing proteins form nitrosyl complexes. Heme proteins, iron-sulfur proteins, and other iron proteins such as nonheme iron dioxygenases all form characteristic nitrosyl complexes. In enzymes in which the metal center has an open coordination position, NO often can be bound without severe disruption of the site. This introduces the possibility of reversibility of inhibition. 

It is usually believed that NO inhibits enzymes by reacting with heme or nonheme iron or copper or via the S-nitrosilation or oxidation of sulfhydryl groups, although precise mechanisms are not always evident. By the use of ESR spectroscopy, Ichimori et al. [76] has showed that NO reacts with the sulfur atom coordinated to the xanthine oxidase molybdenum center, converting xanthine oxidase into a desulfo-type enzyme. Similarly, Sommer et al. [79] proposed that nitric oxide and superoxide inhibited calcineurin, one of the major serine and threonine phosphatases, by oxidation of metal ions or thiols. 

Iron speciation is a major factor in Fenton chemistry. As previously discussed, iron solubility, redox potentials, and concentrations of Fe2+ and Fe3+ are all dependent on the ligands that coordinate iron. In order to produce hydroxyl radical, there must be a readily accessible coordination site for H202 to bind to [9,10]. Very strong iron chelators, therefore, inhibit the formation of hydroxyl radical. Iron ligands can also act as hydroxyl radical scavengers. Because the radical is always formed in close proximity to these ligands, they are more likely to react with hydroxyl radical than pollutants that are not in close proximity to the iron. 

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