Dinuclear site agents

Iron chelators (type 2) are of medical interest as agents that can block cell proliferation. To what extent this is due to interference with RNR is not well understood. However, recent experiments on the isolated proteins show that an agent such as desferrioxamine can destroy the radical and chelates iron from the active form of the HSVl protein 111), whereas it has no direct effect on the tyrosyl radical of mouse R2 112). However, it seems that the iron in the dinuclear sites without neighboring tyrosyl radical is accessible to desferrioxamine complex-ation in mouse as well as HSVl R2, again suggesting a structural difference between iron sites with and without a neighboring radical. 

Type 1 copper proteins are the class of proteins for which cupredoxins were originally named. Type 1 copper proteins include both proteins with known electron transfer function (e.g., plastocyanin and rusticyanin), and proteins whose biological functions have not been determined conclusively (e.g., stellacyanin and plantacyanin). Although these proteins with unknown function cannot be called cupredoxins by the strict functional definition, they have been classified as cupredoxins because they share the same overall structural fold and metal-binding sites as cupredoxins. In addition, many multidomain proteins, such as laccase, ascorbate oxidase, and ceruloplasmin, contain multiple metal centers, one of which is a type 1 copper. Those cupredoxin centers are also included here. Finally, both the Cua center in cytochrome c oxidase (CcO) and nitrous oxide reductase (N2OR), and the red copper center in nitrocyanin will be discussed in this chapter because their metal centers are structurally related to the type 1 copper center and the protein domain that contains both centers share the same overall structural motif as those of cupredoxins. The Cua center also functions as an electron transfer agent. Like ferredoxins, which contain either dinuclear or tetranuclear iron-sulfur centers, cupredoxins may include either the mononuclear or the dinuclear copper center in their metal-binding sites. 

With this cautionary note in mind, we should note that a related enzyme, prolidase from P. furiosus, has also been reported to be a dicobalt enzyme. In contrast to the aminopeptidases discussed above, prolidase specifically cleaves dipeptides containing a C-terminal proline. Prolidase is present in humans and a variety of bacteria, and appears to be identical to the enzyme previously known as organophosphorus acid anhydrolase, which can hydrolyze and detoxify organophosphorus nerve agents.A function in hydrolyzing peptides, rather than nerve agents that have only been known for a few decades, seems much more probable for these enzymes, which are found in both eukaryotes and prokaryotes. Whether prolidases actually utilize a dinuclear cobalt site in catalysis will require further investigation. 

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