Tyrosyl radical cation

Hydroxyurea is a simple molecule (Fig. 15-17) which inhibits ribonucleotide reductase. This enzyme accepts the four NDPs, UDP, CDP, ADP and GDP, as substrates and reduces them to the corresponding dNDP. The mechanism of catalysis involves the formation of an unusual tyrosyl radical cation which then induces formation of a radical form of the NDP substrate. Hydroxyurea quenches this tyrosyl radical cation intermediate leading to depletion of all four dNTPs required as substrates for the synthesis of DNA. 

A likely mechanism for the ribonucleotide reductase reaction is illustrated in Figure 22-41. The 3 -ribonu-cleotide radical formed in step (T) helps stabilize the cation formed at the 2 carbon after the loss of H20 (steps and (3)). Two one-electron transfers accompanied by oxidation of the dithiol reduce the radical cation (step ). Step (5) is the reverse of step ( ) regenerating the active site radical (ultimately, the tyrosyl radical) and forming the deoxy product. The oxidized dithiol is reduced to complete the cycle (step ). Ini , coli, likely sources of the required reducing equivalents for this reaction are thioredoxin and glutaredoxin, as noted above. 

This tyrosyl radical will not exist in a newly translated enzyme molecule, and once it is there, it may be lost due to capture of a hydrogen from somewhere else than the substrate. There thus has to be a mechanism for its formation or regeneration. This mechanism is provided by the heme in the peroxidase active site. The heme radical cation, which forms as an intermediate during the peroxidase reaction, can abstract a hydrogen atom from the tyrosine -OH group, which thus may act as a reductant in place of one of... 

Stopped-flow UV-vis absorption and rapid freeze-qnench (RFQ) EPR and Mossbauer stndies have shown that the reaction pathway diagrammed in Fignre 4 for formation of the tyrosyl radical is essentially accurate except that the diiron(IV) species labeled Q in Figured has never been detected in R2. Instead, an intermediate labeled U (not shown in Figured), occurring prior to X, has properties consistent with a protonated tryptophan cation radical. This radical may shuttle an electron from an external donor to the diiron site in order to reach intermediate In... 

The behaviour of the tyrosyl radicals involved in different processes and environments is not yet well understood Relatively little is known about the structure and selectivity of aryloxylium cations (Ar—0+) that are produced in the phenolic oxidation reactions and implicated in biological processes such as isoflavone synthesis . The thermochemistry which is relevant to the antioxidant properties of phenols as well as the solvent effects on their reactivity ° remain also a largely under-explored topic. Finally, the structure of phenol dimers and oligomers or even of some specific phenols also deserve more attention. We expect that these problems will be subjects for theoretical research in the coming years. 

The chemical transformation involves the conversion of a secondary alcohol to a methylene group. This process is chemically difficult, as hydroxide is a poor leaving roup, and no evidence has been found for 2 -phosphorylated or 2 -pyrophosphorylated activated intermediates (39). Furthermore, Sn2 displacement at C-2 is unlikely given the steric crowding by the ds-vicinal base at C-1, whereas cationic intermediates at C-2 formed via an SnI mechanism are likewise precluded as a result of the adjacent electron-deficient anomeric center at C-1 (40-42). The discovery of the tyrosyl radical in RDPR has led investi-... 

The active site of this enzyme in its Cu(II) form contains fom amino acids, two tyrosins one of which is a tyrosyl radical, two histidines, and one solvent molecule that together form a five-coordinate metal complex (54,76). During the reduction-oxidation reactions, the coordination sphere changes. In the Cu(I) state, only three amino adds are coordinated to the central cation. The unusual two-electron oxidation reaction involves the reduction of the central Cu(II) cation and the tyrosyl radical. 

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