Tetrahydropterin oxidation

The action of sulfur nucleophiles like sodium bisulfite and thiophenols causes even pteridines that are unreactive towards water or alcohols to undergo covalent addition reactions. Thus, pteridin-7-one smoothly adds the named S-nucleophiles in a 1 1 ratio to C-6 (65JCS6930). Similarly, pteridin-4-one (73) yields adducts (74) in a 2 1 ratio at C-6 and C-7 exclusively (equation 14), as do 4-aminopteridine and lumazine with sodium bisulfite. Xanthopterin forms a 7,8-adduct and 7,8-dihydropterin can easily be converted to sodium 5,6,7,8-tetrahydropterin-6-sulfonate (66JCS(C)285), which leads to pterin-6-sulfonic acid on oxidation (59HCA1854). 

Chen D, PA Frey (1998) Phenylalanine hydroxylase from Chromobacterium violaceum. Uncoupled oxidation of tetrahydropterin and the role of iron in hydroxylation. J Biol Chem 273 25594-25601. 

Dioxygenases often have broad substrate specificity and require only a minimal characteristic structure for substrate recognition [310], Transition metal or an organic cofactor mediates dioxygen activation needed by the oxygenases action. Iron and copper, in their lower oxidation states are the metals most commonly used, but also organic co-factors like dihydroflavin and tetrahydropterin are able to activate the oxygen molecule. 

The importance of the dihydro and tetrahydro oxidation states of pterins in biology has stimulated interest in the study of the chemical properties of these compounds, especially with respect to electron-transfer and radical reactions. It has become apparent, perhaps unsurprisingly, that the stability and reactivity of these oxidation states are very sensitive to substituent effects and the much greater stability of the fully conjugated pteridines is most evident. The oxidation of tetrahydropterins and the reduction of dihydropterins have become especially important in the chemistry of nitric oxide production in nature and in oxidative stress but the accumulation of relevant facts has not led so far to a detailed understanding of the chemical property relationships. Relevant information is summarized in the following section. 

Tetrahydropterins are highly reactive towards oxidation (e.g. 542 — 544) even molecular oxygen can cause hydroxylation. The autoxidation is due to the electron donating groups such as amino and hydroxy, whereas removal of such substituents enhances the stability of the reduced pteridine nucleus tremendously (96CHEC-li(7)70l). The reaction appears to proceed via single electron transfer. The radical cation (543) can be observed by cyclic voltammetry. 

Naturally occurring pterin derivatives have existed in 3 oxidation states pterin (4 aromatic), dihydropterin (e.g., 5-8) and tetrahydropterin (9). In the present review, we do not refer to reduced pterin derivatives with reduced pyrimidine structures. The reduced pterin derivatives, dihydropterin and tetrahydropterin are readily oxidized to the corresponding aromatic form (4) under aerobic conditions. Based on the location to which hydrogen atoms are added, 4 kinds of dihydropterin have been defined 7,8-dihydropterin (5), quinonoid dihydropterin (6), 5,6-dihydropterin (7) and 5,8-dihydropterin (8). Of these, only 7,8-dihydropterin derivatives can be stored for long periods under non-aerobic conditions. Indeed, several 7,8-... 

A convenient HPLC technique known as the Fukushima-Nixon method has been widely used for selective analyses of tetrahydrobiopterin and tetrahy-droneopterin in biological samples [49]. This method allows the estimation of concentrations of tetrahydropterins based on difference in the concentrations of the corresponding aromatic pterins in the samples, which are prepared in situ by treatment with iodine under acidic and basic conditions. The Fukushima-Nixon method does not require special techniques or equipment for the chemical reaction the sample is simply subjected to oxidation just before its injection into the HPLC column. For example, tetrahydrobiopterin (43) was selectively oxidized to biopterin (30) by iodine in the presence of... 

Pterins are redox active in their own right and can adopt one of several oxidation levels, for example, fully oxidized, dihydro, or tetrahydro (Fig. 18). The stereochemical nature of MPT observed in each protein crystallographic study (13) is equivalent to that of the fully reduced, or tetrahydropterin, state. This argues against the existence of dihydropterin states such as 5,6-dihydrop-terin or 7,8-dihydropterin, and one of the various quininoid forms of the dihydropterin, in the crystalline forms of these enzymes that have been characterized by X-ray crystallography. However, it is important to note that, for the tricyclic structure of MPT, the tetrahydropterin state is equivalent to that of a dihydropterin, as manifest in the pyran ring-opened form of the bicyclic... 

At 30°C in the absence of Arg, the ferrous-oxi complex transforms very slowly to the ferric state. In the presence of substrate and H4B, a new species with the 12-nm shifted Sorey band is detected. A decay of this species is accompanied by the formation ofN -hydroxy-L-arginine. Because the presence of HUB is necessary for these reactions, the main function of this compound is to be a reducing agent. This suggestion is supported by experiments on the stabilizing effect of ascorbic acid on the chemical stabilization of tetrahydropterin in the endothelial nitric oxide synthesis (Heller et al., 2001). At the same time, a significant increase in the half lifetime of H4B in solution is demonstrated. As is shown (Wei et al., 2001), a ferrous-dioxy intermediate in iNOS forms for 53 s 1 and then is transformed to the [S-Fe(IV)=0] state. The rate of the [S-Fe(IV)=0] decay is equal to the rate ofH4B radical formation and the rate of Arg hydroxylation. In contrast,... 

The absence of such fluorescence in intact enzymes led to the original proposal that molybdopterin (1) is a tetrahydropterin (25). However, fluorescence from an oxidized pterin ring is also effectively quenched (>95%) in model complexes that contain a metallodithiolate on the C(6) side chain 54). Urothione (7), the proposed metabolic excretory product of molybdopterin, is also nonfluorescent (25). In general, the fluorescence behavior of model molybdenum complexes has received little attention (75). 

As it is seen from Figure 2, SAR can play the role of both oxidant and reducer. Its oxidative potential is relatively small but within cells SAR can oxidize catecholamines, low molecular weight thiols, ascorbate, tetrahydropterins. At alkaline pH SAR forms hydroperoxyl radical H02 (pKa 4.8) being better oxidizer but its amount is no more than 1% of the total SAR pool. 

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