Hydroxyl radical proline

Rather scanty evidence exists for the participation of free radicals in Alzheimer s disease and Down s syndrome. However, more recendy, reports have appeared that suggest possible free-radical involvement in the pathogenesis of these two conditions. Zemlan et al. (1989) repotted that the activity of the free-radical scavenging enzyme, SOD, was significantly increased in fibroblast cell lines derived from familial Alzheimer s and Down s patients. They hypothesized that the elevation in SOD activity observed in the Alzheimer patients supports the theory that paired helical filaments are formed by free-radical hydroxylation of proline residues. They further su ested that SOD levels might also be increased in the brains of Alzheimer s and Down s patients, and that the increase in SOD may reflect an enhanced generation of free radicals. 

Figure 1.18 Reaction of proline, arginine, and lysine residues with hydroxyl radical results in oxidation of side-chain structures that form carbonyls. Both arginine and proline oxidation result in the same product.

Nonspecific cytochrome P450-mediated oxidation involves enzyme-catalyzed formation of reactive oxygen species (superoxide anions and hydroxyl radicals), which oxidize susceptible amino acids such as proline, arginine, lysine, and histidine. 

It has long been known that ascorbate is oxidized during the reaction, but not stoichiometricaUy with hydroxylation of proline and decarboxylation of 2-oxoglutarate. The purified enzyme is active in the absence of ascorbate but, after 5 to 10 seconds (about 15 to 30 cycles of enzyme action), the rate of reaction begins to fall. The loss of activity is from a side reaction of the highly reactive ferryl radical in which the iron is oxidized to Fe +, which is catalyticaUy inactive - so-called uncoupled decarboxylation of 2-oxoglutarate. Activity is only restored by ascorbate, which reduces the iron back to Fe + (Kivirikko and Pihlajaniemi, 1998). 

Oxidation of amino acid residues - Conditions that generate oxygen radicals cause many proteins to undergo mixed-function oxidation of particular residues. Conditions require Fe + and hydroxyl radical, and the amino acids most susceptible to oxidation are lysine, arginine, and proline. E. coli and rat liver each contain a protease that cleaves oxidized glutamine synthetase in vitro, but does not attack the native enzyme. Presumably, other oxidized proteins are also targets for this enzyme. 

The interaction of thiols (including cysteine and GSH) with metals, especially Fe (II), enhances the reduction ability of thiols considerably superoxide and thiyl radicals can be formed, as well as hydroxyl radicals [88]. Xenobiotic thiols such the antihypertensive agent, captopril (l-(3-mercapto-2-methyl-l-oxo-propyl)-L-proline) can also similarly form thiyl radicals [89]. 

Floyd, R.A. Zs-Nagy (1984). Formation of long lived hydroxyl free radical adducts of proline and hydroxyproline in a Fenton reaction. Biochimica Bio-physica Acta, 790, 94-7. 

A20. Ayala, A., and Cutler, R. G., The utilization of 5-hydroxyl-2-amino valeric acid as a specific marker of oxidised arginine and proline residues in proteins. Free Radicals Biol. Med. 21,65-80 (1996). 

In practice 136 was not made from proline. Breaking open the other, more functionalised, ring 136a is possible with the idea of a radical cyclisation onto an alkene 137. FGI of hydroxyl for iodine reveals the elements of another amino acid, serine 140 and an allylic bromide 139. 

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