Targets of Free Radicals

Due to their reactive nature, free radicals can indiscriminately attack macromolecules such as DNA, protein, and lipid to cause damage to these molecules. Much is known about oxidative damage of these molecules caused by ROS, but less is known about damage by RNS.

ROS can react with DNA to generate various oxidation products, which include the abundant forms of 8-oxoguanine

(8-oxodG) and thymine glycol (55-57). Oxidation of DNA can lead to mutations and deletions of DNA and can block DNA replication and transcription by interfering interactions between DNA and proteins.

ROS, when unchecked, can also cause oxidation of proteins in various ways. For example, highly reactive fragment OH can react with the protein polypeptide backbone through sequential reactions to generate a carbon-center radical, which in turn can react with molecular oxygen and superoxide to form peroxyl radicals, alkyl peroxide, and alkoxyl radical and the hydroxyl derivative (55). The most abundant forms of protein oxidation are protein carbonyl derivatives, which are produced by a number of mechanisms, including amidation and glutamic acid oxidation pathways (35,47,55,56). Most susceptible amino acid residues to carbonyl formation include lysine, arginin, proline, and threonine.

RNS can also inflict damage to proteins through the formation of peroxynitrite from the reaction between NO and superoxide anion (48). Peroxynitrite can (i) nitrosate cysteine sulfhydryl groups and tyrosine and tryptophan residues, and (ii) oxidize methionine residue to methionine sulfoxide and generate various radicals, e.g., ONOOCO2- formed by reacting with CO2. Oxidation of proteins can lead to alterations of function, stability, and degradation of proteins.

Lipids are the most sensitive molecules to free radicals due to the presence of bisallylic structures in polyunsaturated fatty acids. Lipid peroxidation can produce a variety of end products by chain reactions with free radicals. The end products include malonaldehyde, 4-hydroxy-2-nonenol, and F2-isoprostanes, which tend to be accumulated in the cell, especially in the membranes (48,55,56,58). F2-isoprostanes generated from the peroxidation of arachidonic acid are the biomarkers often used to determine the level of lipid peroxidation (59). b-Formation of isoprostanes is initiated by formation of peroxyl radicals, which are produced by abstraction of a bisallylic hydrogen atom and the addition of oxygen to arachidonic acid. Peroxyl radicals can react with another molecule of oxygen to produce prostaglan-din-like compounds, which are then converted to isoprostanes (56). Lipid peroxidation can lead to damage to cellular membranes, lipid packing, and loss of cell integrity since lipids are essential components of cell membranes and various lipoproteins (47,58-60).

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