Reactive Oxygen Species

Types of ROS include the hydroxyl radical, the superoxide anion radical, hydrogen peroxide, singlet oxygen, nitric oxide radical, hypochlorite radical, and various lipid peroxides. All are capable of reacting with membrane lipids, nucleic acids, proteins and enzymes, and other small molecules, resulting in cellular damage. ROS are generated by a number of pathways.

Damage to cells caused by free radicals is believed to play a central role in various human disorders like rheumatoid arthritis, hemorrhagic shock, cardiovascular disease, cystic fibrosis, metabolic disorders, neurodegenerative disease, gastrointestinal ulcerogenesis, and AIDS. Some specific examples of ROS mediated diseases are Alzheimer’s disease, Parkinson’s disease, oxidative modification of low-density lipoprotein in atherosclerosis, cancer, and ischemic reperfusion injury in different tissues. Among these, the role of ROS in atherosclerosis and ischemic injury in heart and brain has been studied extensively.

ROS are wide range of molecules that include the superoxide radical anion (O^•−₂); hydrogen peroxide(H₂O₂);the hydroxylradical (OH^•+ OH⁻); peroxynitrite (ONOO⁻), formed of the diffusion-controlled reaction between NO and O^•−₂ ; and the derived radicals such as NO₂ and CO^•−. Low levels of ROS are necessary to mediate physiologic responses and to maintain homeostasis through the regulation of signal transduction events. Nevertheless,when cellular levels of ROS exceed the cell’s ability to reduce excess free radicals, oxidative stress develops. The physiological concentration of ROS molecules may vary under different conditions and in different cellular compartments. The intracellular concentration of superoxide exceeds 1nM, while the normal physiological concentration of H₂O₂ is less than 15 μM. Most ROS react with multiple biomolecules (proteins, DNA, RNA, and lipids) and cause the loss of enzyme function, breaks in DNA strands, cause DNA mutations, lipid peroxidation, and cellular death. Protein cross-links, fragmentation, hydroxylation, nitration, halogenation, carboxylation, and reactive aldehyde formation are common outcomes of the interaction of proteins with various oxidants. Most of the ROS effects on proteins are irreversible and result in loss of function of those proteins, which eventually are degraded and removed by proteasomes. Some amino acids such as cysteine, methionine, proline, arginine, tyrosine, and tryptophan have generally higher susceptibility to ROS modifications. One important way in which ROS exert their effect is by modifying the thiol group of proteins interfering with signaling molecules. ROS can oxidize low molecular weight biomolecules such as glutathione, generating secondary oxidative products which then may react with protein thiols. ROS reactions can also lead to the formation of lipid oxides, which are oxygenated products of the primordial lipid radical. Lipid peroxidation is self-perpetuating and thus amplifies several-fold the initial damage of ROS-induced oxidation. The accumulation of reactive lipid peroxides and lipid-derived aldehydes also contributes to oxidant-mediated signaling and cell damage. DNA is a frequent target of ROS. The most common ROS induced modifications to DNA include single-strand breaks (Fig. 2).