Proteins carbonylation/nitration

Many questions still remain, such as whether extracellular Ap modulates intracellular Ap, or the mechanism by which Ap accumulation leads to synaptic dysfunction. Other factors, such as oxidative stress, which is extensive in AD, may aid the early accumulation of Ap (Butterfield et al., 2(X)2b). AP peptides stimulate oxidative stress by direct and indirect mechanisms. AP-induced oxidative stress may result from an imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS), which could react with a number of cellular macromolecular targets including proteins, lipids, carbohydrates, DNA, and RNA. An early marker for oxidative stress is the formation of protein carbonyls, 4-hydroxy-2-tra 5-nonenal (4-HNE) and 3-nitrotyrosme (3-NT), a marker for the nitration of proteins (Butterfield, 2002). Ap peptide can bind to mitochondrial proteins to generate free radicals, or it can promote oxidative stress via neuroinflanunation. Ap peptides stimulate microglial cells to release a neurotoxin, quinoUnic acid, which may also play a role in neurotoxicity (Guillemin et al., 2003). 

Oxidative modification of proteins is indicated by the high concentrations of protein carbonyls, by nitration of tyrosine residues, and by the cross-linking of proteins... 

Protein Functions Carbonylated Proteins Nitrated Proteins References... 

Evidence of selective oxidative damage, resulting from redox imbalance, involving neurons tied to AD is accumulating. The advanced gly-cation end products, nitration, lipid peroxidation adduction products, carbonyl-modified neurofilament protein, and free carbonyls belong to the list (200). The question remains whether the oxidative damage is caused by A)3, known to possess oxidative and hydrolytic properties (286, 287), or by other factors, whereas Aj3 is released as an antioxidant in response to oxidative stress (200). As in other groups of potential AD therapeutics there is a noticeable difference between their behavior in vitro and in vivo. A number of potential antioxidants are or have been in clinical trials... 

Amino acid residues are potential targets of free radical oxidation and nitration. Carbonyl derivatives of proteins may be formed by the interaction of protein amino acid side chains, mainly cysteine, histidine, and lysine residues with reactive aldehydes, such as HNE and ONE generated by peroxidation of PUFAs (polyunsaturated fatty acids). Amino acid and peptide biomarkers of oxidative stress are typically focused on specific proteins related to disease pathology. For instance, the oxidation of histidine and methionine are typically discussed in (3-amyloid plaque formation and HNE-derived histidine adducts are the main focus of modifications on low-density lipoprotein (LDL) (An-nangudi et al., 2008). However, there are several specific examples of general biomarkers of oxidative stress that include endogenous histidine containing dipeptides such as carnosine and anserine as well as the very stable o,o -dityrosine. These will be discussed below. 

ROS and RON can react with the DNA molecule and induce purine or p)u imidine base or sugar lesions, nitration and deaminations of purines, and DNA-DNA or DNA-protein cross-links (Dizdaroglu et al., 2002). These processes lead to mutations and impaired transcriptional and posttranscriptional processes and compromise protein synthesis (Colurso et al., 2003). In addition, DNA damage, oxidative phosphorylation, and altered cell metabolism may lead to apoptosis and promote neuronal death (Fishel et al., 2007 Becker and Bonni, 2004). ROS and RNS can also attack amino acids, leading to the formation of carbonyl derivatives (Stadtman and Levine, 2003). Oxidation of protein also leads to protein fragmentation and protein cross-linking. In addition, peroxynitrite and a hydroxyl radical can react with tyrosine and form other indexes of protein oxidation,... 

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