# Oxidatively Modified Proteins: Cause and Control of Diseases
## 3 Redox Stress and oxPTMs as the Cause of Different Diseases  
Intracellular compartments, such as mitochondria, peroxisome, and endoplasmic reticulum, generate endogenous ROS. ROS can be classified in independently existing heavy reactive radicals and non-radical species. Radical species include superoxide (O2\({}^{\circ}\)-), oxygen radicals (O2\({}^{\circ\circ}\)), hydroxyl (OH\({}^{\circ}\)), alkoxy radical (RO\({}^{\circ}\)), peroxyl radical (ROO\({}^{\circ}\)), nitric oxide (NO\({}^{\circ}\)), and nitrogen dioxide (NO\({}_{2}^{\circ}\)). Examples for non-radicals include hydrogen peroxide (H\({}_{2}\)O\({}_{2}\)), hypochlorous acid (HOCI), hypobromous acid (HOBr), ozone (O\({}_{3}\)), singlet oxygen (\({}^{1}\)O\({}_{2}\)), and peroxynitrite (ONOOH). ROS interact with intracellularly present proteins and induce modifications resulting in altered protein activity and function [29]. Although a balance of ROS level is sustained via enzymes and antioxidants, increased concentration of ROS is sometimes inevitable and leads to oxidative stress. Several diseases link to redox stress and ROS due to an unbalanced ROS homeostasis, such as diabetes, atherosclerosis, neurodegenerative diseases, macular degeneration, cancer, and others [30; 31; 32; 33]. As a consequence, significant differences in enzyme activity lead to increased oxidative damage and lipid peroxidation [34; 35; 36; 37]. Since many diseases can arise from redox stress, they show a specific fingerprint. Therefore, biomarkers of oxidative stress become increasingly relevant in the diagnosis of neurodegenerative diseases [38]. Oxidative stress, but also hypoxia, inflammation, and mutations in particular proteins, are just a few of the causes that lead to unfolded protein response (UPR). For example, tumor necrosis factor receptor-associated periodic syndrome is caused by UPR, and enhanced production of ROS in monocytes was determined in patients [39; 40], suggesting a role for ROS-induced PTMs. For UPR, a somewhat more complex, but not negligible, correlation is shown between proteins and diseases [41; 42; 43; 44]. UPR and redox stress are not only present in AD, atherosclerosis, diabetes, and inflammatory diseases, but also in asthma [45; 46]. Evidence shows an increased amount of redox stress inhibitor hypoxia-inducible factor-1 during the development of allergic airway inflammation, and modulation of ROS improves the hyperresponsiveness suggesting ROS as a cause for asthma [47; 48]. Since ROS can be scavenged and dampened by antioxidants, a number of therapies based on antioxidants have been postulated. In analogy to the phosphorylation system, oxidases and reductases regulate thiol groups on proteins for their activation or inactivation as signaling molecules, or transcription factors [5; 49]. To control redox-signaling transmission, homeostasis of intracellular ROS levels requires enzymes and other antioxidant proteins [50; 51; 52]. The most important enzymes for ROS homeostasis are nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, superoxide dismutase (SOD), nitric oxide synthase (NOS), NADPH oxidase (NOX), and myeloperoxidase (MPO) (Figure 1). An imbalance of the mentioned enzymes and their activity can lead to diseases. Figure 1: Intracellular generation of reactive species. For instance, SOD catalyzes the dismututation of radical superoxide anion (O\({}_{2}^{-}\)) into hydrogen peroxide (H\({}_{2}\)O\({}_{2}\)) or ordinary molecular oxygen (O\({}_{2}\)). Dysregulation of SOD and total antioxidant capacity leads to oxidative stress and chronic hyperglycemia, as evident in diabetic disease [53; 54; 55]. Altered SOD levels, oxidative stress, and cytoplasmatic aggregates have also been shown in amyotrophic lateral sclerosis [56; 57]. Another relevant protein, myeloperoxidase (MPO), catalyzes the oxidation of chloride ion and coverts thiocyanate to generate isocyanic acid. Isocyanic acid induces immunogenic PTMs as \(\alpha\)-carbamylation and homocitrulline (\(\varepsilon\)-carbamyl-lysine) [58].