- 1 What are functional oxidative modifications?
- 1.1 1. Introduction
- 1.2 The earlier studies:
- 1.2.1 2. Cellular sources of Oxygenates
- 1.2.2 3. Reversible modifications to proteins’ oxidative properties
- 18.104.22.168 3.1. Protein carbonyls
- 22.214.171.124 3.2. Protein nitrotyrosine
- 126.96.36.199 4. Reversible protein oxidative modifications: protein cysteine modifications
- 188.8.131.52 4.2. Protein sulfenic acids formation (S-sulfenation)
- 184.108.40.206.1 THE PROCESS:
- 220.127.116.11.2 4. Protein s-glutathionylation
- 18.104.22.168.3 5. Protein disulfides
- 22.214.171.124.3.1 Ischemic tolerance
- 126.96.36.199.3.2 Summary and Perspectives
- 188.8.131.52.3.3 Shacter E. Protein oxidative damage. Methods Enzymol. 2000;319:428-436. [PubMed] [Google Scholar]
- 184.108.40.206.3.4 Mori T, Muramatsu H, Matsui T, McKee A, Asano T. Possible involvement of superoxide anion for the formation of neuronal tolerance after ischaemic preconditioning in rodents. Neuropathol Appl Neurobiol. 2000;26:31-40. [PubMed] [Google Scholar]
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What are functional oxidative modifications?
Protein Oxidative modifications also referred to as protein oxidation, constitute the most important class of posttranslational changes to proteins. They are caused by the reaction between amino acid residues of proteins as well as reactive oxygen species (ROS) or reactive nitrogen species (RNS) and are divided into two categories that are irreversible modifications and irreversible modifications. The authors think that selected proteins, when altered by reversible means through prophylactic strategies like preconditioning or Ischemia tolerance, could offer benefits in keeping healthy and fighting off disease. Protein s-nitrosylation
- To deal with environmental stressors, cells rely on a range of posttranslational mechanisms to enhance the function of proteins 11 – 4.]. Of all the posttranslational modifications that have been documented in the body, oxidative modifications of side chains in a variety of amino acid residues constitute the most significant category of posttranslational changes 57 77. The oxidative modification of proteins can generally be divided into two categories that are irreversible oxidation as well as irreversible oxidation 810 – 10respectively] which are triggered via reactive oxygen species (ROS) and reactive nitrogen species (RNS) (RNS) 11, 12]., 12[ 11, 12].
The earlier studies:
- The earlier studies on protein oxidation were primarily focused on the negative consequences of protein oxidation during aging and disease 5, 9, 13– 1713-17. It is now accepted that protein oxidation is also able to be a beneficial factor in various cell functions. This growing awareness of the benefits of the oxidation of proteins could be due to the growing evidence that RNS and ROS are vital for the survival of cells [18-22] as well as regeneration . In the majority of cases they are essential to restore cells by creating positive stress conditions that allow the survival mechanisms of cells are reprogrammed to prolong life [24-27] or withstand extreme, or even fatal threats [28-3128-31.
- This article will review both irreversible and reversible modifications that are beneficial for the treatment of both diseases and health. Modification adducts we’ll discuss include protein carbonyls, 3-nitrotyrosine, and cysteine Oxidation products (Fig. 1). Since the protein cysteine substance is one of the ones that typically undergoes reversible modifications to redox through RNS or ROS 3234]. 34We are been compelled to spend more time on cysteine modifications such as the s-sulfonation process, s nitrosylation, and disulfide production that is all easily reversible 3535 – 3838. It is important to note that changes to proteins that can have negative effects on health as well as in diseases are outside our scope in this study and will be mentioned sporadically. Protein s-nitrosylation
2. Cellular sources of Oxygenates
- There are many components within the cell that generate ROS. Mitochondria are identified as the main source of ROS production 39– 41The two Complexes I as well III are proven as the primary locations for mitochondrial ROS production ([42-45]). 4245 – 45[ 42- 45]. In addition to mitochondria, many enzymes also have the capability of producing ROS. They include, but are not only, NADPH oxidase [46, 47], xanthine-oxidase [48 49, 49], A-ketoglutarate dehydrogenase complex, [50-52], D-amino acid oxidases [53-55] as well as dihydrolipoamide dehydrogenase (56-62. On the other hand, the production of nitric dioxide in vivo is mostly accomplished through nitric oxide synthases [63 – 65however under certain conditions, deoxygenated myoglobin  and xanthine an oxidoreductase or the cytochrome c oxidase could be associated with NO generation and in vitro, nitric oxide donors are frequently utilized for research purposes [69-71or to treat patients [72-74and for therapeutic use [72-74]. It is important to note that, in the presence of a superoxide anion, the nitric oxide is able to rapidly respond to superoxide anion and produce peroxynitrite 75– 77] an oxidizing species that are extremely sensitive to redox-sensitive amino acids residues, including cysteine and tyrosine Cystine and tyrosine the latter being 78, 79and cysteine [ 78, 79].
3. Reversible modifications to proteins’ oxidative properties
- We would first be interested in discussing briefly the potential benefits of irreversible changes. These kinds of modifications comprise mostly protein carbonylation as well as tyrosine nitration 11, 80– 84]. Both of these modifications are frequently linked to oxidative damage and have been utilized as biomarkers used to determine the oxidative stress that occurs in aging and other diseases 13, 1515 – 17, 8515-17, 85. Although both carbonylation and the nitration process can have adverse consequences for the proteins targeted, however, there is evidence that these modifications may have positive effects on the functioning of cells under stressful circumstances.
3.1. Protein carbonyls
- Protein carbonyls derived from a variety of amino acid residues, such as Histidine, arginine proline, threonine, proline, and cysteine, are among the most commonly used biomarkers to measure the oxidative stress and oxidation of proteins in diseases and aging [5 8-11-14, 85-90[5, 8, 11-14, 86-90]. Because the modifications occur on numerous amino acid residues of specific protein targets [15-17, the magnitude is far greater than other modification that occurs only on one amino acid residue [11, 12] and therefore is more easily detected. Numerous studies have utilized carbonylation of proteins in order to assess the negative consequences of protein oxidation as well as stress oxidative 1316 – 16, 87– 90Evidence for positive results of this modification is starting to build up. For instance, carbonylation of proteins has been demonstrated to play a role in the process of signal transduction [92to 95and has been shown to play a role in the preconditioning of ischemic tissue, resulting in defense against reperfusion-induced injury (92-95, [96, 97].
3.2. Protein nitrotyrosine
- The chemical compound, known as 3-nitrotyrosine is created by the reaction of nitrogen species and proteins’ tyrosine residue 78, 98, 99]. This is highly selective because it is not the case that all proteins or all tyrosine residues of the target protein are changed to 100100. The formation of nitrotyrosine is typically believed to be associated with chronic or acute inflammation diseases [101-104], causing a rise in the levels of nitric oxygen is increased [102, 104-606[102, 104-106]. Many studies have looked into the detrimental consequences of 3-nitrotyrosine (107, 108], in conjunction with developing methods for detection and quantification [109, 110The modification has been observed in normal physiological conditions, such as pregnancy in healthy women [111 112 and 112], suggesting that the formation of 3-nitrotyrosine serves a physiological significance.
4. Reversible protein oxidative modifications: protein cysteine modifications
- 4.1. Chemistry of cysteine residues of proteins
- When pH is neutral under normal conditions, free cysteine residues have a pH value of around 8.5 which renders oxidative modifications unattainable 112]. To be vulnerable to oxygenation, the pKa of a cysteine molecule has to be lower than its normal pH (pH 7.4) which is the condition in which the cysteine -SH group is in a state of violating (thiolate anion) (thiolate anion) 113– 115]. It is these thiolated residues that are redox reactive 35, 116[ 35, 116]. The process of thiolation, which reduces the pKa to 7.2 or less, could be accomplished in a variety of ways like hydrogen bonding [117,118as well as the influence of the amino acid residues adjacent to residues [117, the microenvironment around the cysteine residues targeted [117and binding to substrates . For instance, albumin cysteine 34 is known to have an extremely low pKa of 5 120]. Therefore, under physiological conditions, it can be found as an anion thiolate and is extremely reactive to oxidants and metals, thiols, and disulfides 120and 123The pKa values are 121 to 123.
- As mentioned above the thiols that have low pKa values are more reactive due to the fact that they are generally deprotonated, or thiolated when pH is at a physiological level (pH between 124to 126– 126. This is why the oxidation of protein cysteines which are redox reactive also is highly selective [127, 128128. As is evident in Fig. 2 cysteine oxidation typically begins with the formation of sulfenic acid from which a myriad of compounds of oxidation may be produced. Many of these are reversible and are well-identified chemically. These products of cysteine oxidation are disulfide production (S-S-) and S-glutathionylation (protein-SSG) S-nitrosylation (-SNO) and sulfenic acid formation (-SOH S-sulfonation, also known as S-sulfonation) and are all been proven to be involved in the regulation of proteins’ redox processes through ROS and RNS 35, 129, 130]. It is important to note that all of them are believed to play a role in the field of health and disease since they can protect targets from further oxidation that could cause permanent damage to the protein targets 130and 133]. Another reason is that these modifications contribute to the signaling cascades of redox that help boost cell defense systems to counteract stress-related insults The redox signaling cascades can also help to counteract stress-related insults 341334 – 136].
- This sulfur-hydroxylation substance (P-SOH) has a powerful chemical redox reaction and has been shown to play an important role in the regulation of redox reactions in an increasing number of proteins 34, 138– 140]. Its development is usually triggered by ROS like hydrogen peroxide, and alkyl-hydroperoxides as well as RNS like peroxynitrite (38, 129, and 137 140 and 143, 143, 38, 129. While it’s a straightforward chemical modification, the sulfenic acid formation can have an enormous impact on the function of proteins 130, 137, 144]. It was long considered to be an intermediate, unstable cysteine oxidation product that is still the case for various proteins 137, 145, 146]., 145, 146]. The evidence is growing, however, has shown that stable-SOH exists, which makes trapping, marking, detecting the presence of it, and determining its quantity the formation of the -SOH that is formed 142-147, 147– 150]. A positive effect of SOH-protein formation has been demonstrated with great clarity by studies showing that s-sulfonation aldose reductase shields the heart from injury caused by ischemic or reperfusion [151-153]. 150to 150-153]. In particular, these studies revealed that case-298’s sulfation process of al reductase with peroxynitrite provides the greatest defense against cardiac ischemic damage as well as the using peroxynitrite scavengers to remove it doesn’t just stop cys-298’s Sulfenation however, it also eliminates the protection of the heart against ischemic injuries. In unrelated studies, Michalek et al. showed that protein sulfonation was vital for T-cell proliferation and proliferation, as the stoppage of sulfenic acid greatly hinders the maturation of T cells 54]. Another positive effect of P-SOH is it is involved in the sulfonation of Nitrile Hydrase. The formation of sulfenic acids on the enzyme’s Cys114 residue is vital to catalyze the enzyme’s function 155[ 155].
- The process is activated by the nitric oxide peroxynitrite and the nitric oxide Peroxynitrite, nitroxyl, nitroxyl, as well as the nitric oxide 56,157[157, 157]. This modification is believed to be functionally equivalent to protein phosphorylation and dephosphorylation ([158-160161 and 160161 and 160. It can also occur on cysteine-containing amino acids that do not belong to serine, tyrosine, or threonine residues. It is also possible to distinguish it from phosphorylation since it does not require a complex network comprised of kinases and enzymes that catalyze processes of denitrosylation as well as nitrosylation there is evidence that there are denitrosylases (such as bilirubin and CuZn-superoxide dismutase are described 161-161-[161- 161]. However, s-nitrosylation has been confirmed to be an important modification of cysteine residues during different pathophysiological and physical conditions 170, 166and 167[170, 166, 167]. Particularly with regard to specific nitric oxide’s control of the function of proteins through Redox, it is evident that s-nitrosylation can play the role of protecting mechanisms associated with a range of diseases 170-157 1, 168, 170, or 168- 170. For instance, Sheng et al. have proved the chemically enhanced process of nitrosylation may aid in recovering from hemorrhage in the subarachnoid 171, and Penna and co. have proved that protein s-nitrosylation enhances the blood quality during postconditioning of cardiac function [172and 172.
4. Protein s-glutathionylation
- Protein cysteine residues can be subject to s-glutathionylation in conditions of oxidative stress 173175 to 173. Glutathione (GSH) is the primary antioxidant within cells, but it can also alter proteins via mixed disulfide production (P-S-S-G) which can trigger functional changes to proteins it targets 176. The irreversible reduction of essential cysteine residues within proteins has been demonstrated to be a key component in the oxidative signal transmission process, as well as controlling cell growth, gene expression, and apoptosis, as well as cell defense mechanisms to protect important regulators from damage caused by oxidative stress (176-1 778). 173, 176-1, 176-1 173, 176-1, 176-1, 173, 176-1, 176-1. As with S-nitrosylation and s-sulfonation, the protein-S-S –G could be associated with a negative impact on the function of the protein. It could also alter the functions of the protein targeted 171 and 182. However, it could serve as a method to shield the protein from irreparable and permanent damage 183-186and 186. Therefore, the process of protein glutathionylation has received increasing interest as a possible way to regulate the state of redox in proteins in response to oxidative stress in conditions that are physical and pathological [187[187, 187]. The 187, 185]. In particular, glutathionylation of actin is a way to regulate the activity of neutrophils’ actin with multimorphonuclear morphology, and manipulation of the glutathionylation of the uncoupling protein 2 could provide a way to improve the treatment of cancer , and glutathionylation process of the adenine nuclear translocase, which is activated through preconditioning may cause mitochondrial membrane permeabilization to stop and cause death 191.
5. Protein disulfides
- For instance, intra-protein disulfide production in Cdc25c after exposure to hydrogen peroxide is responsible for regulating the protein’s stability 211and, in the brain type creatine-kinase disulfide bonds formed within 2 cysteine sites (cys74 and Cys254) is an innate defense mechanism within the cell [ 212].
- Posttranslational modifications to proteins specifically cysteine modifications, are implicated in ischemic tolerance or preconditioning [168,225 231231-]. It is the condition that alters the defense mechanisms of cells to protect themselves from devastating injuries 231231 – 237237- -. Preconditioning appears universal, in that all mammalian tissues and all living things are preconditioned. Particularly, the brain and the heart are preconditioned by a variety of mechanisms to prevent further injury caused by reperfusion Ischemia 232 238[232, 238]. 238[232 and 238. Therefore, preconditioning can be beneficial and beneficial to the body. While there has been a great deal of research on the mechanism behind preconditioning it’s not completely understood. Yet, ROS are known to be the most significant molecules in the process of developing preconditioning. 239-244 antioxidants that are injected during the preconditioning process can hinder the effectiveness of preconditioning. 28-3030. Furthermore, moderately elevated levels of ROS particularly H2O2 have been proven to protect neurons ([221 244-246221-244-246]. However, the method by which ROS plays a role in preconditioning the process of induction and protecting tissue remains unclear. Because ROS can affect their effects through altering proteins and proteins, the determination of the proteins that are targets of ROS could help in understanding the ways to protect yourself that are initiated through Ischemic tolerance. This suggests that the determination of the targets of altered proteins that undergo oxidative modifications and those that experience reversible changes to their oxidative properties may offer insight into the development of innovative therapeutic strategies for the treatment of Ischemic Tolerance. It is important to keep in mind that postconditioning is a concept that allows reperfusion processes can be altered or modified to offer protection against injury that could be fatal is something that has recently been found to be the postconditioning concept. 247247 -250[ 247-250250 – 247 [ 247-250]. Postconditioning might be considered to be part of the context of Ischemic tolerance. Preconditioning and postconditioning may share the same mechanisms or routes 250254 – 254254-2504
Summary and Perspectives
- While research on the harmful or harmful consequences of protein oxidative changes continues to dominate the research field of protein oxidation studies of the beneficial effects of oxidation of proteins seem to be receiving increasing attention The potential benefits of protein oxidation are gaining increasing attention 135, 263To benefit the human body the focus should be on the identification of proteomically altered proteins that might show protective effects. Additionally, research that provides a complete understanding of the processes or pathways that govern the reversible nature of these modifications must be conducted. This is particularly important in the case of reversible cysteine-oxidation which is not only an indicator of changes in the state of cellular redox and can also shield the proteins of interest from damage. Furthermore, reversible cysteine oxidation is also involved in the redox signaling cascades that trigger signaling cascades between 264267 – 267that trigger positive stress responses that can prevent unexpected catastrophes like a heart attack or stroke.
- FootnotesConflict of Interest: None declared.
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