scholarly journals An evolutionary-conserved redox regulatory mechanism in human Ser/Thr protein kinases

2019 ◽  
Author(s):  
Dominic P. Byrne ◽  
Safal Shrestha ◽  
Natarajan Kannan ◽  
Patrick A. Eyers
Keyword(s):  
Regulatory Mechanism ◽  
Oxygen Metabolism ◽  
Enzyme Assays ◽  
Oxygen Species ◽  
Eukaryotic Protein Kinase ◽  
Direct Modification ◽  
Activation Segment ◽  
Redox Sensitivity ◽  
Redox Switching ◽  
Conserved Residue

ABSTRACTReactive oxygen species (ROS) are products of oxygen metabolism, but are also recognized as endogenous physiological mediators of cellular signaling. Eukaryotic protein kinase (ePK) regulation occurs through reversible phosphorylation events in the flexible activation segment. In this study, we demonstrate that the catalytic phosphotransferase output from the mitotic Ser/Thr kinase Aurora A is also controlled by cysteine (Cys) oxidation. Reversible regulation occurs by direct modification of a conserved residue (Cys 290), which lies adjacent to Thr 288, the activating site of phosphorylation. Strikingly, redox modulation of the Cys 290-equivalent in other ePKs is predicted to be an underappreciated regulatory mechanism, since ~100 human Ser/Thr kinases possess a Cys at this position in the conserved activation loop. Using real-time enzyme assays, we confirm that the presence of the equivalent Cys residue is prognostic for redox-sensitivity amongst a cohort of human CAMK, AGC and AGC-like kinases, including AKT, AMPK, CAMK1, MAPKAP-K2/3 and SIK1-3. Our findings demonstrate that dominant Cys-based redox-switching in the activation segment represents an evolutionary-conserved mode of regulation for a significant subset of the human kinome. This finding has important implications for understanding physiological and pathological signaling responses to ROS, and emphasises the importance of multivalent activation segment regulation in ePKs.ONE-SENTENCE SUMMARYThe catalytic activity of Ser/Thr kinases is regulated through a conserved Cys-based redox mechanism.

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

2017 ◽  
Vol 398 (11) ◽  
pp. 1209-1227 ◽  
Author(s):  
Nidhi Kuksal ◽  
Julia Chalker ◽  
Ryan J. Mailloux
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Oxygen ◽  
Reactive Oxygen ◽  
Oxygen Metabolism ◽  
Antioxidant Systems ◽  
Oxygen Species ◽  
Oxygen Paradox ◽  
Secondary Messenger ◽  
Cell Structures ◽  
By Products

AbstractThe molecular oxygen (O2) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O2is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H2O2, are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H2O2elimination pathways are well characterized in mitochondria. However, less is known about how H2O2production is controlled. The present review examines the importance of mitochondrial H2O2in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H2O2can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H2O2production.

Article Commentary: Regulation of Protein Function by Residue Oxidation

2010 ◽  
Vol 3 ◽  
pp. PRI.S3327 ◽  
Author(s):  
Xing-Hai Zhang
Keyword(s):  
Protein Function ◽  
Regulatory Mechanism ◽  
Cellular Metabolism ◽  
Life Forms ◽  
Biological Macromolecules ◽  
Oxygen Species ◽  
Cellular Processes ◽  
Methionine Residues ◽  
Living Organisms ◽  
Face Generation

A majority of extant life forms require O2 to survive and thrive. Oxidation is inevitably one of the most active cellular processes and one constant challenge that living organisms must face. Generation of oxidants including reactive oxygen species is a natural consequence of cellular metabolism of all biological systems during normal life cycle under different environments. These oxidants oxidize many biological macromolecules such as proteins and affect their functions. Oxidation of specific amino acids in proteins may cause damage to protein structure and impair function, or may also activate protein activities and promote cellular metabolism. As an example, the reversible oxidation of cysteine and methionine residues has a profound impact on protein function and cellular process. A recent study that examines the effect of Met oxidation on Ser phosphorylation in a mitochondrial enzyme, pyruvate dehydrogenase, provides another demonstration that protein oxidation is an important regulatory mechanism for organisms to deal with developmental and environmental challenges throughout life processes.

scholarly journals Imidacloprid - Induced Pathophysiological Damage in the Midgut of Locusta Migratoria (Orthoptera: Acrididae) in the Field

2021 ◽  
Author(s):  
Lamia M. El-Samad ◽  
Mohamed S. El-Gerbed ◽  
Hanaa S. Hussein ◽  
Justin Flaven-Pouchon ◽  
Abeer El Wakil ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Physiological Function ◽  
Locusta Migratoria ◽  
Reactive Oxygen ◽  
Oxygen Metabolism ◽  
Oxygen Species ◽  
Beneficial Insects ◽  
Markers Of Oxidative Stress ◽  
Activity Of Enzymes

Abstract Neonicotinoids are modern insecticides widely used in agriculture worldwide. Their impact on target (nervous system) and non-target (midgut) tissues has been well studied in beneficial insects including honeybees. However, their effects on pest insects on the field are comparably rarely described. Here, we have studied the effects of the neonicotinoid imidacloprid on the midgut of the pest insect Locusta migratoria caught in the field. We found that in the midgut of imidacloprid-exposed locusts the activity of enzymes involved in reactive oxygen metabolism was perturbed. By contrast, the activity of P450 enzymes that have been shown to be activated in a detoxification response and that were also reported to produce reactive oxygen species was elevated. Probably as a consequence, markers of oxidative stress including protein carbonylation and lipid peroxidation accumulated in midgut samples of these locusts. Histological analyses revealed that their midgut epithelium is disorganized and that the brush border of the epithelial cells is markedly reduced. Indeed, microvilli are significantly shorter, misshapen and possibly non-functional in imidacloprid-treated locusts. We hypothesize that imidacloprid induces oxidative stress in the locust midgut, thereby changing the shape of midgut epithelial cells and probably in turn compromising their physiological function. Presumably, these effects reduce the survival rate of imidacloprid-treated locusts and the damage they cause in the field.

scholarly journals Mutations in a Conserved Residue in the Influenza Virus Neuraminidase Active Site Decreases Sensitivity to Neu5Ac2en-Derived Inhibitors

1998 ◽  
Vol 72 (3) ◽  
pp. 2456-2462 ◽  
Author(s):  
Jennifer L. McKimm-Breschkin ◽  
Anjali Sahasrabudhe ◽  
Tony J. Blick ◽  
Mandy McDonald ◽  
Peter M. Colman ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Active Site ◽  
Liquid Culture ◽  
Specific Inhibitor ◽  
Side Chain ◽  
Enzyme Assays ◽  
Hydrophobic Group ◽  
Influenza Virus Neuraminidase ◽  
Conserved Residue

ABSTRACT The influenza virus neuraminidase (NA)-specific inhibitor zanamivir (4-guanidino-Neu5Ac2en) is effective in humans when administered topically within the respiratory tract. The search for compounds with altered pharmacological properties has led to the identification of a novel series of influenza virus NA inhibitors in which the triol group of zanamivir has been replaced by a hydrophobic group linked by a carboxamide at the 6 position (6-carboxamide). NWS/G70C variants generated in vitro, with decreased sensitivity to 6-carboxamide, contained hemagglutinin (HA) and/or NA mutations. HA mutants bound with a decreased efficiency to the cellular receptor and were cross-resistant to all the NA inhibitors tested. The NA mutation, an Arg-to-Lys mutation, was in a previously conserved site, Arg292, which forms part of a triarginyl cluster in the catalytic site. In enzyme assays, the NA was equally resistant to zanamivir and 4-amino-Neu5Ac2en but showed greater resistance to 6-carboxamide and was most resistant to a new carbocyclic NA inhibitor, GS4071, which also has a hydrophobic side chain at the 6 position. Consistent with enzyme assays, the lowest resistance in cell culture was seen to zanamivir, more resistance was seen to 6-carboxamide, and the greatest resistance was seen to GS4071. Substrate binding and enzyme activity were also decreased in the mutant, and consequently, virus replication in both plaque assays and liquid culture was compromised. Altered binding of the hydrophobic side chain at the 6 position or the triol group could account for the decreased binding of both the NA inhibitors and substrate.

scholarly journals Oxidative Stress Level in Onco-Surgical Treatment Dynamics at Patients with Malignant Colo-Rectal Tumors

2020 ◽  
Vol 71 (5) ◽  
pp. 450-461
Author(s):  
Maria Iuliana Gruia ◽  
Serban Marinescu ◽  
Dragos Predescu ◽  
George Jinescu ◽  
Bogdan Socea ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Invasive Procedure ◽  
Surgical Excision ◽  
Oxygen Metabolism ◽  
Oxygen Species ◽  
Active Metabolites ◽  
Endogenous Antioxidant

Colorectal cancer (CRC) is one of the most common human malignancies, affecting one of 20 persons in areas with high socio-economic standard. In Romania, the frequency of colorectal cancer is growing rapidly placing the country among countries with an average incidence of the disease. There are some etiologic factors involved and treatment of disease is carried out after proper staging. Biochemical mechanisms underlying malignant transformation in colorectal cancer are not all fully understood, therefore our work trying to enter in the path of oxygen metabolism at patients surgically treated. The aim of the study is to follow the production of active metabolites of oxygen, in the dynamics of the surgical procedure, and how the endogenous natural protection systems are activated, following the invasive procedure. Oxidative stress biochemistry assays, realized before and after surgical excision showed a direct relationship between the production of reactive oxygen species and the presence of tumor, without being able to distinguish exactly if malignant tissue is able to induce oxidative stress, or the latter occurs due to neoplastic changes. Based on the results we can say with certainty that the reactive oxygen species ROS primary attack occurs in the lipids, and then the proteins, following activation of endogenous antioxidant defence.

scholarly journals T-2 Toxin Induces Oxidative Stress, Apoptosis and Cytoprotective Autophagy in Chicken Hepatocytes

Toxins ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 90 ◽  
Author(s):  
Huadong Yin ◽  
Shunshun Han ◽  
Yuqi Chen ◽  
Yan Wang ◽  
Diyan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanism ◽  
Regulatory Mechanism ◽  
Fusarium Species ◽  
Cereal Grains ◽  
Oxygen Species ◽  
Related Protein ◽  
Pathological Changes ◽  
Toxicological Effect ◽  
Type A Trichothecenes

T-2 toxin is type A trichothecenes mycotoxin, which produced by fusarium species in cereal grains. T-2 toxin has been shown to induce a series of toxic effects on the health of human and animal, such as immunosuppression and carcinogenesis. Previous study has proven that T-2 toxin caused hepatotoxicity in chicken, but the regulatory mechanism is unclear. In the present study, we assessed the toxicological effect of T-2 toxin on apoptosis and autophagy in hepatocytes. The total of 120 1-day-old healthy broilers were allocated randomly into four groups and reared for 21 day with complete feed containing 0 mg/kg, 0.5 mg/kg, 1 mg/kg or 2 mg/kg T-2 toxin, respectively. The results showed that the apoptosis rate and pathological changes degree hepatocytes were aggravated with the increase of T-2 toxin. At the molecular mechanism level, T-2 toxin induced mitochondria-mediated apoptosis by producing reactive oxygen species, promoting cytochrome c translocation between the mitochondria and cytoplasm, and thus promoting apoptosomes formation. Meanwhile, the expression of the autophagy-related protein, ATG5, ATG7 and Beclin-1, and the LC3-II/LC3-I ratio were increased, while p62 was downregulated, suggesting T-2 toxin caused autophagy in hepatocytes. Further experiments demonstrated that the PI3K/AKT/mTOR signal may be participated in autophagy induced by T-2 toxin in chicken hepatocytes. These data suggest a possible underlying molecular mechanism for T-2 toxin that induces apoptosis and autophagy in chicken hepatocytes

scholarly journals Chemiluminescence of Peripheral Blood Neutrophils in Mares with Endometritis

2012 ◽  
Vol 56 (1) ◽  
pp. 51-56
Author(s):  
Wiesław Krumrych ◽  
Janusz Danek
Keyword(s):  
Reactive Oxygen Species ◽  
Peripheral Blood ◽  
Oxygen Metabolism ◽  
Oxygen Species ◽  
Significant Relation ◽  
Cytological Examination ◽  
Blood Samples ◽  
Severe Inflammation ◽  
Activated Neutrophils ◽  
Blood Neutrophils

Abstract The aim of the study was to evaluate the oxygen metabolism of neutrophils in peripheral blood of mares in relation to intensity of endometrium inflammations. The study involved 36 half-breed mares, aged 4-22 years, showing fertility disturbances. In 26 mares neutrophils were found in uteral smears, which indicated endometritis (15 - moderate inflammation and 11 - severe inflammation). In the rest mares, cytological examination excluded inflammation. Blood samples were evaluated in terms of neutrophils chemiluminescence without stimulation (CL-WS) and with stimulation by opsonised zymosan (CL-OZ). The study demonstrated (only in case of CL-WS) an increase in chemiluminescence of cells in mares with a severe inflammation of the endometrium. The increased chemiluminescence activity was accompanied by a decrease in activation index (OZ/WS) of neutrophils, suggesting some imbalance between production and elimination of reactive oxygen species (ROS). The correlation analysis demonstrated a statistically significant relation between the intensity of the uterus inflammation, which was verified by cytological examination and CL-WS of peripheral blood neutrophils, as well as their activation index. The obtained results suggest that activated neutrophils are an important source of ROS which can play a role in the pathogenesis of endometritis in mares.

scholarly journals Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Qian Wang ◽  
Ci Xu ◽  
Qiang Fan ◽  
Haihua Yuan ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gastric Cancer ◽  
Reactive Oxygen Species ◽  
Stress Response ◽  
Cancer Cells ◽  
Regulatory Mechanism ◽  
Reactive Oxygen ◽  
Oxidative Stress Response ◽  
Oxygen Species ◽  
Gastric Cancer Cells

AbstractMAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.

scholarly journals A Transcriptome Profile Reveals The Regulatory Mechanism of Verticillium Dahliae Against Bacillus

2021 ◽  
Author(s):  
Wenhui Tian ◽  
Zhenrui Cheng ◽  
Junxia Wang ◽  
Fengfeng Cheng ◽  
Luping Li ◽  
...  
Keyword(s):  
Verticillium Dahliae ◽  
Regulatory Mechanism ◽  
Pathogenic Fungi ◽  
Oxygen Species ◽  
Rna Seq ◽  
Transcriptome Profile ◽  
Biocontrol Bacteria ◽  
Expression Of Genes ◽  
Prevention And Treatment

Abstract Background: Verticillium dahliae, the causal agent of Verticillium wilt, is notoriously invasive in many crops and has been involved in numerous epidemics worldwide. Bacillus species, as representatives of biocontrol bacteria, produce a variety of lipopeptides (LPs), which are useful as biofungicides to many pathogenic fungi, including Verticillium dahliae. This study will explore the mechanism of resistance of V. dahliae to Bacillus and biocontrol bacteria.Results: By using in vitro confrontation bioassays, we found that under the stress induced by Bacillus, the spore vitality of V. dahliae with larger colonies was higher, and more abundant microsclerotia were formed. Then, according to the RNA-Seq analysis, the target of rapamycin (TOR) and mitophagy pathways were enriched among the significantly upregulated 542 genes observed in two co-culture groups with different colony sizes. In addition, in the group of V. dahliae with large colonies, the pathways related to cell wall synthesis, microsclerotia formation and the clearance of reactive oxygen species were regulated, and the expression of genes was up-regulated.Conclusion: This study found that the larger colonies of V. dahliae were more resistant to the antagonistic actions of Bacillus and the likelihood of the formation of homeostasis. Therefore, the prevention of Verticillium wilt by Bacillus is more effective than the treatment of an active fungal infection. These transcriptomic insights provide direction for the use of fungicides in the prevention and treatment of diseases such as Verticillium wilt.

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