scholarly journals Redox regulation as a platform for search and design of new type drugs. Search of gastroprotectors among sunstituted coumarins

2014 ◽  
Vol 12 (4) ◽  
pp. 22-42
Author(s):  
Edgar Andreevich Parfenov ◽  
Vladimir Alexandrovich Trapkov ◽  
Petr Dmitriyevich Shabanov
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Complex Compounds ◽  
Active Metabolites ◽  
Defence Mechanisms ◽  
Redox Active ◽  
Acute Ethanol ◽  
New Type ◽  
Important Position ◽  
Effective Drugs

Redox homeostasis controls most or all processes of normal and pathological physiology. Important position in the defence mechanisms are redox active metabolites As a robust platform for the development of new effective drugs is not screened, but directed the design and search for low molecular weight metabolites natural redox active compounds. This statement confirms the synthesis and study of new gastroprotektors of complex compounds of copper and zinc with coumarin ligands. On the model of acute ethanol rat gastric ulcer shown that preprocessing all tested complex compounds in equimolar doses of 0.15 mmol/kg leads to a considerable reduction in the size of the damage to the wall of the stomach, compared to control, and sucralfat (for 72,5-87,9 %, sucralfat - 52,3%).

scholarly journals A novel redox-active switch in Fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

2020 ◽  
Author(s):  
Safal Shrestha ◽  
Samiksha Katiyar ◽  
Carlos E. Sanz-Rodriguez ◽  
Nolan R. Kemppinen ◽  
Hyun W. Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Disulfide Bonds ◽  
Redox Regulation ◽  
Mutational Analysis ◽  
Redox Homeostasis ◽  
Kinase Domain ◽  
Origin And Evolution ◽  
Redox Active ◽  
Solution Studies ◽  
Redox Metabolites

AbstractAberrant regulation of metabolic kinases by altered redox homeostasis is a major contributing factor in aging and disease such as diabetes. However, the biochemical mechanisms by which metabolic kinases are regulated under oxidative stress is poorly understood. In this study, we demonstrate that the catalytic activity of a conserved family of Fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases (ePKs), are regulated by redox-active cysteines in the kinase domain. By solving the crystal structure of FN3K homolog from Arabidopsis thaliana (AtFN3K), we demonstrate that it forms an unexpected strand-exchange dimer in which the ATP binding P-loop and adjoining beta strands are swapped between two chains in the dimer. This dimeric configuration is characterized by strained inter-chain disulfide bonds that stabilize the P-loop in an extended conformation. Mutational analysis and solution studies confirm that the strained disulfides function as redox “switches” to reversibly regulate FN3K activity and dimerization. Consistently, we find that human FN3K (HsFN3K), which contains an equivalent P-loop Cys, is also redox-sensitive, whereas ancestral bacterial FN3K homologs, which lack a P-loop Cys, are not. Furthermore, CRISPR knockout of FN3K in human HepG2 cells results in significant upregulation of redox metabolites including glutathione. We propose that redox regulation evolved progressively in FN3Ks in response to changing cellular redox conditions. Our studies provide important new insights into the origin and evolution of redox regulation in the protein kinase superfamily and open new avenues for targeting HsFN3K in diabetic complications.

PHOTOSYNTHESIS AND METABOLISM IN MARINE ALGAE: VII. PRODUCTS OF PHOTOSYNTHESIS IN FRONDS OF FUCUS VESICULOSUS AND THEIR USE IN RESPIRATION

1967 ◽  
Vol 45 (9) ◽  
pp. 1557-1565 ◽  
Author(s):  
R. G. S. Bidwell
Keyword(s):  
Sodium Carbonate ◽  
Marine Algae ◽  
Fucus Vesiculosus ◽  
Complex Compounds ◽  
Major Product ◽  
Dilute Acid ◽  
Active Metabolites

Samples of Fucus vesiculcsus fronds were permitted to assimilate 14CO2 for 5 h and were then maintained in alternating periods of light and darkness for 3 days. Samples were collected at intervals, and the radioactivity of various simple and complex compounds was measured. The major product of photosynthesis was mannitol; relatively small amounts of 14C entered other compounds. From its behavior, it appears that mannitol is the major substrate of respiration in these plants; there may be secondary substrates among the complex polysaccharides. The complex polysaccharides are not formed directly from mannitol in light, but from some common precursors, or else from a small isolated pool of mannitol which is separated from the main cellular supplies. In darkness, the complex polysaccharides appear to be derived from stored mannitol. One of the more active metabolites, judged from its behavior, is a component of the residue left after dilute acid and sodium carbonate extraction. This component undergoes turnover, i.e. breakdown and resynthesis from newly-acquired photosynthate in the light, and is formed from stored photosynthate in the darkness.

scholarly journals Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

2020 ◽  
Author(s):  
Carla Umansky ◽  
Agustín Morellato ◽  
Marco Scheidegger ◽  
Matthias Rieckher ◽  
Manuela R. Martinefski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Redox Homeostasis ◽  
Thiol Group ◽  
Cellular Damage ◽  
Repair Pathway ◽  
Cellular Redox ◽  
Redox Active ◽  
Development And Aging

AbstractFormaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

scholarly journals Redox Regulation and Oxidative Stress: The Particular Case of the Stallion Spermatozoa

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 567 ◽  
Author(s):  
Fernando J. Peña ◽  
Cristian O’Flaherty ◽  
José M. Ortiz Rodríguez ◽  
Francisco E. Martín Cano ◽  
Gemma L. Gaitskell-Phillips ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Redox Regulation ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Mitochondrial Activity ◽  
Oxygen Species ◽  
Redox Biology ◽  
Major Interest ◽  
And Oxidative Stress

Redox regulation and oxidative stress have become areas of major interest in spermatology. Alteration of redox homeostasis is recognized as a significant cause of male factor infertility and is behind the damage that spermatozoa experience after freezing and thawing or conservation in a liquid state. While for a long time, oxidative stress was just considered an overproduction of reactive oxygen species, nowadays it is considered as a consequence of redox deregulation. Many essential aspects of spermatozoa functionality are redox regulated, with reversible oxidation of thiols in cysteine residues of key proteins acting as an “on–off” switch controlling sperm function. However, if deregulation occurs, these residues may experience irreversible oxidation and oxidative stress, leading to malfunction and ultimately death of the spermatozoa. Stallion spermatozoa are “professional producers” of reactive oxygen species due to their intense mitochondrial activity, and thus sophisticated systems to control redox homeostasis are also characteristic of the spermatozoa in the horse. As a result, and combined with the fact that embryos can easily be collected in this species, horses are a good model for the study of redox biology in the spermatozoa and its impact on the embryo.

Synthesis of a ferrocene-linked biscyclam: a new type of redox active bismacrocyclic ligand

1999 ◽  
Vol 23 (12) ◽  
pp. 1133-1135 ◽  
Author(s):  
Fre´de´ric Bellouard, ◽  
Françoise Chuburu, ◽  
Jean-Jacques Yaouanc ◽  
Henri Handel ◽  
Yves Le Mest
Keyword(s):  
Redox Active ◽  
New Type

Voltammetric profiling of redox-active metabolites expressed by Pseudomonas aeruginosa for diagnostic purposes

2015 ◽  
Vol 51 (18) ◽  
pp. 3789-3792 ◽  
Author(s):  
T. Seviour ◽  
L. E. Doyle ◽  
S. J. L. Lauw ◽  
J. Hinks ◽  
S. A. Rice ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Potential Bias ◽  
Active Metabolites ◽  
Voltammetric Analysis ◽  
Redox Active

Voltammetric analysis ofPseudomonas aeruginosagrowth cultures unveils the interplay between PQS and phenazines under a potential bias.

Redox behavior of novel nickel and palladium complexes supported by trianionic non-innocent ligand containing β-diketiminate and phenol groups

2015 ◽  
Vol 19 (01-03) ◽  
pp. 377-387 ◽  
Author(s):  
Yuma Morimoto ◽  
June Takaichi ◽  
Shinichi Hanada ◽  
Kei Ohkubo ◽  
Hideki Sugimoto ◽  
...  
Keyword(s):  
Palladium Complex ◽  
Protonated Form ◽  
Palladium Complexes ◽  
Dalton Trans ◽  
Tert Butyl ◽  
Redox Active ◽  
Amino Phenol ◽  
New Type ◽  
The One ◽  
Nickel And Palladium Complexes

A new type of nickel and palladium complexes with non-innocent β-diketiminate ligand having redox active phenol groups, 2,4-di-tert-butyl-6-(((1E,2E)-3-((3,5-di-tert-butyl-2-hydroxyphenyl)amino)-2-nitroallylidene)amino)phenol ( L H 3, fully protonated form) have been developed, and the structure, physical properties, and reactivity of their one-electron and two-electron oxidized complexes, [MII(L•2-)] and [MII(L-)]+ ( M = Ni II or Pd II ) have been examined in detail. The two-electron oxidized forms of both complexes, [MII(L-)]+, exhibited hydrogen atom abstraction ability from 1,4-cyclohexadiene (CHD) comparable to its copper analog [ Cu II ( L -)]+ (Dalton Trans. 2013; 42: 2438-2444). The one-electron oxidized form of palladium complex, [ Pd II ( L •2-)], was also found to oxidize CHD, whereas the nickel analog, [ Ni II ( L •2-)], exhibited photo-induced oxidation ability of CHD.

The redox switch that regulates molecular chaperones

2015 ◽  
Vol 6 (4) ◽  
pp. 269-284 ◽  
Author(s):  
Myra E. Conway ◽  
Christopher Lee
Keyword(s):  
Redox Regulation ◽  
Structural Rearrangement ◽  
Antioxidant Systems ◽  
Cysteine Oxidation ◽  
Hydrophobic Region ◽  
Physiological Importance ◽  
Redox Active ◽  
Polypeptide Folding ◽  
Integral Role ◽  
The Impact

AbstractModification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.

scholarly journals A universal entropy-driven mechanism for thioredoxin–target recognition

2015 ◽  
Vol 112 (26) ◽  
pp. 7960-7965 ◽  
Author(s):  
Prakash B. Palde ◽  
Kate S. Carroll
Keyword(s):  
Protein Interactions ◽  
Redox Regulation ◽  
Noncovalent Interactions ◽  
Target Recognition ◽  
Redox Homeostasis ◽  
Titration Calorimetry ◽  
Conformational Restriction ◽  
Target Proteins ◽  
Thiol Oxidoreductase ◽  
Insight Into

Cysteine residues in cytosolic proteins are maintained in their reduced state, but can undergo oxidation owing to posttranslational modification during redox signaling or under conditions of oxidative stress. In large part, the reduction of oxidized protein cysteines is mediated by a small 12-kDa thiol oxidoreductase, thioredoxin (Trx). Trx provides reducing equivalents for central metabolic enzymes and is implicated in redox regulation of a wide number of target proteins, including transcription factors. Despite its importance in cellular redox homeostasis, the precise mechanism by which Trx recognizes target proteins, especially in the absence of any apparent signature binding sequence or motif, remains unknown. Knowledge of the forces associated with the molecular recognition that governs Trx–protein interactions is fundamental to our understanding of target specificity. To gain insight into Trx–target recognition, we have thermodynamically characterized the noncovalent interactions between Trx and target proteins before S-S reduction using isothermal titration calorimetry (ITC). Our findings indicate that Trx recognizes the oxidized form of its target proteins with exquisite selectivity, compared with their reduced counterparts. Furthermore, we show that recognition is dependent on the conformational restriction inherent to oxidized targets. Significantly, the thermodynamic signatures for multiple Trx targets reveal favorable entropic contributions as the major recognition force dictating these protein–protein interactions. Taken together, our data afford significant new insight into the molecular forces responsible for Trx–target recognition and should aid the design of new strategies for thiol oxidoreductase inhibition.

scholarly journals The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress

2008 ◽  
Vol 28 (24) ◽  
pp. 7451-7464 ◽  
Author(s):  
Christos Polytarchou ◽  
Raymond Pfau ◽  
Maria Hatziapostolou ◽  
Philip N. Tsichlis
Keyword(s):  
Redox Regulation ◽  
Replicative Senescence ◽  
Redox Homeostasis ◽  
Histone H3 ◽  
Quinone Oxidoreductase ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Jmjc Domain ◽  
Peptidase Inhibitor ◽  
Induced Apoptosis

ABSTRACT The histone H3 demethylase Ndy1/KDM2B protects cells from replicative senescence. Changes in the metabolism of reactive oxygen species (ROS) are important for establishing senescence, suggesting that Ndy1 may play a role in redox regulation. Here we show that Ndy1 protects from H2O2-induced apoptosis and G2/M arrest and inhibits ROS-mediated signaling and DNA damage, while knockdown of Ndy1 has the opposite effects. Consistent with these observations, whereas Ndy1 overexpression promotes H2O2 detoxification, Ndy1 knockdown inhibits it. Ndy1 promotes the expression of genes encoding the antioxidant enzymes aminoadipic semialdehyde synthase (Aass), NAD(P)H quinone oxidoreductase-1 (Nqo1), peroxiredoxin-4 (Prdx4), and serine peptidase inhibitor b1b (Serpinb1b) and represses the expression of interleukin-19. At least two of these genes (Nqo1 and Prdx4) are regulated directly by Ndy1, which binds to specific sites within their promoters and demethylates promoter-associated histone H3 dimethylated at K36 and histone H3 trimethylated at K4. Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells was sufficient to suppress the Ndy1 redox phenotype.

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