scholarly journals Mechanism of Two-/Four-Electron Reduction of Nitroaromatics by Oxygen-Insensitive Nitroreductases: The Role of a Non-Enzymatic Reduction Step

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1672 ◽  
Author(s):  
Benjaminas Valiauga ◽  
Lina Misevičienė ◽  
Michelle H. Rich ◽  
David F. Ackerley ◽  
Jonas Šarlauskas ◽  
...  
Keyword(s):  
Reduction Step ◽  
Enzymatic Reduction ◽  
Electron Reduction

scholarly journals Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2911
Author(s):  
Miriam Navarrete-Miguel ◽  
Antonio Francés-Monerris ◽  
Miguel A. Miranda ◽  
Virginie Lhiaubet-Vallet ◽  
Daniel Roca-Sanjuán
Keyword(s):  
Electron Transfer ◽  
Energy Barrier ◽  
Ring Opening ◽  
Dna Lesions ◽  
Barrier Heights ◽  
Dna Lesion ◽  
Electron Reduction ◽  
The Stability ◽  
Electron Transfer Processes

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.

The role of Lewis acids in promoting the electrocatalytic four-electron reduction of dioxygen

1987 ◽  
pp. 1537 ◽  
Author(s):  
James P. Collman ◽  
Neil H. Hendricks ◽  
Kimoon Kim ◽  
C. Susana Bencosme
Keyword(s):  
Lewis Acids ◽  
Electron Reduction

scholarly journals Role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ.

2005 ◽  
Vol 52 (4) ◽  
pp. 937-942 ◽  
Author(s):  
Ausra Nemeikaite-Ceniene ◽  
Aldona Dringeliene ◽  
Jonas Sarlauskas ◽  
Narimantas Cenas
Keyword(s):  
Regression Analysis ◽  
Redox Cycling ◽  
Apoptosis Induction ◽  
Electron Reduction ◽  
Induced Apoptosis ◽  
Phenylene Diamine

We aimed to characterize the role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by antitumour quinones RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) and MeDZQ (2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone). Digitonin-permeabilized FLK cells catalyzed NADPH-dependent single- and two-electron reduction of RH1 and MeDZQ. At equitoxic concentrations, RH1 and MeDZQ induced apoptosis more efficiently than the nonalkylating duroquinone or H(2)O(2). The antioxidant N,N'-diphenyl-p-phenylene diamine, desferrioxamine, and the inhibitor of NQO1 dicumarol, protected against apoptosis induction by all compounds investigated, but to a different extent. The results of multiparameter regression analysis indicate that RH1 and MeDZQ most likely induce apoptosis via NQO1-linked formation of alkylating species but not via NQO1-linked redox cycling.

scholarly journals Aerobic Cytotoxicity of Aromatic N-Oxides: The Role of NAD(P)H:Quinone Oxidoreductase (NQO1)

2020 ◽  
Vol 21 (22) ◽  
pp. 8754
Author(s):  
Aušra Nemeikaitė-Čėnienė ◽  
Jonas Šarlauskas ◽  
Lina Misevičienė ◽  
Audronė Marozienė ◽  
Violeta Jonušienė ◽  
...  
Keyword(s):  
Human Colon ◽  
Redox Cycling ◽  
Geometric Average ◽  
Hct 116 ◽  
Radical Generation ◽  
Electron Reduction ◽  
Catalyzed Reactions ◽  
Hct 116 Cells ◽  
Derivatives Of

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.

Role of Selenium in the Enzymatic Reduction of Hydroperoxides

1998 ◽  
Vol 136 (1) ◽  
pp. 25-42 ◽  
Author(s):  
Leopold Flohé ◽  
Klaus-Dieter Aumann ◽  
Peter Steinert
Keyword(s):  
Enzymatic Reduction

The role of distal tryptophan in the bifunctional activity of catalase-peroxidases

2001 ◽  
Vol 29 (2) ◽  
pp. 99-105 ◽  
Author(s):  
G. Regelsberger ◽  
C. Jakopitsch ◽  
P. G. Furtmüller ◽  
F. Rueker ◽  
J. Switala ◽  
...  
Keyword(s):  
Catalase Activity ◽  
Intermediate Compound ◽  
Stopped Flow ◽  
Wild Type ◽  
Compound I ◽  
Wild Type Enzyme ◽  
Catalase Peroxidase ◽  
Electron Reduction ◽  
The One

Catalase-peroxidases are bifunctional peroxidases exhibiting an overwhelming catalase activity and a substantial peroxidase activity. Here we present a kinetic study of the formation and reduction of the key intermediate compound I by probing the role of the conserved tryptophan at the distal haem cavity site. Two wild-type proteins and three mutants of Synechocystis catalase-peroxidase (W122A and W122F) and Escherichia coli catalase-peroxidase (W105F) have been investigated by steady-state and stopped-flow spectroscopy. W122F and W122A completely lost their catalase activity whereas in W105F the catalase activity was reduced by a factor of about 5000. However, the mutations did not influence both formation of compound I and its reduction by peroxidase substrates. It was demonstrated unequivocally that the rate of compound I reduction by pyrogallol or o-dianisidine sometimes even exceeded that of the wild-type enzyme. This study demonstrates that the indole ring of distal Trp in catalase-peroxidases is essential for the two-electron reduction of compound I by hydrogen peroxide but not for compound I formation or for peroxidase reactivity (i.e. the one-electron reduction of compound I).

Role of Glutamine in Metabolic and Epigenetic Reprogramming in AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2559-2559
Author(s):  
Juliana Vélez Luján ◽  
Niki Zacharias ◽  
Dinesh Rakheja ◽  
Tushar D Bhagat ◽  
Jaehyuk Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Epigenetic Reprogramming ◽  
Cellular Growth ◽  
Hypoxic Conditions ◽  
Enhanced Production ◽  
Enzymatic Reduction ◽  
Isocitrate Dehydrogenase 2

Abstract Glutamine (Gln) was shown to play a role in generation of oncometabolite 2-hydroxyglutarate (2-HG) in tumors with high GLS (glutaminase) expression, whereby IDH2 (Isocitrate Dehydrogenase 2) enzyme catalyzes carboxylating reduction of glutamine-derived α-ketoglutarate (α-KG) to isocitrate and noncarboxylating reduction to 2-HG (Wise PNAS 2011). 2-HG in turn is known to inhibit α-KG dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation (Licht Cancer Cell 2010). A recent report demonstrated that hypoxia induces production of the L-enantiomer of 2-HG (L-2HG), through enzymatic reduction of α-KG by lactate dehydrogenase A (LDHA) (Intlekofer Cell Metabolism 2015). We have previously demonstrated that leukemic bone marrow microenvironment is highly hypoxic (Benito PLoS One 2011). Further, our unpublished data indicate upregulation of GLS protein and increase production of total 2-HG in AML (acute myeloid leukemia) cells cultured under hypoxia. We therefore propose a link between hypoxia, Gln metabolism, and epigenetic regulation in AML. Since increased methylation (and decreased hydroxymethylation) is seen in AML, we hypothesize that GLS inhibition can abrogate these changes via reduction of 2-HG levels. First, we examined effects of hypoxia and selective GLS inhibitor CB-839 (Calithera Biosciences) on cellular growth of AML cells with wild type IDH (OCI-AML3 and HL-60), cultured alone or co-cultured with bone marrow derived stromal cells (MSC). The culture of untreated OCI-AML3 alone in normoxic and hypoxic conditions caused a decrease in viability from 96 ± 2.5% to 84 ± 4.1% respectively, while the treatment with CB-839 (1 mM) for 6 days decreased viability in OCI-AML3 cells from 94 ± 0.23% to 71 ± 2.3% respectively (P=0.015). While MSC co-cultures improved survival of floating AML cells, the attached cells that were in direct contact with MSC were more affected under hypoxic conditions, having a viability of 64 ± 8.7% at the end of the experiment. These data indicate that GLS inhibitor is more effective under hypoxic conditions mimicking leukemic BM microenvironment. Hypoxia selectively induced the production of L-2HG (measured by liquid chromatography-tandem mass spectrometry) under hypoxic conditions (>40 fold) in OCI-AML3 cells, both with and without MSC co-culture. This increase in L-2HG was partially inhibited by co-treating OCI-AML3 cells with GLS inhibitor CB-839 (reduction of 1.7-fold in media only and 1.3-fold in MSC co-culture). Determination of hydroxymethylation (hmc) levels using HELP-GT assay demonstrated a significant increase in hmc in cells treated with CB-839. Of importance, genes that were differentially hydroxymethylated after CB-839 treatment belonged to important functional categories with cancer being the dominant pathway affected by these changes. Under hypoxia, glucose metabolism is known to be directed towards anaerobic glycolysis, with increased pyruvate-lactate enzymatic conversion by LDHA. To characterize the role of Gln and GLS on these processes within leukemia microenvironment, we performed nuclear magnetic resonance imaging with hyperpolarized pyruvate in NSG (NOD scid gamma) mice engrafted with GFP/luc-labeled OCI-AML3 cells. Inhibition of GLS in vivo following exposure of mice with 200 mg/kg dose of CB-839 showed a decrease in lactate conversion rate within leukemic bone marrow (femur area) (0.31 + 0.03 (pre) to 0.20 + 0.04 (post) P < 0.05), possibly due to the reduction of the level of NADH from decreased flux of Gln in the TCA cycle. In summary, our results indicate that Gln and GLS contribute towards hypoxia-induced production of L-2HG and critical epigenetic changes in AML; as well as playing a role in enhanced production of lactate from pyruvate. These findings suggest a major importance of Gln in metabolic and epigenetic reprogramming of microenvironment. Disclosures Off Label Use: CB-839 is a potent, selective, reversible and orally bioavailable glutaminase (mitochondrial enzyme able to convert glutamine in glutamate) inhibitor that has shown to reduce cell growth and/or induce cell death in solid tumors and hematological malignancies.. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

One-electron reduction of mitomycin c by rat liver: Role of cytochrome P-450 and NADPH-cytochrome P-450 reductase

Xenobiotica ◽  
1990 ◽  
Vol 20 (9) ◽  
pp. 967-978 ◽  
Author(s):  
R. M. Vromans ◽  
R. van de Straat ◽  
M. Groeneveld ◽  
N. P. E. Vermeulen
Keyword(s):  
Mitomycin C ◽  
Rat Liver ◽  
Nadph Cytochrome ◽  
Electron Reduction ◽  
Cytochrome P 450

FURTHER OBSERVATIONS ON THE ENZYMATIC REDUCTION OF TETRAZOLIUM SALTS BY MONOAMINES

1958 ◽  
Vol 36 (6) ◽  
pp. 587-594 ◽  
Author(s):  
J. R. Lagnado ◽  
T. L. Sourkes
Keyword(s):  
Rat Liver ◽  
Metal Binding ◽  
Enzyme System ◽  
Enzymatic Reaction ◽  
Free Base ◽  
Tetrazolium Salts ◽  
Enzymatic Reduction ◽  
Tissue Homogenates ◽  
Cofactor Activity

Studies on the role of purines as cofactors in the enzymatic reduction of tetrazolium salts by monoamines have led to the following results: (1) With whole rat liver extracts as the source of enzymes, several purines exhibit cofactor activity either as the free base or as the corresponding riboside and ribotide derivatives. (2) In contrast to this, mitochondrial material from rat liver is active only if adenylic acid or one of several ribotidic derivatives containing an adenylyl or similar moiety is used as cofactor. (3) Mitochondrial material utilizes hypoxanthine as cofactor for the amine/tetrazolium system only in combination with the supernatant obtained by centrifugation of tissue homogenates at 20,000 g. The additional factor present in this supernatant portion is heat-labile and nondialyzable. The possibility that this additional factor is an enzyme or enzymes converting the free base to the ribotide is discussed.Inhibition studies have revealed that the amine/tetrazolium enzyme system is sensitive to several metal-binding agents, but no direct evidence for the role of a metal in the enzymatic reaction could be obtained. It was also found that nicotinamide and adenine, neither of which exhibits cofactor activity, are potent inhibitors of the enzyme system studied.

scholarly journals Reduction of ferric haemoproteins by tetrahydropterins: a kinetic study

2005 ◽  
Vol 392 (3) ◽  
pp. 583-587 ◽  
Author(s):  
Chantal Capeillere-Blandin ◽  
Delphine Mathieu ◽  
Daniel Mansuy
Keyword(s):  
Electron Transfer ◽  
Cytochrome C ◽  
Cytochrome B5 ◽  
Reduction Rate ◽  
Cation Radical ◽  
Order Reduction ◽  
Reduction Potentials ◽  
Electron Reduction ◽  
The One

We previously showed that one-electron transfer from tetrahydropterins to iron porphyrins is a very general reaction, with formation of an intermediate cation radical similar to the one detected in NO synthase. As a model reaction, the rates of reduction of eight haemoproteins by diMePH4 (6,7-dimethyltetrahydropterin) have been studied and correlated with their one-electron reduction potentials, Em (FeIII/FeII). On the basis of kinetic data analyses, a bimolecular collisional mechanism is proposed for the electron transfer from diMePH4 to ferrihaemoproteins. Haemoproteins with reduction potentials below −160 mV were shown not to be reduced by diMePH4 to the corresponding ferrohaemoproteins. For haemoproteins with reduction potentials more positive than −160 mV, such as chloroperoxidase, cytochrome b5, methaemoglobin and cytochrome c, there was a good correlation between the second-order reduction rate constant and the redox potential, Em (FeIII/FeII):The rate of reduction of cytochrome c by BH4 [(6R)-5,6,7,8-tetrahydrobiopterin] was determined to be similar to that of the reduction of cytochrome c by diMePH4. These results confirm the role of tetrahydropterins as one-electron donors to FeIII porphyrins.

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