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At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition

Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting superoxide (O 2 •– ) to molecular oxygen (O 2 ) and hydrogen peroxide (H 2 O 2 ) with proton-coupled electron transfers (PCETs). Human MnSOD has evolved to be highly product inhibited to limit the formation of H 2 O 2 , a freely diffusible oxidant and signaling molecule. The product-inhibited complex is thought to be composed of a peroxide (O 2 2– ) or hydroperoxide (HO 2 – ) species bound to Mn ion and formed from an unknown PCET mechanism. PCET mechanisms of proteins are typically not known due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the mechanism, we combine neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states of the enzyme to reveal the positions of all the atoms, including hydrogen, and the electronic configuration of the metal ion. The data identifies the product-inhibited complex, and a PCET mechanism of inhibition is constructed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

The role of Tyr34 in proton coupled electron transfer and product inhibition of manganese superoxide dismutase

Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O$^{•–}_{2}$) to molecular oxygen (O 2 ) and hydrogen peroxide (H 2 O 2 ) with proton-coupled electron transfers (PCETs). A key catalytic residue, Tyr34, determines the activity of human MnSOD and also becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. Tyr34 has an unusual pK a due to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. Neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations in oxidized, reduced and product inhibited enzymatic states shed light on the role of Tyr34 in MnSOD catalysis. The data identify the contributions of Tyr34 in MnSOD activity that support mitochondrial function and give a thorough characterization of how a single tyrosine modulates PCET catalysis. Product inhibition occurs by an associative displacement mechanism.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Superoxide Mediates Acute Liver Injury in Irradiated Mice Lacking Sirtuin 3

Aims: This study determined whether acute radiation-induced liver injury seen in Sirtuin3 -/- mice after exposure to Cs-137 γ-rays was mediated by superoxide anion (O 2 •- ). Results: Male wild-type (WT) and SIRT3 -/- mice were given 2 x 2Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3 -/- animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3 -/- animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30min before each fraction. Innovation: Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O 2 •- in the liver injury process initiated by whole-body irradiation in SIRT3 -/- mice. Conclusion: These results support the hypothesis that O 2 •- mediates acute liver injury in SIRT3 -/- animals exposed to whole-body γ-radiation and suggest that GC4401 could be used as a radio-protective compound in vivo.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Redox manipulation of the manganese metal in human manganese superoxide dismutase for neutron diffraction

Human manganese superoxide dismutase (MnSOD) is one of the most significant enzymes in preventing mitochondrial dysfunction and related diseases by combating reactive oxygen species (ROS) in the mitochondrial matrix. Mitochondria are the source of up to 90% of cellular ROS generation, and MnSOD performs its necessary bioprotective role by converting superoxide into oxygen and hydrogen peroxide. This vital catalytic function is conducted via cyclic redox reactions between the substrate and the active-site manganese using proton-coupled electron transfers. Owing to protons being difficult to detect experimentally, the series of proton transfers that compose the catalytic mechanism of MnSOD are unknown. Here, methods are described to discern the proton-based mechanism using chemical treatments to control the redox state of large perdeuterated MnSOD crystals and subsequent neutron diffraction. These methods could be applicable to other crystal systems in which proton information on the molecule in question in specific chemical states is desired.

Azadmanesh, Jahaun↗
NASA NTRS1972

Synthesis of calcium superoxide

Efforts to prepare Ca(O2) sub 2 from reactions of calcium compounds with 100% O3 and with O(D-1) atoms generated by photolysis of O3 at 2537 A are described. Samples of Ca(OH) sub 2, CaO, CaO2, Ca metal, and mixtures containing suspected impurities to promote reaction have been treated with excess O3 under static and flow conditions in the presence and absence of UV irradiation. Studies with KO2 suggest that the superoxide anion is stable to radiation at 2537 A but reacts with oxygen atoms generated by the photolysis of O3 to form KO3. Calcium superoxide is expected to behave in an analogous.

Rewick, R. T.↗
NASA NTRS1980

The preparation of calcium superoxide in a flowing gas stream and fluidized bed

Superoxides can be used as sources of chemically stored oxygen in emergency breathing apparatus. The work reported here describes the use of a low-pressure nitrogen gas sweep through the reactant bed, for temperature control and water vapor removal. For a given set of gas temperature, bed thickness, and reaction time values, the highest purity calcium superoxide, Ca(O2)2, was obtained at the highest space velocity of the nitrogen gas sweep. The purity of the product was further increased by flow conditions that resulted in the fluidization of the reactant bed. However, scale-up of the low-pressure fluidized bed process was limited to the formation of agglomerates of reactant particles, which hindered thermal control by the flowing gas stream. A radiofrequency flow discharge inside the reaction chamber prevented agglomeration, presumably by dissipation of the static charges on the fluidized particles.

Wood, P. C.↗
NASA NTRS1992

Theoretical study of the alkaline-earth metal superoxides BeO2 through SrO2

Three competing bonding mechanisms have been identified for the alkaline-earth metal superoxides: these result in a change in the optimal structure and ground state as the alkaline-earth metal becomes heavier. For example, BeO2 has a linear 3Sigma(-)g ground-state structure, whereas both CaO2 and SrO2 have C(2v)1A1 structures. For MgO2, the theoretical calculations are less definitive, as the 3A2 C(2v) structure is computed to lie only about 3 kcal/mol above the 3Sigma(-)g linear structure. The bond dissociation energies for the alkaline-earth metal superoxides have been computed using extensive Gaussian basis sets and treating electron correlation at the modified coupled-pair functional or coupled-cluster singles and doubles level with a perturbational estimate of the triple excitations.

Bauschlicher, Charles W., Jr.↗
NASA NTRS2000

Evidence that the reactivity of the martian soil is due to superoxide ions

The Viking Landers were unable to detect evidence of life on Mars but, instead, found a chemically reactive soil capable of decomposing organic molecules. This reactivity was attributed to the presence of one or more as-yet-unidentified inorganic superoxides or peroxides in the martian soil. Using electron paramagnetic resonance spectroscopy, we show that superoxide radical ions (O2-) form directly on Mars-analog mineral surfaces exposed to ultraviolet radiation under a simulated martian atmosphere. These oxygen radicals can explain the reactive nature of the soil and the apparent absence of organic material at the martian surface.

long duration↗
DOE OSTI2015

The structure of the Caenorhabditis elegans manganese superoxide dismutase MnSOD-3-azide complex

C. elegans MnSOD-3 has been implicated in the longevity pathway and its mechanism of catalysis is relevant to the aging process and carcinogenesis. The structures of MnSOD-3 provide unique crystallographic evidence of a dynamic region of the tetrameric interface (residues 41–54). We have determined the structure of the MnSOD-3-azide complex to 1.77-Å resolution. The analysis of this complex shows that the substrate analog, azide, binds end-on to the manganese center as a sixth ligand and that it ligates directly to a third and new solvent molecule also positioned within interacting distance to the His30 and Tyr34 residues of the substrate access funnel. This is the first structure of a eukaryotic MnSOD-azide complex that demonstrates the extended, uninterrupted hydrogen-bonded network that forms a proton relay incorporating three outer sphere solvent molecules, the substrate analog, the gateway residues, Gln142, and the solvent ligand. This configuration supports the formation and release of the hydrogen peroxide product in agreement with the 5-6-5 catalytic mechanism for MnSOD. The high product dissociation constant k₄ of MnSOD-3 reflects low product inhibition making this enzyme efficient even at high levels of superoxide.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗
DOE OSTI2018

A Critical Review on Superoxide-Based Sodium–Oxygen Batteries

Sodium superoxide (NaO 2 ) based sodium oxygen batteries (Na-O 2 ) possess high theoretical energy density and high energy efficiency that can be an alternative energy storage device to lithium ion batteries (LIBs). However, the state-of-the-art sodium oxygen batteries is still far from real application due to the limited understanding of the cell chemistry and reaction mechanism. In this mini review, we will review the recent advances on NaO 2 based Na-O 2 batteries, especially focusing on the reaction mechanism and the stability of NaO 2 . The parasitic reactions from the highly active NaO 2 will be discussed. We believe this review will provide insightful understanding on the mechanism and the role of the discharge product in NaO 2 batteries.

25 ENERGY STORAGE↗
DOE OSTI2021

Local Environment of Superoxide Radical Formed on the TiO 2 Surface Produced From Ti(OiPr) 4 Exposed to H 2 O 2

A selective heterogeneous catalyst with the superoxide anion O 2 •– stable at room temperature, generated by treating Ti(OR) 4 (R=iPr, nBu) with H 2 O 2 , was previously reported and used for the oxidation of organic compounds. Furthermore, it was proposed that exceptional stability of the O 2 •– is resulted from its stabilization near Ti +4 cation on the TiO 2 surface with participation of water molecules and/or OH groups. In this article, we performed high-resolution pulsed EPR study on the O 2 •– in this catalyst with the aim to obtain quantitative information about its interactions with the surrounding molecules. Our data has shown that the O 2 •– is involved in weak hyperfine interactions with protons in the nearest environment, which do not exceed a value of 2 MHz. It corresponds to an Os…H distance of ≥ 3 Å that exclude the formation of hydrogen bonds. The analysis of possible structures of O 2 •– adsorption on TiO 2 surface taking into account our results and lack of radical mobility at room temperature previously observed in EPR spectra led us to suggest that the O 2 •– is stabilized in the form of superoxo bridge coordinated with two titanium atoms.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Cu/Zn superoxide dismutase and the proton ATPase Pma1p of Saccharomyces cerevisiae

In eukaryotes, the Cu/Zn containing superoxide dismutase (SOD1) plays a critical role in oxidative stress protection as well as in signaling. We recently demonstrated a function for Saccharomyces cerevisiae Sod1p in signaling through CK1γ casein kinases and identified the essential proton ATPase Pma1p as one likely target. The connection between Sod1p and Pma1p was explored further by testing the impact of sod1Δ mutations on cells expressing mutant alleles of Pma1p that alter activity and/or post-translational regulation of this ATPase. We report here that sod1Δ mutations are lethal when combined with the T912D allele of Pma1p in the C-terminal regulatory domain. This “synthetic lethality” was reversed by intragenic suppressor mutations in Pma1p, including an A906G substitution that lies within the C-terminal regulatory domain and hyper-activates Pma1p. Surprisingly the effect of sod1Δ mutations on Pma1-T912D is not mediated through the Sod1p signaling pathway involving the CK1γ casein kinases. Rather, Sod1p sustains life of cells expressing Pma1-T912D through oxidative stress protection. The synthetic lethality of sod1Δ Pma1-T912D cells is suppressed by growing cells under low oxygen conditions or by treatments with manganese-based antioxidants. We now propose a model in which Sod1p maximizes Pma1p activity in two ways: one involving signaling through CK1γ casein kinases and an independent role for Sod1p in oxidative stress protection. - Highlights: • In yeast, the anti-oxidant enzyme SOD1 promotes activity of the proton ATPase Pma1p. • Cells expressing a T912D variant of Pma1p are not viable without SOD1. • SOD1 is needed to protect Pma1-T912D expressing cells from severe oxidative damage. • SOD1 activates Pma1p through casein kinase signaling and oxidative stress protection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Superoxide dismutase 2 (SOD2) contributes to genetic stability of native and T315I-mutated BCR-ABL expressing leukemic cells

Highlights: • This is the first report evaluating the role of SOD2 in native and T351-mutated BCR-ABL-expressing cells and in a large cohort of CML patients. • shRNA-mediated SOD2 invalidation led to alteration in several chromosomal loci including in regions coding for glypican and β-defensin genes. • In leukemic cells silenced for SOD2 expression a specific down-regulation of the expression of PRDX2 gene was found. • Gene set enrichment analysis performed between two SOD2-dependent classes of CML patients revealed a significant enrichment of ROS pathway. • In a large cohort of patients with CML, a significant decrease of SOD2 mRNA was observed. • This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. Manganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted). In a large cohort of patients with chronic myeloid leukemia (CML), a significant decrease of SOD2 mRNA was observed. This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. The analysis of anti-oxidant gene expression analysis revealed a specific down-regulation of the expression of PRDX2 in UT7-BCR-ABL and UT7-T315I cells silenced for SOD2 expression. Gene set enrichment analysis performed between the two SOD2-dependent classes of CML patients revealed a significant enrichment of Reactive Oxygen Species (ROS) Pathway. Our data provide the first evidence for a link between SOD2 expression and genetic instability in CML. Consequently, SOD2 mRNA levels should be analyzed in prospective studies as patients with low SOD2 expression could be more prone to develop a mutator phenotype under TKI therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase

Highlights: • Leflunomide decreases oxidative stress in fetal human lung endothelial cells. • Leflunomide induces catalase, NQO1, and SOD2 enzymes in fetal human lung cells. • Leflunomide effects on oxidative stress, catalase, and SOD2 are AhR-independent. • AhR deficiency abrogates leflunomide-mediated induction of NQO1 enzyme. Hyperoxia-induced oxidative stress contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common respiratory morbidity of preterm infants. Importantly, the disease lack specific therapies and is associated with long-term cardio-pulmonary and neurodevelopmental morbidities, signifying the need to discover novel therapies and decrease the disease burden. We and others have demonstrated that leflunomide, a food and drug administration approved drug to treat humans with rheumatoid arthritis, increases the expression of the anti-oxidant enzymes, NAD(P)H quinone dehydrogenase 1 (NQO1), catalase, and superoxide dismutase (SOD). However, whether this drug can decrease oxidative stress in fetal human pulmonary arterial endothelial cells (HPAECs) is unknown. Therefore, we tested the hypothesis that leflunomide will decrease hyperoxia-induced oxidative stress by upregulating these anti-oxidant enzymes in HPAECs. Leflunomide decreased hydrogen peroxide (H{sub 2}O{sub 2}) levels and increased the mRNA and protein levels of catalase, NQO1, and SOD2 in HPAECs at basal conditions. Further, leflunomide-treated cells continued to have decreased H{sub 2}O{sub 2} and increased SOD2 levels upon hyperoxia exposure. Leflunomide did not affect the expression of other anti-oxidant enzymes, including hemoxygenase-1 and SOD1. AhR-knockdown experiments suggested that leflunomide regulated NQO1 levels via AhR-dependent mechanisms and H{sub 2}O{sub 2}, catalase, and SOD2 levels via AhR-independent mechanisms. Collectively, the results support the hypothesis that leflunomide decreases oxidative stress in HPAECs via SOD2-and catalase-dependent, but AhR- and NQO1-independent mechanisms. Our findings indicate that leflunomide is a potential drug for the management of BPD in preterm infants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Effects of Altered Levels of Extracellular Superoxide Dismutase and Irradiation on Hippocampal Neurogenesis in Female Mice

Purpose: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. Methods and Materials: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, and long-term survival of newborn neurons were determined. Results: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC-SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. Conclusion: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Electronic properties of Ir 3 Li and ultra-nanocrystalline lithium superoxide formation

Current lithium-oxygen (Li-O 2 ) batteries suffer from large charge overpotentials related to electronic resistivity of the insulating lithium peroxide (Li 2 O 2 ) discharge product. One potential solution to this challenge is the stabilization of the lithium superoxide (LiO 2 ) discharge intermediate, which has much higher electronic conductivity compared to Li 2 O 2 . Cathodes based on small iridium (Ir) nanoparticles have been recently used in a LiO 2 battery to successfully stabilize the LiO 2 product, however, the LiO 2 had a short lifetime. In the previous study, researchers found that the LiO 2 was stabilized on Ir 3 Li surfaces which were formed from Ir nanoparticles during battery operation. Little is known about the electronic properties of Ir 3 Li and its role in stabilizing LiO 2 product formation. This work provides the first study of the electronic properties of Ir 3 Li, which was thermally synthesized in bulk prior to implementation on the reduced graphene oxide (rGO) cathode of a Li-O 2 cell. Here, the bulk Ir 3 Li was found to have comparable electrical conductivity to Ir metal, possess metal-like magnetic properties, and has an affinity towards O 2 adsorption. The LiO 2 discharge product formed from the Li-O 2 battery discharge was characterized using Raman spectroscopy, titration, along with a comprehensive transmission electron microscopy (TEM) study. This analysis revealed the formation of ultra-nanocrystalline LiO 2 particles greater than 200 nm. This result was attributed to the use of large micron sized Ir 3 Li particles, which could stabilize larger LiO 2 particles compared to previous cathodes that utilized Ir nanoparticles that partially converted to Ir 3 Li during cycling. These results demonstrate that cathode properties can be modified to stabilize the bulk LiO 2 discharge product, which can be useful for the further development of LiO 2 -based Li-O 2 batteries.

25 ENERGY STORAGE↗