The peroxidase activity of mitochondrial superoxide dismutase

Ansenberger-Fricano, Kristine; Ganini, Douglas; Mao, Mao; Chatterjee, Saurabh; Dallas, Shannon; Mason, Ronald P.; Stadler, Krisztián; Santos, Janine H.; Bonini, Marcelo G.

doi:10.1016/j.freeradbiomed.2012.08.573

Cited by 56 publications

(40 citation statements)

References 53 publications

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“…For example, MnSOD reacts with ONOO -at log k red (ONOO -) = 5, while MnPs reacts at log k red (ONOO -) = 7.34 (28,84,86). Cu,ZnSOD was shown to have Px-like activity, and, most recently, Bonini's group showed that MnSOD has Px-like activity also (7). The cysteine oxidase activity of Cu,ZnSOD was reported to be log k *5 (294).…”

Section: ) (D)mentioning

confidence: 99%

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

Batinić‐Haberle

Tovmasyan

Roberts

et al. 2014

Antioxidants & Redox Signaling

202

458

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Significance: Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O 2 $ -; no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored. Recent Advances: Structure-activity relationship (half-wave reduction potential [E 1/2 ] versus log k cat ), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E 1/2 of *+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O 2 $ -) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants. Critical Issues: Although log k cat (O 2 $ -) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor jB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells. Future Directions: Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs. Antioxid. Redox Signal. 20, 2372Signal. 20, -2415

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Section: ) (D)mentioning

confidence: 99%

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

Batinić‐Haberle

Tovmasyan

Roberts

et al. 2014

Antioxidants & Redox Signaling

202

458

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“…A low antioxidant status, defined either by individual genetics and/or dietary intake, could facilitate the cycling of H 2 O 2 to more ROS that are potentially mutagenic and therefore carcinogenic. Alternatively, peroxidase activity of the MnSOD protein may directly result in the oxidation of protein and DNA (Ansenberger-Fricano et al, 2013). Thus, the same allelic variant may be beneficial under some circumstances and detrimental under others.…”

Section: Epidemiological Evidence For a Role Of Mnsod In Cancermentioning

confidence: 99%

It takes 2 antioxidants to tango: the interaction between manganese superoxide dismutase and glutathione peroxidase-1

Ekoue¹,

Diamond²

2014

Turk J Biol

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The generation of ATP via oxidative phosphorylation provides the energy required by aerobic organisms to sustain themselves. This process is localized to the mitochondria, where electrons are passed among the components of the electron transport chain where there is an inevitability of leakage of the highly reactive oxygen species (ROS) superoxide, with it having been estimated that 1%-2% of the oxygen being used for mitochondrial respiration is converted to superoxide. With its short halflife and extreme reactivity, there is a strong potential for the superoxide radical to interact with biomolecules, resulting in oxidative damage that could have a profound effect on cellular function and survivability. As described below, eukaryotic cells have evolved defense mechanisms to protect themselves from the adverse effects of superoxide accumulation and the strategic location of manganese superoxide dismutase (MnSOD) in the mitochondria is a principle one of these. As a consequence of the dismutation of superoxide by MnSOD, the less reactive hydrogen peroxide (H 2 O 2 ) is generated, which can diffuse through the mitochondrial membrane where it can have its own host of biological consequences. The management of the appropriate levels of ROS is the domain of a host of antioxidant molecules such as glutathione and enzymes that can neutralize ROS. Oxidative stress occurs when the levels of ROS exceed the cell's abilities to maintain them at their appropriate levels. While less considered, the elimination of ROS past the ideal levels to support cellular function may also occur, and this has been referred to as reductive stress. ROS as important signaling moleculesAerobic organisms have not only evolved to take advantage of the enhanced energy production that can be achieved by the consumption of oxygen via the electron transport chain, but have also evolved to use ROS as potent signaling molecules. Fluctuations in ROS can be due to changes in environmental stimuli or intrinsic metabolic activity, and examples abound throughout phylogeny indicating the sensing of and response to one ROS, H 2 O 2 . As examples, plants use an oxidative burst that generates H 2 O 2 that serves as a diffusible signal to induce apoptosis in pathogenexposed cells while stimulating antioxidant enzymes in adjacent tissues (Levine et al., 1994), and a H 2 O 2 gradient generated at the tissue level in zebrafish mediates wound healing and leukocyte recruitment (Niethammer et al., 2009). One of the first examples of H 2 O 2 being critical for normal mammalian functions was the demonstration that the production of H 2 O 2 could stimulate platelet-Abstract: Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism. Accumulation of ROS without an effective antioxidant response can lead to oxidative stress, resulting in macromolecular damage that is implicated in the etiology of various diseases including cancer. ROS detoxification is regulated by various antioxidant proteins, specifically manganese superoxide dismutase (MnSOD),...

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“…However, the protein tertiary structure of SOD enzyme allows for its high specificity towards small O 2 · -while much lower reactivities towards larger species, such as ONOO -and CO 3 · -. Thus SOD enzyme reacts with ONOO -at > 2 log units slower than Mn(III) porphyrin, MnTE-2PyP 5+ (Quijano et al, 2001;Demicheli et al, 2007;Ansenberger-Fricano et al, 2013). Both enzymes and their mimics react with · NO also (Spasojevic et al, 2000;Filipovic et al, 2007).…”

Section: Sod Mimics Similar To Sod Enzymes Have Similar Types Of Rementioning

confidence: 99%

“…Both enzymes and their mimics react with · NO also (Spasojevic et al, 2000;Filipovic et al, 2007). Both SOD enzyme and MnTE(or nHex)-2-PyP 5+ are further able to act as thiol oxidases and peroxidases (Winterbourn et al, 2002;Tovmasyan et al, 2012;Ansenberger-Fricano et al, 2013). Electrostatic interactions are involved in the reactivity of SOD enzymes; the surface charges of the enzyme guide O 2 · -towards the metal active site (Koppenol, 1981;Getzoff et al, 1983;Desideri et al, 1988).…”

Section: Sod Mimics Similar To Sod Enzymes Have Similar Types Of Rementioning

confidence: 99%

The complex mechanistic aspects of redox-active compounds, commonly regarded as SOD mimics

Batinić‐Haberle

Tovmasyan

Spasojević

2013

BioInorganic Reaction Mechanisms

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This review aims to clarify (1) what is a true mimic of superoxide dismutase family of enzymes, SOD; and (2) whether such compound could act as SOD mimic in a complex biological milieu. Several groups of compounds (metalloporphyrins, metallocorroles, Mn biliverdins, Mn cyclic polyamines, Mn salens, and metal oxides and salts) have been described. Their ability to catalyze the dismutation of O 2 · -, [k cat (O 2 · -)], thermodynamic property that supports high catalytic ability (E 1/2 ), kinetic factors that facilitate the catalysis, and the stability of compounds, which assures the integrity of metal coordination sphere where reactions of interest occur have been discussed. The other possible in vivo actions of those compounds, such as peroxynitrite and hypochlorite reduction, peroxidase-like activity, thiol oxidase activity etc., have been described as well. Based on in vivo studies it appears that k cat (O 2 · -) for Mn(III) N-substituted pyridylporphyrins parallels their therapeutic ability. The reason for that lies in their electrophilic nature which favors reactions with nucleophilic (anionic) reactive species (O 2 · -, ONOO -, ClO -, HO 2 -, CO 3 · -) and simple or protein thiolates. Their in vivo multiple rather than single modes of actions, would be determined by: (a) their redox properties; (b) localization at targeted cellular site; and (c) redox environment of diseased or mutated/cancer cell. Quality of any drug preparation and the knowledge of researchers on its properties are essential when its mechanistic aspects are explored.List of Abbreviations: SOD, superoxide dismutase; peroxynitrite, ONOO -+ ONOOH, given its pKa = 6.6 at pH 7.8 peroxynitrite exists predominantly as ONOO -; O 2 · -, superoxide; · NO, nitric oxide; CO 3 · -, carbonate radical; FeP, Fe porphyrin; MnP, Mn porphyrin, when cationic porphyrins bear 5+ charge they have Mn in +3 oxidation state (Mn III P 5+ ), and with 4+ total charge Mn is in +2 (Mn II P 4+ ) or +4 oxidation states (O = Mn IV P 4+ ); MnTM-2-PyP 5+ , AEOL10112, Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (AEOL originates in the name of pharmaceutical company, Aeolus Pharmaceuticals, word Aeolus originates from Aeolian islands situated north of Sicily); MnTE-2-PyP 5+ (AEOL10113, BMX-010, FBC-007), Mn(III) meso-tetrakis(Nethylpyridinium-2-yl)porphyrin; MnTnHex-2-PyP 5+ , Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin; MnTnBuOE-2-PyP 5+ , Mn(III) meso-tetrakis(N-(n-butoxyethyl)pyridinium-2-yl)porphyrin, BMX-001; MnTDE-2-ImP 5+ , AEOL10150, Mn(III) tetrakis(N,N′-diethylimidazolium-2-yl)porphyrin; MnTAlkyl-2(3 or 4)-PyPs, Mn(III) meso-tetrakis(N-alkylpyridinium-2(3 or 4)-yl)porphyrins; 2, 3 and 4 relate to ortho, meta and para isomers, respectively; MnHalTAlkyl-2(3 or 4)-PyP 5+ s, Mn(III) β-halogenated meso-tetrakis(N-alkylpyridinium-2(3 or 4)-yl)porphyrins; MnTAlkoxyalkyl-2-PyP 5+ s, Mn(III) meso-tetrakis(N-alkoxyalkylpyridinium-2-yl)porphyrins; MnTAlkoxyalkyl-3-PyP 5+ s, Mn(III) meso-tetrakis(N-alkoxyalkylpyridinium-3-yl)porphyrins;MnTN-sub-2-ImP 5+ ...

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The peroxidase activity of mitochondrial superoxide dismutase

Cited by 56 publications

References 53 publications

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

It takes 2 antioxidants to tango: the interaction between manganese superoxide dismutase and glutathione peroxidase-1

The complex mechanistic aspects of redox-active compounds, commonly regarded as SOD mimics

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