Potentiometric titrations and oxidation-reduction potentials of several iron superoxide dismutases

Barrette, William C.; Sawyer, Donald T.; Fee, James A.; Asada, Kozi

doi:10.1021/bi00272a015

Cited by 91 publications

(85 citation statements)

References 24 publications

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“…(1) (2) Consequently, the k ox and k red are nearly identical as is the case with SOD enzymes [38,39] themselves, and with our porphyrins [3,40]. As the redox potential increases further the oxidation of Mn(II) porphyrin becomes rate-limiting step, as is the cases with octabrominated porphyrins, leading eventually to a drop in k cat ; a bell-shaped curve in the k cat vs E ½ plot is observed [2,4,41].…”

Section: Resultssupporting

confidence: 62%

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

DeFreitas-Silva

Rebouças

Spasojević

et al. 2008

Archives of Biochemistry and Biophysics

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Mn porphyrins are among the most efficient SOD mimics with potency approaching that of SOD enzymes. The most potent ones, Mn(III) N-alkylpyridylporphyrins bear positive charges in a close proximity to the metal site, affording thermodynamic and kinetic facilitation for the reaction with negatively charged superoxide. The addition of electron-withdrawing bromines onto β-pyrrolic positions dramatically improves thermodynamic facilitation for the O 2 •− dismutation. We have previously characterized the para isomer, Mn II Br 8 TM-4-PyP 4+ [Mn(II) β-octabromo-meso-tetrakis (N-methylpyridinium-4-yl)porphyrin]. Herein we fully characterized its meta analogue, Mn II Br 8 TM-3-PyP 4+ with respect to uv/vis spectroscopy, electron spray mass spectrometry, electrochemistry, O 2 •− dismutation, metal-ligand stability, and the ability to protect SOD-deficient E. coli in comparison with its para analogue. The increased electron-deficiency of the metal center stabilizes Mn in its +2 oxidation state. The metal-centered Mn III /Mn II reduction potential, E ½ = + 468 mV vs NHE, is increased by 416 mV with respect to non-brominated analogue, Mn III TM-3-PyP 5+ and is only 12 mV less positive than for para isomer. Yet, the complex is significantly more stable towards the loss of metal than its para analogue. As expected, based on the structure-activity relationships, a large increase in E ½ results in exceptionally high catalytic rate constant for the O 2 •− dismutation, log k cat ≥ 8.85; 1.5-fold increase with respect to the para isomer. The IC 50 was calculated to be ≤ 3.7 nM. Manipulation of the electron-deficiency of a cationic porphyrin resulted, therefore, in the highest k cat ever reported for a metalloporphyrin, being essentially identical to the k cat of superoxide dismutases (log k cat = 8.84 -9.30). The positive kinetic salt effect points to the unexpected, unique and first time recorded behavior of Mn β-octabrominated porphyrins when compared to other Mn porphyrins studied thus far. When species of opposing charges react, the increase in ionic strength invariably results in the decreased rate constant; with brominated porphyrins the opposite was found to be true. The effect is 3.5 -fold greater with meta than with para isomer, which is discussed with respect to the closer proximity of the quaternary nitrogens of the meta isomer to the metal center than that of the para isomer. The potency of Mn II Br 8 TM-3-PyP 4+ was corroborated by in vivo studies, where 500 nM allows SOD-deficient E. coli to grow ≥ 60% of the growth of wild type; at concentrations ≥5 μM it exhibits toxicity. Our work shows that exceptionally high k cat for the O 2 •− disproportionation can be achieved not only with an N 5 -type *Corresponding authors: Ynara Marina Idemori, Ph. D., Departamento de Química, ICEx, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil., Tel: +55-31-3499-5762, Fax: +55-31-3499-5700, e-mail: ynara@ufmg.br NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH...

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Section: Resultssupporting

confidence: 62%

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

DeFreitas-Silva

Rebouças

Spasojević

et al. 2008

Archives of Biochemistry and Biophysics

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“…g′ values are indicated for several features; the six lines at g′ ) 2.07 in the spectrum of Mn 2+ SOD are most likely due to adventitious Mn 2+ since MnSOD was never treated with EDTA. In contrast to the numerous published measurements of the E m of FeSOD (16,43), only a single attempt to determine that of MnSOD had yet been published at the time this work was done (44), and that was effectively unmediated. In addition, the oxidized state extinction coefficient required to interpret a titration was frequently not known, since many MnSODs are isolated as a mixture of the oxidized and reduced states (34).…”

Section: Characterization Of Mn(fe)sodmentioning

confidence: 99%

“…•-+ 2H + to O 2 + H 2 O 2 in a two-step reaction in which the metal ion (M ) Fe or Mn here) cycles between the 2+ and 3+ oxidation states (15 (16). Fe (or Mn) is coordinated in a trigonal bipyramid by three histidines, an Asp -, and a molecule of solvent.…”

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confidence: 99%

Novel Insights into the Basis for Escherichia coli Superoxide Dismutase's Metal Ion Specificity from Mn-Substituted FeSOD and Its Very High E_m

2001

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Fe and Mn are both entrained to the same chemical reaction in apparently superimposable superoxide dismutase (SOD) proteins. However, neither Fe-substituted MnSOD nor Mn-substituted FeSOD is active. We have proposed that the two SOD proteins must apply very different redox tuning to their respective metal ions and that tuning appropriate for one metal ion results in a reduction potential (E m ) for the other metal ion that is either too low (Fe) or too high (Mn) [Vance and Miller (1998) J. Am. Chem. Soc. 120, 461-467]. We have demonstrated that this is true for Fe-substituted MnSOD from Escherichia coli and that this metal ion-protein combination retains the ability to reduce but not oxidize superoxide. We now demonstrate that the corollary is also true: Mn-substituted FeSOD [Mn(Fe)SOD] has a very high E m . Specifically, we have measured the E m of E. coli MnSOD to be 290 mV vs NHE. We have generated Mn(Fe)SOD and find that Mn is bound in an environment similar to that of the native (Mn)SOD protein. However, the E m is greater than 960 mV vs NHE and much higher than MnSOD's E m of 290 mV. We propose that the different tuning stems from different hydrogen bonding between the proteins and a molecule of solvent that is coordinated to the metal ion in both cases. Because a proton is taken up by SOD upon reduction, the protein can exert very strong control over the E m , by modulating the degree to which coordinated solvent is protonated, in both oxidation states. Thus, coordinated solvent molecules may have widespread significance as "adapters" by which proteins can control the reactivity of bound metal ions.

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“…With our ongoing goals to improve SOD-like activity in vitro and the efficacy in vivo, we recently synthesized and characterized the b-brominated meta isomer, MnBr 8 TM-3-PyP 4þ ; with an E 1=2 of þ 468 mV versus NHE and log k cat > 8. 85, this complex has, thus far, the highest dismuting ability among metalloporphyrins (85), which approximates that of the enzyme itself (21,26,100,136,218,269,325). As observed for the para analogue, MnBr 8 TM-4-PyP 4þ , the meta isomer has Mn in its þ 2 oxidation state and, thus, has insufficient metal=ligand stability for in vivo studies.…”

mentioning

confidence: 91%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

471

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Potentiometric titrations and oxidation-reduction potentials of several iron superoxide dismutases

Cited by 91 publications

References 24 publications

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

Novel Insights into the Basis for Escherichia coli Superoxide Dismutase's Metal Ion Specificity from Mn-Substituted FeSOD and Its Very High E_m

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

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Potentiometric titrations and oxidation-reduction potentials of several iron superoxide dismutases

Cited by 91 publications

References 24 publications

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

Novel Insights into the Basis for Escherichia coli Superoxide Dismutase's Metal Ion Specificity from Mn-Substituted FeSOD and Its Very High Em

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

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Product

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Novel Insights into the Basis for Escherichia coli Superoxide Dismutase's Metal Ion Specificity from Mn-Substituted FeSOD and Its Very High E_m