Spectroscopic and Computational Studies on Iron and Manganese Superoxide Dismutases:  Nature of the Chemical Events Associated with Active-Site pKs

Jackson, Timothy A.; Xie, Juan; Yikilmaz, Emine; Miller, Ann L.; Brunold, Thomas C.

doi:10.1021/ja0266058

Cited by 59 publications

(99 citation statements)

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“…Recent magnetic circular dichroism (MCD) spectroscopic and computational studies of Mn-and FeSOD confirmed the importance of these second coordination sphere amino acids as they participate in an extended H-bonding network that affects the protonation state of the axially coordinated solvent (shown in superscript in Eq. (1)) [65,66]. This interaction is essential in tuning the redox potential of the Mn center for each half-reaction with superoxide.…”

Section: Past Studiesmentioning

confidence: 99%

Multifrequency pulsed EPR studies of biologically relevant manganese(II) complexes

et al. 2007

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Electron paramagnetic resonance studies at multiple frequencies (MF EPR) can provide detailed electronic structure descriptions of unpaired electrons in organic radicals, inorganic complexes, and metalloenzymes. Analysis of these properties aids in the assignment of the chemical environment surrounding the paramagnet and provides mechanistic insight into the chemical reactions in which these systems take part. Herein, we present results from pulsed EPR studies performed at three different frequencies (9, 31, and 130 GHz) on [Mn(II)(H 2 O) 6 ] 2+ , Mn(II) adducts with the nucleotides ATP and GMP, and the Mn(II)-bound form of the hammerhead ribozyme (MnHH). Through line shape analysis and interpretation of the zero-field splitting values derived from successful simulations of the corresponding continuous-wave and field-swept echodetected spectra, these data are used to exemplify the ability of the MF EPR approach in distinguishing the nature of the first ligand sphere. A survey of recent results from pulsed EPR, as well as pulsed electron-nuclear double resonance and electron spin echo envelope modulation spectroscopic studies applied to Mn(II)-dependent systems, is also presented. Mn-Containing Biological SystemsManganese operates as a cofactor in numerous proteins, serving both catalytic and structural roles [1][2][3][4]. Many Mn-dependent enzymes take advantage o f the rich redox chemistry available to the metal, accessing the +2, +3, +4, and perhaps even the +5 oxidation states during their turnover. For example, Mn-superoxide dismutase (MnSOD), which detoxifies the cell of the superoxide radical , cycles between the Mn(II) and Mn(III) oxidation states via the ping-pong type mechanism shown below [5][6][7][8][9].(1a) (1b) Other examples of such mononuclear redox-active enzymes include the manganese peroxidase responsible for lignin degradation by white-rot fungus [10][11][12]; a unique Mndependent form of lipoxygenase [13][14][15][16]; oxalate decarboxylase [17,18]; as well as an extradiol catechol dioxygenase [19][20][21]. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn order to help minimize kinetic and thermodynamic penalties associated with electron transfer events and the execution of chemical reactions, two or more metal centers can be coupled together to provide active sites capable of conducting multiple electrons while still operating within a physiologically accessible range of reduction potentials [22]. Only three such examples of redox-active polynuclear Mn enzymes are known: Mn-catalase that disproportionates hydrogen peroxide [23][24][25][26]; a Mn form of ribonucleotide reductase (Mn-RNR) [27,28]; and, arguably the most recognized Mn-dependent enzyme, the photosynthetic core of green plants, algae, and certain cyanobacteria termed photosystem II (PSII) [29,30]. Through a series of photoinitiated electron transfer events, oxidizing equivalents are stored on the tetranuclear Mn core of PSII -the oxygen-evolving complex (OEC) -which then extracts four electr...

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Section: Past Studiesmentioning

confidence: 99%

Multifrequency pulsed EPR studies of biologically relevant manganese(II) complexes

et al. 2007

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“…Herein, we show that the redox properties of the brominated non-N-alkylated and the N-alkylated Mn(III) ortho-pyridylporphyrins are indeed nearly identical, allowing us to evaluate the electrostatic contribution in the catalysis of O 2 . dismutation.…”

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“…The redox potential of all superoxide dismutases was found to be similar, independently of the type of the metal in the active site. It is around midway (ϩ360 mV versus NHE) 1 (17) between the potential for the oxidation (Ϫ160 mV versus NHE) and for the reduction of O 2 .…”

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confidence: 99%

“…1 The abbreviations used are: NHE, normal hydrogen electrode; SOD, superoxide dismutase; meso, refers to the substituents at the 5, 10, 15, and 20 (meso carbon) position of the porphyrin core; ␤, refers to the substituents at ␤-pyrrolic carbons; Mn III T-2-PyP ϩ , Mn(III) 5,10,-15,20-tetrakis(2-pyridyl)porphyrin; Mn III TE-2-PyP 5ϩ (Mn-2E 5ϩ ) (AEOL-10113), manganese(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin; Mn III TM-2(3,4)-PyP 5ϩ (Mn-2(3,4)M 5ϩ ), manganese(III) 5,10,15,20-tetrakis(N-methylpyridinium-2(3,4)-yl)porphyrin, where 2 (AEOL-10112), 3, and 4 refer to ortho, meta, and para isomers, respectively; Mn III Br 8 T-2-PyP ϩ (Mn-Br 8 ϩ ), Mn(III) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(2-pyridyl)porphyrin; Mn II Br 8 TM-4-PyP 4ϩ , Mn(II) 2,3,7,8,12,13,17,10,15,porphyrin; Mn II Cl 5 TE-2-PyP 4ϩ , Mn(II) ␤-pentachloro-5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin; {Mn III BV 2Ϫ } 2 , Mn(III) biliverdin IX; {Mn III BVDME} 2 , Mn(III) biliverdin IX dimethyl ester.…”

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confidence: 99%

“…However, when manganese was replaced by iron in the active site of Mn-SOD the enzymatic activity was lost (18), which has been attributed to the decrease of the redox potential below that required for the oxidation of superoxide ion (3,18). Such metal ion specificity (2) has been recently explained by the higher affinity of Fe 3ϩ than Mn 3ϩ for hydroxide (6,8).…”

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Electrostatic Contribution in the Catalysis of O 2·_Dismutation by Superoxide Dismutase Mimics

Spasojević

Batinić‐Haberle

Rebouças

et al. 2003

Journal of Biological Chemistry

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The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)-porphyrin (Mn III TE-2-PyP 5؉ ) is a potent superoxide dismutase (SOD) mimic in vitro and was beneficial in rodent models of oxidative stress pathologies. Its high activity has been ascribed to both the favorable redox potential of its metal center and to the electrostatic facilitation assured by the four positive charges encircling the metal center. (ϩ890 mV versus NHE). Thus it allows equal driving force (hence k ox ϭ k red ϭ ϳ2 ϫ 10 9 M Ϫ1 s Ϫ1 ) for both half-reactions of the catalytic cycles (Reactions 1 and 2) (18 -20). For Escherichia coli Fe-SOD,the E1 ⁄2 is ϩ223 mV versus NHE at pH 7.4, and for Mn-SOD from the Bacillus stearothermophilus and E. coli the E1 ⁄2 were ϩ260 and ϩ310 mV versus NHE at pH 7 (1, 21, 22). However, when manganese was replaced by iron in the active site of Mn-SOD the enzymatic activity was lost (18), which has been attributed to the decrease of the redox potential below that required for the oxidation of superoxide ion (3, 18). Such metal ion specificity (2) has been recently explained by the higher affinity of Fe 3ϩ than Mn 3ϩ for hydroxide (6, 8).The crystal structures of different SODs reveal a highly conserved electrostatic "funnel" (13,14,16) that is believed to guide the negatively charged superoxide toward the active site of the enzyme. In the past there have been considerable efforts to evaluate the extent of electrostatic facilitation, but a major difficulty lies in the inability to specifically modify the positively charged residues without affecting the structural integrity of the active site (9).The Mn(III) porphyrin, Mn III TE-2-PyP 5ϩ (AEOL-10113) has been shown (23-27) to possess high SOD-like activity in vitro * This work was supported in part by Grant BA1-0103-1 from the Christopher Reeve Paralysis Foundation and by Aeolus/Incara Pharmaceuticals, Research Triangle Park, NC. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed. 1 The abbreviations used are: NHE, normal hydrogen electrode; SOD, superoxide dismutase; meso, refers to the substituents at the 5, 10, 15, and 20 (meso carbon) position of the porphyrin core; ␤, refers to the substituents at ␤-pyrrolic carbons; Mn III T-2-PyP ϩ , Mn(III) 5,10,-15,20-tetrakis(2-pyridyl)porphyrin; Mn III TE-2-PyP 5ϩ (Mn-2E 5ϩ ) (AEOL-10113), manganese(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl)porphyrin; Mn III TM-2(3,4)-PyP 5ϩ (Mn-2(3,4)M 5ϩ ), manganese(III) 5,10,15,20-tetrakis(N-methylpyridinium-2(3,4)-yl)porphyrin, where 2 (AEOL-10112), 3, and 4 refer to ortho, meta, and para isomers, respectively; Mn III Br 8 T-2-PyP ϩ (Mn-Br 8 ϩ ), Mn(III) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(2-pyridyl)porphyrin; Mn II Br 8 TM-4-PyP 4ϩ , Mn(II) 2,3,7,8,12,13,17,10,15,porphyrin; Mn II Cl 5 TE-2-PyP 4ϩ , Mn(II) ␤-pentachloro-5,10,15,20-tetrakis(N-ethylpyridi...

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Spectroscopic and Computational Investigation of Low‐Spin MnIII Bis(scorpionate) Complexes

et al. 2015

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Six-coordinate MnIII complexes are typically high-spin (S = 2), however, the scorpionate ligand, both in its traditional, hydridotris(pyrazolyl)borate form, Tp− and Tp*− (the latter with 3,5-dimethylpyrazole substituents) and in an aryltris(carbene)borate (i.e., N-heterocyclic carbene, NHC) form, [Ph(MeIm)3B]−, (MeIm = 3-methylimidazole) lead to formation of bis(scorpionate) complexes of MnIII with spin triplet ground states; three of which were investigated herein: [Tp2Mn]SbF6 (1SBF6), [Tp*2Mn]SbF6 (2SBF6), and [{Ph(MeIm)3B}2Mn]CF3SO3 (3CF3SO3). These trigonally symmetric complexes were studied experimentally by magnetic circular dichroism (MCD) spectroscopy (the propensity of 3 to oxidize to MnIV precluded collection of useful MCD data) including variable temperatures and fields (VTVH-MCD) and computationally by ab initio CASSCF/NEVPT2 methods. These combined experimental and theoretical techniques establish the 3A2g electronic ground state for the three complexes, and provide information on the energy of the “conventional” high-spin excited state (5Eg) and other, triplet excited states. These results show the electronic effect of pyrazole ring substituents in comparing 1 and 2. The tunability of the scorpionate ligand, even by perhaps the simplest change (from pyrazole in 1 to 3,5-dimethylpyrazole in 2) is quantitatively manifested through perturbations in ligand-field excited-state energies that impact ground-state zero-field splittings. The comparison with the NHC donor is much more dramatic. In 3, the stronger σ-donor properties of the NHC lead to a quantitatively different electronic structure, so that the lowest lying spin triplet excited state, 3Eg, is much closer in energy to the ground state than in 1 or 2. The zero-field splitting (zfs) parameters of the three complexes were calculated and in the case of 1 and 2 compare closely to experiment (lower by < 10%, < 2 cm−1 in absolute terms); for 3 the large magnitude zfs is reproduced, although there is ambiguity about its sign. The comprehensive picture obtained for these bis(scorpionate) MnIII complexes provides quantitative insight into the role played by the scorpionate ligand in stabilizing unusual electronic structures.

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Spectroscopic and Computational Studies on Iron and Manganese Superoxide Dismutases: Nature of the Chemical Events Associated with Active-Site pKs

Cited by 59 publications

References 56 publications

Multifrequency pulsed EPR studies of biologically relevant manganese(II) complexes

Multifrequency pulsed EPR studies of biologically relevant manganese(II) complexes

Electrostatic Contribution in the Catalysis of O 2·_Dismutation by Superoxide Dismutase Mimics

Spectroscopic and Computational Investigation of Low‐Spin MnIII Bis(scorpionate) Complexes

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