Pure Manganese(III) 5,10,15,20-tetrakis(4-benzoic Acid)porphyrin (MnTBAP) is Not a Superoxide Dismutase Mimic in Aqueous Systems: a Case of Structure-activity Relationship As a Watchdog Mechanism in Experimental Therapeutics and Biology

Overview

Journal J Biol Inorg Chem

Publisher Springer

Specialty Biochemistry

Date 2007 Nov 30

PMID 18046586

Citations 42

Authors

Julio S Reboucas

Ivan Spasojevic

Ines Batinic-Haberle

Affiliations

Soon will be listed here.

Abstract

Superoxide is involved in a plethora of pathological and physiological processes via oxidative stress and/or signal transduction pathways. Superoxide dismutase (SOD) mimics have, thus, been actively sought for clinical and mechanistic purposes. Manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP) is one of the most intensely explored "SOD mimics" in biology and medicine. However, we show here that this claimed SOD activity of MnTBAP in aqueous media is not corroborated by comprehensive structure-activity relationship studies for a wide set of Mn porphyrins and that MnTBAP from usual commercial sources contains different amounts of noninnocent trace impurities (Mn clusters), which inhibited xanthine oxidase and had SOD activity in their own right. In addition, the preparation and thorough characterization of a high-purity MnTBAP is presented for the first time and confirmed that pure MnTBAP has no SOD activity in aqueous medium. These findings call for an assessment of the relevance and suitability of using MnTBAP (or its impurities) as a mechanistic probe and antioxidant therapeutic; conclusions on the physiological and pathological role of superoxide derived from studies using MnTBAP of uncertain purity should be examined judiciously. An unequivocal distinction between the biological effects due to MnTBAP and that of its impurities can only be unambiguously made if a pure sample is/was used. This work also illustrates the contribution of fundamental structure-activity relationship studies not only for drug design and optimization, but also as a "watchdog" mechanism for checking/spotting eventual incongruence of drug activity in chemical and biological settings.

Citing Articles

MnSOD Mimetics in Therapy: Exploring Their Role in Combating Oxidative Stress-Related Diseases.

Grujicic J, Allen A Antioxidants (Basel). 2025; 13(12.

PMID: 39765773 PMC: 11672822. DOI: 10.3390/antiox13121444.

Cobinamide is a strong and versatile antioxidant that overcomes oxidative stress in cells, flies, and diabetic mice.

Chang S, Tat J, Pal China S, Kalyanaraman H, Zhuang S, Chan A PNAS Nexus. 2022; 1(4):pgac191.

PMID: 36276587 PMC: 9578022. DOI: 10.1093/pnasnexus/pgac191.

Microwave-assisted synthesis of [Mn]Mn-porphyrins: Applications in cell and liposome radiolabelling.

Gawne P, Pinto S, Nielsen K, Keeling G, Pereira M, T M de Rosales R Nucl Med Biol. 2022; 114-115:6-17.

PMID: 36088876 PMC: 10236072. DOI: 10.1016/j.nucmedbio.2022.08.006.

HO-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways.

Batinic-Haberle I, Tovmasyan A, Huang Z, Duan W, Du L, Siamakpour-Reihani S Oxid Med Cell Longev. 2021; 2021:6653790.

PMID: 33815656 PMC: 7987459. DOI: 10.1155/2021/6653790.

Catalytic Antioxidants in the Kidney.

Hong Y, Park C Antioxidants (Basel). 2021; 10(1).

PMID: 33477607 PMC: 7831323. DOI: 10.3390/antiox10010130.

References

Szabo C, Ischiropoulos H, Radi R . Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007; 6(8):662-80. DOI: 10.1038/nrd2222. View

Lahaye D, Muthukumaran K, Hung C, Gryko D, Reboucas J, Spasojevic I . Design and synthesis of manganese porphyrins with tailored lipophilicity: investigation of redox properties and superoxide dismutase activity. Bioorg Med Chem. 2007; 15(22):7066-86. PMC: 2111292. DOI: 10.1016/j.bmc.2007.07.015. View

Tse H, Milton M, Piganelli J . Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation-reduction reactions in innate immunity. Free Radic Biol Med. 2004; 36(2):233-47. DOI: 10.1016/j.freeradbiomed.2003.10.029. View

Moeller B, Batinic-Haberle I, Spasojevic I, Rabbani Z, Anscher M, Vujaskovic Z . A manganese porphyrin superoxide dismutase mimetic enhances tumor radioresponsiveness. Int J Radiat Oncol Biol Phys. 2005; 63(2):545-52. DOI: 10.1016/j.ijrobp.2005.05.026. View

Dismukes G . Manganese Enzymes with Binuclear Active Sites. Chem Rev. 1996; 96(7):2909-2926. DOI: 10.1021/cr950053c. View

Culotta V, Yang M, OHalloran T . Activation of superoxide dismutases: putting the metal to the pedal. Biochim Biophys Acta. 2006; 1763(7):747-58. PMC: 1633718. DOI: 10.1016/j.bbamcr.2006.05.003. View

WOOD P . The potential diagram for oxygen at pH 7. Biochem J. 1988; 253(1):287-9. PMC: 1149288. DOI: 10.1042/bj2530287. View

Riley D . Functional mimics of superoxide dismutase enzymes as therapeutic agents. Chem Rev. 2001; 99(9):2573-88. DOI: 10.1021/cr980432g. View

Spasojevic I, Chen Y, Noel T, Yu Y, Cole M, Zhang L . Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria. Free Radic Biol Med. 2007; 42(8):1193-200. PMC: 1931511. DOI: 10.1016/j.freeradbiomed.2007.01.019. View

10.

Ferrer-Sueta G, Hannibal L, Batinic-Haberle I, Radi R . Reduction of manganese porphyrins by flavoenzymes and submitochondrial particles: a catalytic cycle for the reduction of peroxynitrite. Free Radic Biol Med. 2006; 41(3):503-12. DOI: 10.1016/j.freeradbiomed.2006.04.028. View

11.

Saba H, Batinic-Haberle I, Munusamy S, Mitchell T, Lichti C, Megyesi J . Manganese porphyrin reduces renal injury and mitochondrial damage during ischemia/reperfusion. Free Radic Biol Med. 2007; 42(10):1571-8. PMC: 1924492. DOI: 10.1016/j.freeradbiomed.2007.02.016. View

12.

Goldstein S, Czapski G, Heller A . Osmium tetroxide, used in the treatment of arthritic joints, is a fast mimic of superoxide dismutase. Free Radic Biol Med. 2005; 38(7):839-45. DOI: 10.1016/j.freeradbiomed.2004.10.027. View

13.

Pervaiz S, Clement M . Superoxide anion: oncogenic reactive oxygen species?. Int J Biochem Cell Biol. 2007; 39(7-8):1297-304. DOI: 10.1016/j.biocel.2007.04.007. View

14.

Munroe W, Kingsley C, Durazo A, Gralla E, Imlay J, Srinivasan C . Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes. J Inorg Biochem. 2007; 101(11-12):1875-82. PMC: 3237304. DOI: 10.1016/j.jinorgbio.2007.07.008. View

15.

Spasojevic I, Batinic-Haberle I, Stevens R, Hambright P, Thorpe A, Grodkowski J . Manganese(III) biliverdin IX dimethyl ester: a powerful catalytic scavenger of superoxide employing the Mn(III)/Mn(IV) redox couple. Inorg Chem. 2001; 40(4):726-39. DOI: 10.1021/ic0004986. View

16.

Tauskela J, Brunette E, OReilly N, Mealing G, Comas T, Gendron T . An alternative Ca2+-dependent mechanism of neuroprotection by the metalloporphyrin class of superoxide dismutase mimetics. FASEB J. 2005; 19(12):1734-6. DOI: 10.1096/fj.05-3795fje. View

17.

Pasternack R, HUBER P, Boyd P, Engasser G, Francesconi L, Gibbs E . On the aggregation of meso-substituted water-soluble porphyrins. J Am Chem Soc. 1972; 94(13):4511-7. DOI: 10.1021/ja00768a016. View

18.

Spasojevic I, Batinic-Haberle I, Reboucas J, Idemori Y, Fridovich I . Electrostatic contribution in the catalysis of O2*- dismutation by superoxide dismutase mimics. MnIIITE-2-PyP5+ versus MnIIIBr8T-2-PyP+. J Biol Chem. 2002; 278(9):6831-7. DOI: 10.1074/jbc.M211346200. View

19.

Culotta V, Yang M, Hall M . Manganese transport and trafficking: lessons learned from Saccharomyces cerevisiae. Eukaryot Cell. 2005; 4(7):1159-65. PMC: 1168969. DOI: 10.1128/EC.4.7.1159-1165.2005. View

20.

Day B, Shawen S, Liochev S, Crapo J . A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced endothelial cell injury, in vitro. J Pharmacol Exp Ther. 1995; 275(3):1227-32. View