title: Differential coordination demands in Fe versus Mn water-soluble cationic metalloporphyrins translate into remarkably different aqueous redox chemistry and biology.
abstract: The different biological behavior of cationic Fe and Mn pyridylporphyrins in Escherichia coli and mouse studies prompted us to revisit and compare their chemistry. For that purpose, the series of ortho and meta isomers of Fe(III) meso-tetrakis-N-alkylpyridylporphyrins, alkyl being methyl to n-octyl, were synthesized and characterized by elemental analysis, UV/vis spectroscopy, mass spectrometry, lipophilicity, protonation equilibria of axial waters, metal-centered reduction potential, E(1/2) for M(III)P/M(II)P redox couple (M = Fe, Mn, P = porphyrin), kcat for the catalysis of O2(•-) dismutation, stability toward peroxide-driven porphyrin oxidative degradation (produced in the catalysis of ascorbate oxidation by MP), ability to affect growth of SOD-deficient E. coli, and toxicity to mice. Electron-deficiency of the metal site is modulated by the porphyrin ligand, which renders Fe(III) porphyrins ≥5 orders of magnitude more acidic than the analogous Mn(III) porphyrins, as revealed by the pKa1 of axially coordinated waters. The 5 log units difference in the acidity between the Mn and Fe sites in porphyrin translates into the predominance of tetracationic (OH)(H2O)FeP complexes relative to pentacationic (H2O)2MnP species at pH ∼7.8. This is additionally evidenced in large differences in the E(1/2) values of M(III)P/M(II)P redox couples. The presence of hydroxo ligand labilizes trans-axial water which results in higher reactivity of Fe relative to Mn center. The differences in the catalysis of O2(•-) dismutation (log kcat) between Fe and Mn porphyrins is modest, 2.5-5-fold, due to predominantly outer-sphere, with partial inner-sphere character of two reaction steps. However, the rate constant for the inner-sphere H2O2-based porphyrin oxidative degradation is 18-fold larger for (OH)(H2O)FeP than for (H2O)2MnP. The in vivo consequences of the differences between the Fe and Mn porphyrins were best demonstrated in SOD-deficient E. coli growth. On the basis of fairly similar log kcat(O2(•-)) values, a very similar effect on the growth of SOD-deficient E. coli was anticipated by both metalloporphyrins. Yet, while (H2O)2MnTE-2-PyP(5+) was fully efficacious at ≥20 μM, the Fe analogue (OH)(H2O)FeTE-2-PyP(4+) supported SOD-deficient E. coli growth at as much as 200-fold lower doses in the range of 0.1-1 μM. Moreover the pattern of SOD-deficient E. coli growth was different with Mn and Fe porphyrins. Such results suggested a different mode of action of these metalloporphyrins. Further exploration demonstrated that (1) 0.1 μM (OH)(H2O)FeTE-2-PyP(4+) provided similar growth stimulation as the 0.1 μM Fe salt, while the 20 μM Mn salt provides no protection to E. coli; and (2) 1 μM Fe porphyrin is fully degraded by 12 h in E. coli cytosol and growth medium, while Mn porphyrin is not. Stimulation of the aerobic growth of SOD-deficient E. coli by the Fe porphyrin is therefore due to iron acquisition. Our data suggest that in vivo, redox-driven degradation of Fe porphyrins resulting in Fe release plays a major role in their biological action. Possibly, iron reconstitutes enzymes bearing [4Fe-4S] clusters as active sites. Under the same experimental conditions, (OH)(H2O)FePs do not cause mouse arterial hypotension, whereas (H2O)2MnPs do, which greatly limits the application of Mn porphyrins in vivo.
authors: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, United States.
authors: Artak
authors: A
authors: Tovmasyan
authors: Tin
authors: T
authors: Weitner
authors: Huaxin
authors: H
authors: Sheng
authors: MiaoMiao
authors: M
authors: Lu
authors: Zrinka
authors: Z
authors: Rajic
authors: David S
authors: DS
authors: Warner
authors: Ivan
authors: I
authors: Spasojevic
authors: Julio S
authors: JS
authors: Reboucas
authors: Ludmil
authors: L
authors: Benov
authors: Ines
authors: I
authors: Batinic-Haberle
mesh_terms: D000818:Animals; D002412:Cations / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D005290:Ferric Compounds / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008345:Manganese / Q000737:chemistry*; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D002412:Cations; D005290:Ferric Compounds; D008665:Metalloporphyrins; D014867:Water; D008345:Manganese
references: Biochemistry. 1987 Aug 25;26(17):5471-7
references: 2823881
references: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9
references: 18678913
references: J Inorg Biochem. 2006 Nov;100(11):1897-902
references: 16965820
references: Burns. 2011 Aug;37(5):842-50
references: 21345593
references: Chem Commun (Camb). 2003 Feb 7;(3):418-9
references: 12613641
references: J Biol Chem. 1987 Apr 5;262(10):4724-7
references: 3031031
references: J Pharmacol Exp Ther. 2005 Jul;314(1):53-60
references: 15784653
references: Microbiol Rev. 1987 Dec;51(4):509-18
references: 2963952
references: Amino Acids. 2012 Jan;42(1):95-113
references: 20473774
references: J Biol Chem. 2012 Apr 20;287(17):13541-8
references: 22247543
references: Shock. 2011 Jun;35(6):560-6
references: 21263378
references: Inorg Chem. 2002 Jul 15;41(14):3647-52
references: 12099867
references: Inorg Chem. 2001 Feb 12;40(4):726-39
references: 11225116
references: J Biol Chem. 1993 Oct 25;268(30):22369-76
references: 8226748
references: J Bacteriol. 1995 May;177(9):2305-14
references: 7730258
references: Med Princ Pract. 2013;22(2):103-30
references: 23075911
references: J Biol Chem. 1998 Apr 24;273(17):10313-6
references: 9553085
references: J Biol Chem. 2003 Feb 28;278(9):6831-7
references: 12475974
references: Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L167-75
references: 21075825
references: Trends Biochem Sci. 1999 Mar;24(3):104-9
references: 10203757
references: Free Radic Biol Med. 2009 Jul 1;47(1):72-8
references: 19361553
references: Chem Res Toxicol. 1999 May;12(5):442-9
references: 10328755
references: Dalton Trans. 2011 Apr 28;40(16):4111-21
references: 21384047
references: Free Radic Biol Med. 2011 Sep 1;51(5):1035-53
references: 21616142
references: Free Radic Biol Med. 2008 Jul 15;45(2):201-10
references: 18457677
references: J Med Chem. 2009 Dec 10;52(23):7868-72
references: 19954250
references: Eur J Cardiothorac Surg. 2012 Feb;41(2):391-6
references: 21733708
references: Int J Med Microbiol. 2001 May;291(2):67-79
references: 11437341
references: Shock. 2011 Feb;35(2):148-55
references: 20577150
references: Cancer Biother Radiopharm. 2010 Aug;25(4):439-48
references: 20735206
references: J Pharm Biomed Anal. 2013 Jan 25;73:29-34
references: 22503130
references: Biochim Biophys Acta. 2012 May;1822(5):794-814
references: 22198225
references: Free Radic Res. 2011 Nov;45(11-12):1289-306
references: 21859376
references: Free Radic Biol Med. 2012 May 1;52(9):1828-34
references: 22336516
references: Mech Ageing Dev. 2007 Feb;128(2):173-81
references: 17116320
references: Free Radic Res. 2011 Feb;45(2):188-200
references: 20942564
references: Mol Med. 2002 Oct;8(10):571-80
references: 12477967
references: Arch Biochem Biophys. 2009 Jan 1;481(1):1-15
references: 18977196
references: J Biol Chem. 1991 Oct 15;266(29):19328-33
references: 1655783
references: J Biol Inorg Chem. 2005 May;10(3):294-304
references: 15827730
references: Acc Chem Res. 2000 Jul;33(7):449-55
references: 10913233
references: J Inorg Biochem. 2006 Apr;100(4):434-47
references: 16516297
references: Dalton Trans. 2010 Dec 28;39(48):11568-76
references: 21052598
references: J Biol Chem. 1998 Sep 18;273(38):24521-8
references: 9733746
references: Arch Biochem Biophys. 2002 Jun 1;402(1):104-9
references: 12051688
references: J Bacteriol. 1987 Jul;169(7):2967-76
references: 3298208
references: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5892-6
references: 1631070
references: Front Biosci. 2003 Sep 01;8:s1409-21
references: 12957834
references: Biochemistry. 1979 Aug 7;18(16):3546-52
references: 224911
references: Dalton Trans. 2004 Jun 7;(11):1696-702
references: 15252564
references: J Thorac Cardiovasc Surg. 2012 Jun;143(6):1443-9
references: 22401641
references: J Biol Chem. 2003 Jul 25;278(30):27432-8
references: 12700236
references: Free Radic Biol Med. 2002 Dec 15;33(12):1657-69
references: 12488134
references: J Bacteriol. 1993 Oct;175(19):6212-9
references: 8407793
references: J Pharm Biomed Anal. 2008 Nov 4;48(3):1046-9
references: 18804338
references: J Biol Chem. 1991 Jan 25;266(3):1478-83
references: 1846355
references: Antioxid Redox Signal. 2010 Sep 15;13(6):877-918
references: 20095865
references: Chem Rev. 2004 Sep;104(9):3947-80
references: 15352783
references: Free Radic Res. 2009 Jul;43(7):631-45
references: 19418318
references: J Biol Chem. 1996 Aug 30;271(35):21037-40
references: 8702868
references: Infect Immun. 2010 Dec;78(12):4977-89
references: 20679437
references: J Biol Chem. 1999 Feb 12;274(7):4202-6
references: 9933617
references: Arch Biochem Biophys. 1995 May 10;319(1):10-22
references: 7771772