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• W3165785156 abstract "Porphyrias are rare blood disorders caused by genetic defects in the heme biosynthetic pathway and are associated with the accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures, but very little is known about the cytotoxic effects of these porphyrin nanostructures. Previously, we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin-IX (PP-IX), to cause organelle-selective protein aggregation, which we posited to be a major mechanism by which fluorescent porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein-binding ability. UV–visible spectrophotometry showed pH-mediated reversible transformations of PP-IX nanostructures. Biochemical analysis showed that PP-IX nanostructure size modulated PP-IX-induced protein oxidation and protein aggregation. Furthermore, albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. PP-IX binding quenched albumin intrinsic fluorescence and oxidized His-91 residue to Asn/Asp, likely via a previously described photo-oxidation mechanism for other proteins. Extracellular albumin protected from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX nanostructures in the context of porphyrias and offers insights into potential novel therapeutic approaches. Porphyrias are rare blood disorders caused by genetic defects in the heme biosynthetic pathway and are associated with the accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures, but very little is known about the cytotoxic effects of these porphyrin nanostructures. Previously, we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin-IX (PP-IX), to cause organelle-selective protein aggregation, which we posited to be a major mechanism by which fluorescent porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein-binding ability. UV–visible spectrophotometry showed pH-mediated reversible transformations of PP-IX nanostructures. Biochemical analysis showed that PP-IX nanostructure size modulated PP-IX-induced protein oxidation and protein aggregation. Furthermore, albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. PP-IX binding quenched albumin intrinsic fluorescence and oxidized His-91 residue to Asn/Asp, likely via a previously described photo-oxidation mechanism for other proteins. Extracellular albumin protected from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX nanostructures in the context of porphyrias and offers insights into potential novel therapeutic approaches. Protoporphyrin-IX (PP-IX) is nature’s template for several essential biomolecules including heme, chlorophyll, coenzyme F430 (in methanogenic bacteria), and vitamin B12 (1Dayan F.E. Dayan E.A. Porphyrins: One ring in the colors of life: A class of pigment molecules binds king george iii, vampires and herbicides.Am. Scientist. 2011; 99: 236-243Crossref Scopus (19) Google Scholar). The PP-IX macrocycle consists of four pyrrole rings connected by methene bridges and two ionizable propioniate side chains. The highly conjugated macrocycle with 18 π-electrons confers PP-IX with distinct UV-visible absorbance and fluorescence properties (2Gotardo F. Cocca L.H.Z. Acunha T.V. Longoni A. Toldo J. Gonçalves P.F.B. Iglesias B.A. De Boni L. Investigating the intersystem crossing rate and triplet quantum yield of protoporphyrin ix by means of pulse train fluorescence technique.Chem. Phys. Lett. 2017; 674: 48-57Crossref Scopus (20) Google Scholar). Due to its amphiphilic nature, PP-IX tends to aggregate in aqueous solution (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar). Indeed, PP-IX has been reported to exist as detergent micellarized 0.56 kDa monomers (4Isamu I. Kazutomo U. Association behavior of protoporphyrin ix in water and aqueous poly(n-vinylpyrrolidone) solutions. Interaction between protoporphyrin ix and poly(n-vinylpyrrolidone).Bull. Chem. Soc. Jpn. 1991; 64: 2005-2007Crossref Google Scholar), dimers (5Margalit R. Shaklai N. Cohen S. Fluorimetric studies on the dimerization equilibrium of protoporphyrin ix and its haemato derivative.Biochem. J. 1983; 209: 547-552Crossref PubMed Scopus (92) Google Scholar), tetramers (6Seo J. Jang J. Warnke S. Gewinner S. Schöllkopf W. von Helden G. Stacking geometries of early protoporphyrin ix aggregates revealed by gas-phase infrared spectroscopy.J. Am. Chem. Soc. 2016; 138: 16315-16321Crossref PubMed Scopus (18) Google Scholar), and higher-order structures that are >70 kDa in size (4Isamu I. Kazutomo U. Association behavior of protoporphyrin ix in water and aqueous poly(n-vinylpyrrolidone) solutions. Interaction between protoporphyrin ix and poly(n-vinylpyrrolidone).Bull. Chem. Soc. Jpn. 1991; 64: 2005-2007Crossref Google Scholar). The spontaneous self-association of PP-IX occurs by a combination of hydrogen bonding (between the propionate carboxylate) and π-π stacking of the porphine ring (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar, 6Seo J. Jang J. Warnke S. Gewinner S. Schöllkopf W. von Helden G. Stacking geometries of early protoporphyrin ix aggregates revealed by gas-phase infrared spectroscopy.J. Am. Chem. Soc. 2016; 138: 16315-16321Crossref PubMed Scopus (18) Google Scholar, 7Hunter C.A. Sanders J.K.M. The nature of .Pi.-.Pi. Interactions.J. Am. Chem. Soc. 1990; 112: 5525-5534Crossref Scopus (4832) Google Scholar). The resulting face-to-face or “H-aggregates” have the propionate chains of adjacent PP-IX molecules in a “head-to-tail” orientation (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar, 6Seo J. Jang J. Warnke S. Gewinner S. Schöllkopf W. von Helden G. Stacking geometries of early protoporphyrin ix aggregates revealed by gas-phase infrared spectroscopy.J. Am. Chem. Soc. 2016; 138: 16315-16321Crossref PubMed Scopus (18) Google Scholar, 7Hunter C.A. Sanders J.K.M. The nature of .Pi.-.Pi. Interactions.J. Am. Chem. Soc. 1990; 112: 5525-5534Crossref Scopus (4832) Google Scholar). These supramolecular higher-order structures offer advantages over their constituent monomers (8Zhou J. Li J. Du X. Xu B. Supramolecular biofunctional materials.Biomaterials. 2017; 129: 1-27Crossref PubMed Scopus (121) Google Scholar, 9Lehn J. Supramolecular chemistry.Science. 1993; 260: 1762-1763Crossref PubMed Scopus (594) Google Scholar). The self-assembling property of PP-IX and similar compounds are being explored for a variety of applications (10Magna G. Monti D. Di Natale C. Paolesse R. Stefanelli M. The assembly of porphyrin systems in well-defined nanostructures: An update.Molecules. 2019; 24Crossref PubMed Scopus (23) Google Scholar, 11Elemans J.A.A.W. van Hameren R. Nolte R.J.M. Rowan A.E. Molecular materials by self-assembly of porphyrins, phthalocyanines, and perylenes.Adv. Mater. 2006; 18: 1251-1266Crossref Scopus (619) Google Scholar, 12Wurthner F. Kaiser T.E. Saha-Moller C.R. J-aggregates: From serendipitous discovery to supramolecular engineering of functional dye materials.Angew. Chem. Int. Ed. Engl. 2011; 50: 3376-3410Crossref PubMed Scopus (1595) Google Scholar), e.g., synthetic porphyrins for photodynamic therapy (13Jin C.S. Lovell J.F. Chen J. Zheng G. Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly.ACS Nano. 2013; 7: 2541-2550Crossref PubMed Scopus (290) Google Scholar, 14Constantin C. Neagu M. Ion R.M. Gherghiceanu M. Stavaru C. Fullerene-porphyrin nanostructures in photodynamic therapy.Nanomedicine (Lond.). 2010; 5: 307-317Crossref PubMed Scopus (56) Google Scholar, 15Jin C.S. Cui L. Wang F. Chen J. Zheng G. Targeting-triggered porphysome nanostructure disruption for activatable photodynamic therapy.Adv. Healthc. Mater. 2014; 3: 1240-1249Crossref PubMed Scopus (112) Google Scholar), photovoltaic cells (16Imahori H. Fukuzumi S. Porphyrin- and fullerene-based molecular photovoltaic devices.Adv. Funct. Mater. 2004; 14: 525-536Crossref Scopus (438) Google Scholar, 17Hasobe T. Imahori H. Kamat P.V. Ahn T.K. Kim S.K. Kim D. Fujimoto A. Hirakawa T. Fukuzumi S. Photovoltaic cells using composite nanoclusters of porphyrins and fullerenes with gold nanoparticles.J. Am. Chem. Soc. 2005; 127: 1216-1228Crossref PubMed Scopus (456) Google Scholar, 18Walter M.G. Rudine A.B. Wamser C.C. Porphyrins and phthalocyanines in solar photovoltaic cells.J. Porphyrins Phthalocyanines. 2010; 14: 759-792Crossref Scopus (544) Google Scholar), photocatalysis (19Zhang N. Wang L. Wang H. Cao R. Wang J. Bai F. Fan H. Self-assembled one-dimensional porphyrin nanostructures with enhanced photocatalytic hydrogen generation.Nano Lett. 2018; 18: 560-566Crossref PubMed Scopus (107) Google Scholar, 20Wang Z. Ho K.J. Medforth C.J. Shelnutt J.A. Porphyrin nanofiber bundles from phase-transfer ionic self-assembly and their photocatalytic self-metallization.Adv. Mater. 2006; 18: 2557-2560Crossref Scopus (108) Google Scholar, 21La D.D. Bhosale S.V. Jones L.A. Bhosale S.V. Arginine-induced porphyrin-based self-assembled nanostructures for photocatalytic applications under simulated sunlight irradiation.Photochem. Photobiol. Sci. 2017; 16: 151-154Crossref PubMed Google Scholar, 22Chen Y. Huang Z.-H. Yue M. Kang F. Integrating porphyrin nanoparticles into a 2d graphene matrix for free-standing nanohybrid films with enhanced visible-light photocatalytic activity.Nanoscale. 2014; 6: 978-985Crossref PubMed Google Scholar, 23Medforth C.J. Wang Z. Martin K.E. Song Y. Jacobsen J.L. Shelnutt J.A. Self-assembled porphyrin nanostructures.Chem. Commun. 2009; : 7261-7277Crossref PubMed Scopus (246) Google Scholar), and sensor applications (23Medforth C.J. Wang Z. Martin K.E. Song Y. Jacobsen J.L. Shelnutt J.A. Self-assembled porphyrin nanostructures.Chem. Commun. 2009; : 7261-7277Crossref PubMed Scopus (246) Google Scholar, 24Dini F. Martinelli E. Pomarico G. Paolesse R. Monti D. Filippini D. D'Amico A. Lundstrom I. Di Natale C. Chemical sensitivity of self-assembled porphyrin nano-aggregates.Nanotechnology. 2009; 20055502Crossref PubMed Scopus (34) Google Scholar, 25Wang Z. Medforth C.J. Shelnutt J.A. Porphyrin nanotubes by ionic self-assembly.J. Am. Chem. Soc. 2004; 126: 15954-15955Crossref PubMed Scopus (368) Google Scholar). Although porphyrin macromolecular species have been extensively studied, their role in the context of porphyria and in the context of protein aggregation is not known. Porphyrias include eight genetic disorders that are caused by mutations in any of the eight enzymes in the heme biosynthetic pathway (26Puy H. Gouya L. Deybach J.-C. Porphyrias.Lancet. 2010; 375: 924-937Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Heme biosynthesis starts in the mitochondrion where aminolevulinic acid (ALA) synthase catalyzes the rate-limiting conversion of glycine and succinyl Co-A to δ-ALA (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 28Schultz I.J. Chen C. Paw B.H. Hamza I. Iron and porphyrin trafficking in heme biogenesis.J. Biol. Chem. 2010; 285: 26753-26759Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29Montgomery Bissell D. Chapter 66 - the porphyrias.in: Rosenberg R.N. Pascual J.M. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease. 5th Ed. Academic Press, Boston, MA2015: 731-749Crossref Scopus (0) Google Scholar, 30Ajioka R.S. Phillips J.D. Kushner J.P. Biosynthesis of heme in mammals.Biochim. Biophys. Acta. 2006; 1763: 723-736Crossref PubMed Scopus (330) Google Scholar). Upon translocation to the cytosol, ALA is converted in several steps to the first cyclic tetrapyrrole, uroporphyrinogen, which is then converted to coproporphyrinogen (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 28Schultz I.J. Chen C. Paw B.H. Hamza I. Iron and porphyrin trafficking in heme biogenesis.J. Biol. Chem. 2010; 285: 26753-26759Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29Montgomery Bissell D. Chapter 66 - the porphyrias.in: Rosenberg R.N. Pascual J.M. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease. 5th Ed. Academic Press, Boston, MA2015: 731-749Crossref Scopus (0) Google Scholar, 30Ajioka R.S. Phillips J.D. Kushner J.P. Biosynthesis of heme in mammals.Biochim. Biophys. Acta. 2006; 1763: 723-736Crossref PubMed Scopus (330) Google Scholar). Coproporphyrinogen then enters the mitochondria, where it is converted to heme via formation of protoporphyrinogen and PP-IX (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 28Schultz I.J. Chen C. Paw B.H. Hamza I. Iron and porphyrin trafficking in heme biogenesis.J. Biol. Chem. 2010; 285: 26753-26759Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29Montgomery Bissell D. Chapter 66 - the porphyrias.in: Rosenberg R.N. Pascual J.M. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease. 5th Ed. Academic Press, Boston, MA2015: 731-749Crossref Scopus (0) Google Scholar, 30Ajioka R.S. Phillips J.D. Kushner J.P. Biosynthesis of heme in mammals.Biochim. Biophys. Acta. 2006; 1763: 723-736Crossref PubMed Scopus (330) Google Scholar). Porphyrinogens are colorless, nonfluorescent (31Badminton M.N. Elder G.H. Chapter 28 - the porphyrias: Inherited disorders of haem synthesis.in: Marshall W.J. Lapsley M. Day A.P. Ayling R.M. Clinical Biochemistry: Metabolic and Clinical Aspects. 3rd Ed. Churchill Livingstone, London, UK2014: 533-549Crossref Scopus (2) Google Scholar) compounds, which are auto-oxidized to more stable and fluorescent porphyrins (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Porphyrins are toxic metabolites, and their levels are tightly regulated. In porphyrias, blockages in the heme biosynthetic pathway due to enzyme mutations lead to the accumulation of intermediates with consequent organ and tissue damage (4Isamu I. Kazutomo U. Association behavior of protoporphyrin ix in water and aqueous poly(n-vinylpyrrolidone) solutions. Interaction between protoporphyrin ix and poly(n-vinylpyrrolidone).Bull. Chem. Soc. Jpn. 1991; 64: 2005-2007Crossref Google Scholar, 18Walter M.G. Rudine A.B. Wamser C.C. Porphyrins and phthalocyanines in solar photovoltaic cells.J. Porphyrins Phthalocyanines. 2010; 14: 759-792Crossref Scopus (544) Google Scholar, 25Wang Z. Medforth C.J. Shelnutt J.A. Porphyrin nanotubes by ionic self-assembly.J. Am. Chem. Soc. 2004; 126: 15954-15955Crossref PubMed Scopus (368) Google Scholar). Porphyrin-mediated tissue damage is proposed to occur through reactive oxygen species (ROS) generated by type I/II photosensitized reactions of porphyrins (32Foote C.S. Definition of type i and type ii photosensitized oxidation.Photochem. Photobiol. 1991; 54: 659Crossref PubMed Scopus (906) Google Scholar, 33Takeshita K. Takajo T. Hirata H. Ono M. Utsumi H. In vivo oxygen radical generation in the skin of the protoporphyria model mouse with visible light exposure: An l-band esr study.J. Invest. Dermatol. 2004; 122: 1463-1470Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 34Brun A. Sandberg S. Mechanisms of photosensitivity in porphyric patients with special emphasis on erythropoietic protoporphyria.J. Photochem. Photobiol. B Biol. 1991; 10: 285-302Crossref PubMed Scopus (38) Google Scholar). However, the precise nature of the ROS as well as the specific targets of porphyrin-generated ROS is poorly understood (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Accumulating findings have demonstrated the unique properties of fluorescent porphyrins to cause organelle-selective protein aggregation though a mechanism that involves a “porphyrination-deporphyrination” cycle (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 35Singla A. Griggs N.W. Kwan R. Snider N.T. Maitra D. Ernst S.A. Herrmann H. Omary M.B. Lamin aggregation is an early sensor of porphyria-induced liver injury.J. Cell Sci. 2013; 126: 3105-3112Crossref PubMed Scopus (21) Google Scholar, 36Saggi H. Maitra D. Jiang A. Zhang R. Wang P. Cornuet P. Singh S. Locker J. Ma X. Dailey H. Abrams M. Omary M.B. Monga S.P. Nejak-Bowen K. Loss of hepatocyte beta-catenin protects mice from experimental porphyria-associated liver injury.J. Hepatol. 2019; 70: 108-117Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 37Elenbaas J.S. Maitra D. Liu Y. Lentz S.I. Nelson B. Hoenerhoff M.J. Shavit J.A. Omary M.B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.FASEB J. 2016; 30: 1798-1810Crossref PubMed Scopus (12) Google Scholar, 38Zhang H. Ramakrishnan S.K. Triner D. Centofanti B. Maitra D. Gyorffy B. Sebolt-Leopold J.S. Dame M.K. Varani J. Brenner D.E. Fearon E.R. Omary M.B. Shah Y.M. Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of yap1.Sci. Signal. 2015; 8: ra98Crossref PubMed Scopus (111) Google Scholar, 39Maitra D. Elenbaas J.S. Whitesall S.E. Basrur V. D'Alecy L.G. Omary M.B. Ambient light promotes selective subcellular proteotoxicity after endogenous and exogenous porphyrinogenic stress.J. Biol. Chem. 2015; 290: 23711-23724Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In this cycle, PP-IX binds to target proteins (porphyrination) and induces localized unfolding and conformational change (40Fernandez N.F. Sansone S. Mazzini A. Brancaleon L. Irradiation of the porphyrin causes unfolding of the protein in the protoporphyrin ix/β-lactoglobulin noncovalent complex.J. Phys. Chem. B. 2008; 112: 7592-7600Crossref PubMed Scopus (22) Google Scholar, 41Belcher J. Sansone S. Fernandez N.F. Haskins W.E. Brancaleon L. Photoinduced unfolding of β-lactoglobulin mediated by a water-soluble porphyrin.J. Phys. Chem. B. 2009; 113: 6020-6030Crossref PubMed Scopus (23) Google Scholar). Photosensitization of protein-bound PP-IX generates singlet oxygen (1O2), then oxidation of specific methionines to methionine sulfone or sulfoxide (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 42Maitra D. Carter E.L. Richardson R. Rittie L. Basrur V. Zhang H. Nesvizhskii A.I. Osawa Y. Wolf M.W. Ragsdale S.W. Lehnert N. Herrmann H. Omary M.B. Oxygen and conformation dependent protein oxidation and aggregation by porphyrins in hepatocytes and light-exposed cells.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 659-682.e651Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Subsequent noncovalent interactions lead to protein-PP-IX lattice-like aggregate formation. During deporphyrination, acidic pH or high-salt conditions lead to release of PP-IX and disaggregation of the proteins (27Maitra D. Bragazzi Cunha J. Elenbaas J.S. Bonkovsky H.L. Shavit J.A. Omary M.B. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 535-548Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 42Maitra D. Carter E.L. Richardson R. Rittie L. Basrur V. Zhang H. Nesvizhskii A.I. Osawa Y. Wolf M.W. Ragsdale S.W. Lehnert N. Herrmann H. Omary M.B. Oxygen and conformation dependent protein oxidation and aggregation by porphyrins in hepatocytes and light-exposed cells.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 659-682.e651Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). We posit that this proteotoxic property of porphyrins is a major mechanism for tissue damage in porphyrias that involve fluorescent porphyrin accumulation. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by PP-IX speciation into selective supramolecular structures that lead to differential oxidizing potential and protein binding. PP-IX speciation results in distinct UV–visible and fluorescence emission signatures (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar, 4Isamu I. Kazutomo U. Association behavior of protoporphyrin ix in water and aqueous poly(n-vinylpyrrolidone) solutions. Interaction between protoporphyrin ix and poly(n-vinylpyrrolidone).Bull. Chem. Soc. Jpn. 1991; 64: 2005-2007Crossref Google Scholar, 5Margalit R. Shaklai N. Cohen S. Fluorimetric studies on the dimerization equilibrium of protoporphyrin ix and its haemato derivative.Biochem. J. 1983; 209: 547-552Crossref PubMed Scopus (92) Google Scholar, 43Teng K.W. Lee S.H. Characterization of protoporphyrin ix species in vitro using fluorescence spectroscopy and polar plot analysis.J. Phys. Chem. B. 2019; 123: 5832-5840Crossref PubMed Scopus (4) Google Scholar). In aqueous solution, pH and ionic strength are the principal modulators of PP-IX speciation (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar). We investigated the nature of PP-IX speciation at pH 7.4 (physiological), pH 4.5 (lysosomal), and pH 9, using previously reported spectra (3Scolaro L.M. Castriciano M. Romeo A. Patanè S. Cefalì E. Allegrini M. Aggregation behavior of protoporphyrin ix in aqueous solutions: Clear evidence of vesicle formation.J. Phys. Chem. B. 2002; 106: 2453-2459Crossref Scopus (126) Google Scholar, 4Isamu I. Kazutomo U. Association behavior of protoporphyrin ix in water and aqueous poly(n-vinylpyrrolidone) solutions. Interaction between protoporphyrin ix and poly(n-vinylpyrrolidone).Bull. Chem. Soc. Jpn. 1991; 64: 2005-2007Crossref Google Scholar, 5Margalit R. Shaklai N. Cohen S. Fluorimetric studies on the dimerization equilibrium of protoporphyrin ix and its haemato derivative.Biochem. J. 1983; 209: 547-552Crossref PubMed Scopus (92) Google Scholar, 43Teng K.W. Lee S.H. Characterization of protoporphyrin ix species in vitro using fluorescence spectroscopy and polar plot analysis.J. Phys. Chem. B. 2019; 123: 5832-5840Crossref PubMed Scopus (4) Google Scholar) for assignments. UV–visible and fluorescence spectra were collected by diluting freshly prepared PP-IX stock solutions in the indicated buffers (Fig. 1, A and B). In 100 mM HCl, PP-IX exists as monomers, characterized by the sharp Soret band at 409 nm (Fig. 1A, Table 1). At pH 4.5, PP-IX monomers form H-aggregates (higher-order structures), characterized by a broad Soret band with shoulders at 356 and 466 nm. At pH 9 and in 100 mM NaOH, PP-IX exists exclusively as dimers, as judged from the characteristic Soret peak at 380 nm. Notably, the absorbance spectrum at pH 7.4 shows features of both pH 4.5 and 9, displaying a broad Soret band with slightly red-shifted shoulders (379 and 469 nm) compared with the pH 4.5 spectrum (Fig. 1A, Table 1). This suggests that at pH 7.4, PP-IX consists of a mixture of higher-order aggregates and dimers. In addition to the changes in the Soret band, changes in the Q-bands in the 500–700 nm region were observed. In 100 mM HCl, where the four pyrrole nitrogens are expected to be protonated, two Q-bands are observed (Table 1). The number of Q bands increases to 3 (pH 4.5, 7.4) and 4 (pH 9) as the extent of protonation decreases (Table 1).Table 1Summary of UV-vis and fluorescence spectral features of different PP-IX nanostructuresAbsorbance peaks (nm)Fluorescence peaks (nm)PP-IX speciationSoretQ4Q3Q2Q1[NaOH], 100 mM381516554579633630, 687DimerpH 9384517555587640641, 685pH 7.4379–469-542595648631, 670Dimer, higher-order structurespH 4.5356, 466-539597647662, 720Higher-order structures[HCl], 100 mM409-556597-610, 665MonomerpH 9+Emp408507541581632638, 702pH 7.4+Emp408508541580633638, 702pH 4.5+Emp408505543579635639, 703BSA+PP-IX, pH 4.5355, 469-539597649638, 684BSA+PP-IX higher-order structuresBSA+PP-IX, pH 7.4391516553585629642, 683BSA+PP-IX dimerBSA+PP-IX, pH 9391509553576627642, 682BSA+PP-IX dimerBSA+PP-IX, Emp406504539585629636, 700MonomerThe table shows the absorbance and fluorescence peaks from the plots shown in Figure 1, A, B, and E, and Figure 4, A–D. Open table in a new tab The table shows the absorbance and fluorescence peaks from the plots shown in Figure 1, A, B, and E, and Figure 4, A–D. Fluorescence emission spectra of the different PP-IX species (Fig. 1B) revealed that significant fluorescence quenching is associated with higher-order aggregates of PP-IX. Thus, at pH 4.5, PP-IX displays a minimal fluorescence signal compared with pH 7.4 and 9 (Fig. 1B). We also observed that pH-induced PP-IX speciation is reversible (Fig. 1, C and D). Thus, the higher-order PP-IX stru ctures observed at pH 4.5 converted to a mixture of higher-order structures and dimers (pH 7.4) and then dimers (pH 9) as the pH is increased, albeit conversion is incomplete (Fig. 1C, see shoulder indicated by arrow). The transition in the reverse direction (dimers → higher-order structures) was observed when the pH 9 PP-IX solution at was progressively acidified to pH 7.4, then 4.5 (Fig. 1D). Earlier we had reported that PP-IX induces protein aggregation in buffers containing detergents (e.g., Empigen BB, NP-40) (36Saggi H. Maitra D. Jiang A. Zhang R. Wang P. Cornuet P. Singh S. Locker J. Ma X. Dailey H. Abrams M. Omary M.B. Monga S.P. Nejak-Bowen K. Loss of hepatocyte beta-catenin protects mice from experimental porphyria-associated liver injury.J. Hepatol. 2019; 70: 108-117Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 37Elenbaas J.S. Maitra D. Liu Y. Lentz S.I. Nelson B. Hoenerhoff M.J. Shavit J.A. Omary M.B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.FASEB J. 2016; 30: 1798-1810Crossref PubMed Scopus (12) Google Scholar, 39Maitra D. Elenbaas J.S. Whitesall S.E. Basrur V. D'Alecy L.G. Omary M.B. Ambient light promotes selective subcellular proteotoxicity after endogenous and exogenous porphyrinogenic stress.J. Biol. Chem. 2015; 290: 23711-23724Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 42Maitra D. Carter E.L. Richardson R. Rittie L. Basrur V. Zhang H. Nesvizhskii A.I. Osawa Y. Wolf M.W. Ragsdale S.W. Lehnert N. Herrmann H. Omary M.B. Oxygen and conformation dependent protein oxidation and aggregation by porphyrins in hepatocytes and light-exposed cells.Cell Mol. Gastroenterol. Hepatol. 2019; 8: 659-682.e651Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Given the profound effect of pH on PP-IX speciation, we tested w" @default.
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• W3165785156 date "2021-07-01" @default.
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• W3165785156 title "Protein-aggregating ability of different protoporphyrin-IX nanostructures is dependent on their oxidation and protein-binding capacity" @default.
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