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Bishr M Omary - One of the best experts on this subject based on the ideXlab platform.
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protein aggregating ability of different protoporphyrin ix nanostructures is dependent on their oxidation and protein binding capacity
Journal of Biological Chemistry, 2021Co-Authors: Dhiman Maitra, Bishr M Omary, Benjamin M Pinsky, Haiyan Zheng, Ruma Banerjee, Amenah SoherawardyAbstract: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.
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porphyrin induced protein oxidation and aggregation as a mechanism of porphyria associated cell injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Dhiman Maitra, Herbert L. Bonkovsky, Juliana Bragazzi Cunha, Jared S Elenbaas, Jordan A Shavit, Bishr M OmaryAbstract:Abstract Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent Porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of Porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent Porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with Porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
Herbert L. Bonkovsky - One of the best experts on this subject based on the ideXlab platform.
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porphyrin induced protein oxidation and aggregation as a mechanism of porphyria associated cell injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Dhiman Maitra, Herbert L. Bonkovsky, Juliana Bragazzi Cunha, Jared S Elenbaas, Jordan A Shavit, Bishr M OmaryAbstract:Abstract Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent Porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of Porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent Porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with Porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
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porphyrin and heme metabolism and the porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Ting Li, Manish ThaparAbstract:Porphyrins and metalloPorphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, Porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited Porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365-401, 2013.
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porphyrin and heme metabolism and the porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Weihong Hou, Juntao Guo, Manish ThaparAbstract:Porphyrins and metalloPorphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, Porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited Porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse.
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disorders of porphyrin metabolism
1998Co-Authors: Martin Hahn, Herbert L. BonkovskyAbstract:The porphyrias are metabolic disorders, primarily inherited, in which the principal features are disturbances of normal heme and porphyrin metabolism. Deficiency in the activity of one of the enzymes of heme biosynthesis characterizes the various forms of porphyria. Many patients remain asymptomatic carriers of the (genetic) defect, lacking both clinical features and overproduction of heme precursors. Others have so-called latent disease with no clinical symptoms of porphyria, but have elevated Porphyrins and/or precursors of heme in the urine or feces. To develop manifest disease, other factors, in addition to the deficient enzyme, are necessary (1). Carriers can be detected only by measuring enzyme activities (e.g., in RBCs, fibroblasts, or lymphocytes); whereas those with chemically active, but clinically latent, disease can be detected also by measurement of Porphyrins and/or porphyrin precursors in blood, feces, or urine.
Dhiman Maitra - One of the best experts on this subject based on the ideXlab platform.
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protein aggregating ability of different protoporphyrin ix nanostructures is dependent on their oxidation and protein binding capacity
Journal of Biological Chemistry, 2021Co-Authors: Dhiman Maitra, Bishr M Omary, Benjamin M Pinsky, Haiyan Zheng, Ruma Banerjee, Amenah SoherawardyAbstract: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.
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protoporphyrin ix nanostructures modulate their protein aggregation ability via differential oxidation and protein binding
bioRxiv, 2021Co-Authors: Dhiman Maitra, Benjamin M Pinsky, Amenah Soherwardy, Haiyan Zheng, Ruma Banerjee, Bishr OmaryAbstract:Porphyrias are caused by genetic defects in the heme biosynthetic pathway and are associated with 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 effect of porphyrin speciation on the cytotoxic effects of Porphyrins. Previously we demonstrated the unique ability of fluorescent biological Porphyrins, including protoporphyrin IX (PP-IX), to cause organelle selective protein aggregation, which we posit to be a major mechanism by which 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. We demonstrate that PP-IX nanostructure formation is reversible in nature, and that nanostructure size modulates consequent protein oxidation and aggregation potential. We also show that albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. Additionally, extracellular albumin protects from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX speciation in the context of the porphyrias, and offers insights into potential novel therapeutic approaches.
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porphyrin induced protein oxidation and aggregation as a mechanism of porphyria associated cell injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Dhiman Maitra, Herbert L. Bonkovsky, Juliana Bragazzi Cunha, Jared S Elenbaas, Jordan A Shavit, Bishr M OmaryAbstract:Abstract Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent Porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of Porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent Porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with Porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
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loss of hepatocyte β catenin protects mice from experimental porphyria associated liver injury
Journal of Hepatology, 2019Co-Authors: Harvinder Saggi, Dhiman Maitra, An Jiang, Rong Zhang, Pengcheng Wang, Pamela K Cornuet, Sucha Singh, Joseph Locker, Harry A Dailey, Marc AbramsAbstract:Background & Aims Porphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury. Methods β-Catenin (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a DDC diet for 2 weeks. β-Catenin was exogenously inhibited in hepatocytes by administering β-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were collected; livers were analyzed by histology, western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography-mass spectrometry. Results DDC-fed mice lacking β-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous mice that underwent β-catenin suppression by DsiRNA during DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking β-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of β-catenin, preventing accumulation of toxic protoPorphyrins. Additionally, mice lacking β-catenin exhibited fewer protein aggregates, improved proteasomal activity, and reduced induction of autophagy, all contributing to protection from injury. Conclusions β-Catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for patients with porphyria. Lay summary Porphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause build-up of toxic by-products called Porphyrins. Liver is commonly either a source or a target of excess Porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/β-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting β-catenin affected multiple components of the heme biosynthesis pathway, thus preventing build-up of porphyrin intermediates. Our study suggests that drugs inhibiting β-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.
Jonathan S Lindsey - One of the best experts on this subject based on the ideXlab platform.
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synthesis of thiol derivatized ferrocene Porphyrins for studies of multibit information storage
Journal of Organic Chemistry, 2000Co-Authors: Daniel T Gryko, Kristian M Roth, David F Bocian, Werner G Kuhr, Feng Zhao, Amir A Yasseri, Jonathan S LindseyAbstract:One approach toward storage of multiple bits of information at the molecular level requires the construction of molecular architectures comprised of multiple redox-active units. Four new ferrocene−Porphyrins have been synthesized to investigate questions concerning (1) the scope of redox-active molecules that can be employed in molecular information-storage schemes and (2) writing/reading rates as well as retention of charge in redox-active units located at different sites in a molecular architecture. Three of the ferrocene−Porphyrins have linkers of different lengths between the ferrocene and porphyrin. The fourth ferrocene−porphyrin has two ferrocenes positioned at the lateral sites on the porphyrin. The latter architecture is designed to provide a shorter distance between the electroactive surface and the ferrocene while maintaining an upright orientation of the porphyrin. Each ferrocene−porphyrin affords three cationic oxidation states (ferrocene monocation, porphyrin monocation, porphyrin dication) i...
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synthesis of porphyrin linker thiol molecules with diverse linkers for studies of molecular based information storage
Journal of Organic Chemistry, 2000Co-Authors: Daniel T Gryko, Christian Clausen, Kristian M Roth, Narasaiah Dontha, David F Bocian, Werner G Kuhr, Jonathan S LindseyAbstract:The attachment of redox-active molecules such as Porphyrins to an electroactive surface provides an attractive approach for electrically addressable molecular-based information storage. Porphyrins are readily attached to a gold surface via thiol linkers. The rate of electron transfer between the electroactive surface and the porphyrin is one of the key factors that dictates suitability for molecular-based memory storage. This rate depends on the type and length of the linker connecting the thiol unit to the porphyrin. We have developed different routes for the preparation of thiol-derivatized Porphyrins with eight different linkers. Two sets of linkers explore the effects of linker length and conjugation, with one set comprising phenylethyne units and one set comprising alkyl units. One electron-deficient linker has four fluorine atoms attached directly to a thiophenyl unit. To facilitate the synthesis of the Porphyrins, convenient routes have been developed to a wide range of aldehydes possessing a protected S-acetylthio group. An efficient synthesis of 1-(S-acetylthio)-4-iodobenzene also has been developed. A set of Porphyrins, each bearing one S-acetyl-derivatized linker at one meso position and mesityl moieties at the three remaining meso positions, has been synthesized. Altogether seven new aldehydes, eight free base Porphyrins and eight zinc Porphyrins have been prepared. The zinc Porphyrins bearing the different linkers all form self-assembled monolayers (SAMs) on gold via in situ cleavage of the S-acetyl protecting group. The SAM of each porphyrin is electrochemically robust and exhibits two reversible oxidation waves.
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synthesis and excited state photodynamics of a molecular square containing four mutually coplanar Porphyrins
Journal of Organic Chemistry, 1998Co-Authors: Richard W Wagner, David F Bocian, Jyoti Seth, Sung Ik Yang, Dongho Kim, Dewey Holten, Jonathan S LindseyAbstract:To examine the effect of restricted porphyrin−porphyrin rotation on energy transfer in diphenylethyne-linked porphyrin arrays, a square macrocyclic array of four Porphyrins has been prepared that locks the Porphyrins in a mutually coplanar architecture. The palladium-mediated coupling of Zn(II) 5,10-dimesityl-15,20-bis(4-ethynylphenyl)porphyrin and 5,10-dimesityl-15,20-bis(4-iodophenyl)porphyrin afforded the molecular square (cyclo-Zn2Fb2U) with zinc (Zn) and free base (Fb) Porphyrins on alternating corners. The yield of cyclo-Zn2Fb2U is relatively insensitive to concentration with reactants at 5−0.5 mM but declines significantly at ≤0.05 mM. Transient absorption data from cyclo-Zn2Fb2U in toluene at room temperature indicate that the rate of energy transfer from the photoexcited Zn porphyrin to a neighboring Fb porphyrin is (26 ps)-1. A ZnFb porphyrin (ZnFbU) with an identical diphenylethyne linker but no constraints on rotation exhibits an identical energy-transfer rate. Resonance Raman spectroscopy sho...
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investigation of the one flask synthesis of Porphyrins bearing meso linked straps of variable length rigidity and redox activity
Tetrahedron, 1997Co-Authors: Richard W Wagner, Thomas E Johnson, Jonathan S LindseyAbstract:Abstract The reactions of 18 dialdehydes have been examined in the two-step one-flask room temperature porphyrin synthesis. Efficient alkylation methods were established for the reaction of diols and diacids with m -bromomethylbenzaldehyde. Dialdehydes linked at the o,o′-or m,m′-positions were converted to strapped Porphyrins in yields up to 25%, while the one p,p′-linked dialdehyde that was examined failed to give porphyrin. The resulting Porphyrins bear straps joining adjacent meso -positions rather than across the face of the porphyrin. Dialdehydes incorporating rigid groups provided improved yields in some but not all cases. The yield of strapped porphyrin exhibited a maximum at 10 −2 M reactant concentrations. The o,o′-strapped Porphyrins exist as atropisomers that are sufficiently stable to interconversion at room temperature to be separable chromatographically. No atropisomers of m,m′-strapped Porphyrins could be separated, though some could be observed by 1 H NMR spectroscopy. For two different m,m′-strapped Porphyrins, the ΔG ‡ values for interconversion of the atropisomers were found to be 66 and 68 kJ/mol. The outer rings in these strapped Porphyrins range in size from 14 to 24 atoms. Five Porphyrins with bridging redox-active groups (ferrocene or anthraquinone) have been prepared in one-flask reactions, including a porphyrin bearing one ferrocene and one anthraquinone in straps across adjacent meta-substituted phenyl sites.
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effects of central metal ion mg zn and solvent on singlet excited state energy flow in porphyrin based nanostructures
Journal of Materials Chemistry, 1997Co-Authors: Steve Gentemann, Jonathan S Lindsey, Jyoti Seth, Dewey Holten, William A Kalsbeck, David F BocianAbstract:Zinc Porphyrins have been widely used as surrogates for chlorophyll (which contains magnesium) in photosynthetic model systems and molecular photonic devices. In order to compare the photodynamic behaviour of Mg- and Zn-Porphyrins, dimeric and star-shaped pentameric arrays comprised of free-base (Fb) and Mg- or Zn-Porphyrins with intervening diarylethyne linkers have been prepared. A modular building block approach is used to couple ethynyl- or iodo-substituted Porphyrins in defined metallation states (Fb, Mg or Zn)via a Pd-catalysed reaction in 2–6 h. The resulting arrays are purified in 45–80% overall yields by combinations of size exclusion chromatography and adsorption chromatography (≥95% purity). High solubility of the arrays in organic solvents facilitates chemical and spectroscopic characterization. The star-shaped Mg 4 Fb- and Zn 4 Fb-pentamers, where the Fb-porphyrin is at the core of the array, have pairwise interactions similar to those of dimeric MgFb- and ZnFb-arrays. The arrays have been investigated by static and time-resolved absorption and fluorescence spectroscopy, as well as resonance Raman spectroscopy. The major findings include the following. (1) The rate of singlet excited-state energy transfer from the Mg-porphyrin to the Fb-porphyrin [(31 ps) -1 ] is comparable to that from the Zn-porphyrin to the Fb-porphyrin [(26 ps) -1 ] in the dimeric arrays. Qualitatively similar results are obtained for the star-shaped pentamers. The similar rates of energy transfer for the Mg- and Zn-containing arrays are attributed to the fact that the electronic coupling between the metalloporphyrin and Fb-porphyrin is approximately the same for Mg- vs. Zn-containing arrays. (2) The quantum yield of energy transfer is slightly higher in the Mg-arrays (99.7%) than in the Zn-arrays (99.0%) due to the longer inherent lifetime of Mg-Porphyrins (10 ns) compared with Zn-Porphyrins (2.5 ns). (3) The rate of energy transfer and the magnitude of the electronic coupling are essentially independent of the solvent polarity and the coordination geometry of the metalloporphyrin (four- or five-coordinate for Zn-Porphyrins, five- or six-coordinate for Mg-Porphyrins). (4) Polar solvents diminish the fluorescence yield and lifetime of the excited Fb-porphyrin in arrays containing either Mg- or Zn-Porphyrins. These effects are attributed to charge-transfer quenching of the Fb-porphyrin by the adjacent metalloporphyrin rather than to changes in electronic coupling. The magnitude of the diminution is greater for the Mg-containing arrays, which is due to the greater driving force for charge separation. (5) The Zn-containing arrays are quite robust while the Mg-containing arrays are slightly labile toward demetallation and photooxidation. Taken together, these results indicate that porphyrin-based nanostructures having high energy-transfer efficiencies can be constructed from either Mg- or Zn-Porphyrins. However, Mg-containing arrays may be superior in situations where a succession of energy-transfer steps occurs (due to a slightly higher yield per step) or where charge transfer is a desirable feature. On the other hand, Zn-Porphyrins are better suited when it is desirable to avoid charge transfer quenching reactions. Accordingly, the merits of constructing a device from Mg- vs. Zn-containing Porphyrins will be determined by the interplay of all of the above factors.
Manish Thapar - One of the best experts on this subject based on the ideXlab platform.
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porphyrin and heme metabolism and the porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Ting Li, Manish ThaparAbstract:Porphyrins and metalloPorphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, Porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited Porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365-401, 2013.
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porphyrin and heme metabolism and the porphyrias
Comprehensive Physiology, 2013Co-Authors: Herbert L. Bonkovsky, Tarun Narang, Weihong Hou, Juntao Guo, Manish ThaparAbstract:Porphyrins and metalloPorphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium-containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, Porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate-controlling step is the formation of delta-aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P-450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate-controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin-damaging effects of excess deposited Porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse.
