Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury
| العنوان: | Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury |
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| المؤلفون: | Juliana Bragazzi Cunha, Jordan A. Shavit, Herbert L. Bonkovsky, Dhiman Maitra, Jared S. Elenbaas, M. Bishr Omary |
| المصدر: | Cellular and Molecular Gastroenterology and Hepatology, Vol 8, Iss 4, Pp 535-548 (2019) Cellular and Molecular Gastroenterology and Hepatology |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, ADP, ALA-dehydratase porphyria, BCRP, breast cancer resistance protein, PCT, porphyria cutanea tarda, Protoporphyrins, Review, Protein aggregation, Protein oxidation, Mice, chemistry.chemical_compound, UPR, unfolded protein response, 0302 clinical medicine, polycyclic compounds, Cyp3A1, cytochrome P450 3A1, heterocyclic compounds, Ub, ubiquitin, Heme, Zebrafish, DFO, deferoxamine, IF, intermediate filament, Liver Neoplasms, Gastroenterology, ALAS, aminolevulinic acid synthase, DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, 3. Good health, CLPX, adenosine triphosphate-dependent Clp protease adenosine triphosphate-binding subunit clpX-like, ABCG2, adenosine triphosphate-binding cassette sub-family G member 2, Liver, RP, regulatory particle, CPOX, coproporphyrinogen oxidase, ALA, δ-aminolevulinic acid, 030211 gastroenterology & hepatology, 1O2, singlet oxygen, Oxidation-Reduction, Copro, coproporphyrin, Dermatitis, Phototoxic, FLVCR1, feline leukemia virus subgroup C receptor-related protein 1, PP-IX, protoporphyrin-IX, Carcinoma, Hepatocellular, Porphyrins, AIP, acute intermittent porphyria, EPP, erythropoietic protoporphyria, Uro, uroporphyrin, Phototoxicity, ER, endoplasmic reticulum, Porphyrias, Protein Aggregates, HCP, hereditary coproporphyria, 03 medical and health sciences, FECH, ferrochelatase, GOX, glucose oxidase, ROS, reactive oxygen species, medicine, Animals, Humans, Photosensitivity Disorders, Uroporphyrins, lcsh:RC799-869, NMP, N-methyl protoporphyrin-IX, XLP, X-linked protoporphyria, Porphyria, Hepatology, Endoplasmic reticulum, CP, core particle, medicine.disease, Protein Aggregation, Porphyrin, CEP, congenital erythropoietic porphyria, Oxidative Stress, 030104 developmental biology, Proteostasis, chemistry, Proteotoxicity, UROD, uroporphyrinogen decarboxylase, ABCB6, adenosine triphosphate-binding cassette sub-family B member 6 G2, Biophysics, lcsh:Diseases of the digestive system. Gastroenterology |
| الوصف: | 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. Keywords: Porphyria, Oxidative Stress, Protein Aggregation, Phototoxicity |
| تدمد: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2019.06.006 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b0af3ebb574e4ee6cf3f3b54e0ba117c https://doi.org/10.1016/j.jcmgh.2019.06.006 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b0af3ebb574e4ee6cf3f3b54e0ba117c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2352345X |
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| DOI: | 10.1016/j.jcmgh.2019.06.006 |