Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury
| Autor: | Juliana Bragazzi Cunha, Jordan A. Shavit, Herbert L. Bonkovsky, Dhiman Maitra, Jared S. Elenbaas, M. Bishr Omary |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 8, Iss 4, Pp 535-548 (2019) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2019.06.006 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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