ArticleThe Journal of biological chemistry2011
Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Severe Perinatal Presentations of Günther's Disease: Series of 20 Cases and Perspectives.Life (Basel, Switzerland) · 2024Article
- Metabolic Landscape of the Mouse Liver by QuantitativeHepatology (Baltimore, Md.) · 2021Article
- Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I.International journal of molecular sciences · 2021Article
- Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.The Journal of biological chemistry · 2019Article
- Neonatal hemolytic anemia does not always indicate thalassemia: a case report.BMC research notes · 2017Article
- Article
- Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Review
- Congenital Erythropoietic Porphyria with Undescended Testis.Indian journal of dermatologyArticle
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A single mutation (C73R) in the enzyme uroporphyrinogen III synthase (UROIIIS) is responsible for more than one-third of all of the reported cases of the rare autosomal disease congenital erythropoietic porphyria (CEP). CEP patients carrying this hotspot mutation develop a severe phenotype of the disease, including reduced life expectancy. Here, we have investigated the molecular basis for the functional deficit in the mutant enzyme both in vitro and in cellular systems. We show that a Cys in position 73 is not essential for the catalytic activity of the enzyme but its mutation to Arg speeds up the process of irreversible unfolding and aggregation. In the mammalian cell milieu, the mutant protein levels decrease to below the detection limit, whereas wild type UROIIIS can be detected easily. The disparate response is not produced by differences at the level of transcription, and the results with cultured cells and in vitro are consistent with a model where the protein becomes very unstable upon mutation and triggers a degradation mechanism via the proteasome. Mutant protein levels can be restored upon cell treatment with the proteasome inhibitor MG132. The intracellularly recovered C73R-UROIIIS protein shows enzymatic activity, paving the way for a new line of therapeutic intervention in CEP patients.
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