Molecular basis of congenital erythropoietic porphyria

CIC nanoGUNE Seminars

Oscar Millet, Structural Biology Unit, bioGUNE, Derio, Spain.
nanoGUNE seminar room, Tolosa Hiribidea 76, Donostia - San Sebastian
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Molecular basis of congenital erythropoietic porphyria Congenital erythropoietic porphyria (CEP) is a chronic and severe pathology classified as rare disease. CEP is directly related to a loss in the catalytic activity of the human uroporphyrinogen III synthase enzyme, the third enzyme in the heme group biosynthesys, often as a result of a mutation. A single mutation (C73R) in the enzyme is responsible for more than one third of all the reported CEP cases and patients carrying this hotspot mutation develop a severe phenotype of the disease, including reduced life expectancy. Here, we have investigated deleterious mutants that are related to CEP. All mutants retain measurable activity, consistent with the recessive character of the disease. The integrated analysis of the enzymatic activity and kinetic stability data has been used to gain insight in the relationship between defects in UROIIIS sequence and CEP. UROIIIS is a thermo labile enzyme undergoing irreversible denaturation, a process accelerated upon mutation. Nevertheless, mutant protein levels can be restored upon cell treatment with the proteasome inhibitor MG132. The intracellularly-recovered C73R-UROIIIS protein shows enzymatic activity. All together, our results pave the way for the development of pharmacological chaperones against this devastating disease. The latest results in this direction will also be discussed. **Host** : D. De Sancho