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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bianconi, Silvia Roncador, Alessandro Cellini, Barbara Oppici, Elisa Montioli, Riccardo |
| Description | Author Affiliation: Oppici E ( Department of Life Sciences and Reproduction, Section of Biological Chemistry, University of Verona, Strada Le Grazie 8 37134 Verona, Italy.) |
| Abstract | Primary Hyperoxaluria Type I (PH1) is a severe rare disorder of metabolism due to inherited mutations on liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme whose deficiency causes the deposition of calcium oxalate crystals in the kidneys and urinary tract. PH1 is an extremely heterogeneous disease and there are more than 150 disease-causing mutations currently known, most of which are missense mutations. Moreover, the molecular mechanisms by which missense mutations lead to AGT deficiency span from structural, functional to subcellular localization defects. Gly161 is a highly conserved residue whose mutation to Arg, Cys or Ser is associated with PH1. Here we investigated the molecular bases of the AGT deficit caused by Gly161 mutations with expression studies in a mammalian cellular system paired with biochemical analyses on the purified recombinant proteins. Our results show that the mutations of Gly161 (i) strongly reduce the expression levels and the intracellular half-life of AGT, and (ii) make the protein in the apo-form prone to an electrostatically-driven aggregation in the cell cytosol. The coenzyme PLP, by shifting the equilibrium from the apo- to the holo-form, is able to reduce the aggregation propensity of the variants, thus partly decreasing the effect of the mutations. Altogether, these results shed light on the mechanistic details underlying the pathogenicity of Gly161 variants, thus expanding our knowledge of the enzymatic phenotypes leading to AGT deficiency. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 12 |
| Volume Number | 1832 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-12-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Cytosol Metabolism Hyperoxaluria, Primary Pathology Mutation Genetics Protein Multimerization Proteolysis Transaminases Animals Apoenzymes Blotting, Western CHO Cells Cells, Cultured Chromatography, Gel Cricetulus Half-Life Enzymology Immunoenzyme Techniques Mutagenesis, Site-Directed Protein Conformation Protein Folding RNA, Messenger Real-Time Polymerase Chain Reaction Recombinant Proteins Reverse Transcriptase Polymerase Chain Reaction Chemistry Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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