Natural and Unnatural Compounds Rescue Folding Defects of Human Alanine: Glyoxylate Aminotransferase Leading to Primary Hyperoxaluria Type I

Author(s): Elisa Oppici, Riccardo Montioli, Mirco Dindo, Barbara Cellini

Journal Name: Current Drug Targets

Volume 17 , Issue 13 , 2016

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Graphical Abstract:


The functional deficit of alanine:glyoxylate aminotransferase (AGT) in human hepatocytes leads to a rare recessive disorder named primary hyperoxaluria type I (PH1). PH1 is characterized by the progressive accumulation and deposition of calcium oxalate stones in the kidneys and urinary tract, leading to a life-threatening and potentially fatal condition. In the last decades, substantial progress in the clarification of the molecular pathogenesis of the disease have been made. They resulted in the understanding that many mutations cause AGT deficiency by affecting the folding pathway of the protein leading to a reduced expression level, an increased aggregation propensity, and/or an aberrant mitochondrial localization. Thus, PH1 can be considered a misfolding disease and possibly treated by approaches aimed at counteracting the conformational defects of the variants. In this review, we summarize recent advances in the development of new strategies to identify molecules able to rescue AGT folding and trafficking either by acting as pharmacological chaperones or by preventing the mistargeting of the protein.

Keywords: Primary hyperoxaluria type I, alanine: glyoxylate aminotransferase, misfolding disease, pyridoxal 5’-phosphate, pathogenic variants, pharmacological chaperones.

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Article Details

Year: 2016
Published on: 01 September, 2016
Page: [1482 - 1491]
Pages: 10
DOI: 10.2174/1389450117666160302095254
Price: $65

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