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Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I
Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and f...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916972/ https://www.ncbi.nlm.nih.gov/pubmed/33670179 http://dx.doi.org/10.3390/ijms22041789 |
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author | Gil-Martínez, Jon Macias, Iratxe Unione, Luca Bernardo-Seisdedos, Ganeko Lopitz-Otsoa, Fernando Fernandez-Ramos, David Lain, Ana Sanz-Parra, Arantza Mato, José M Millet, Oscar |
author_facet | Gil-Martínez, Jon Macias, Iratxe Unione, Luca Bernardo-Seisdedos, Ganeko Lopitz-Otsoa, Fernando Fernandez-Ramos, David Lain, Ana Sanz-Parra, Arantza Mato, José M Millet, Oscar |
author_sort | Gil-Martínez, Jon |
collection | PubMed |
description | Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1. |
format | Online Article Text |
id | pubmed-7916972 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79169722021-03-01 Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I Gil-Martínez, Jon Macias, Iratxe Unione, Luca Bernardo-Seisdedos, Ganeko Lopitz-Otsoa, Fernando Fernandez-Ramos, David Lain, Ana Sanz-Parra, Arantza Mato, José M Millet, Oscar Int J Mol Sci Article Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1. MDPI 2021-02-11 /pmc/articles/PMC7916972/ /pubmed/33670179 http://dx.doi.org/10.3390/ijms22041789 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gil-Martínez, Jon Macias, Iratxe Unione, Luca Bernardo-Seisdedos, Ganeko Lopitz-Otsoa, Fernando Fernandez-Ramos, David Lain, Ana Sanz-Parra, Arantza Mato, José M Millet, Oscar Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title | Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title_full | Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title_fullStr | Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title_full_unstemmed | Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title_short | Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I |
title_sort | therapeutic targeting of fumaryl acetoacetate hydrolase in hereditary tyrosinemia type i |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916972/ https://www.ncbi.nlm.nih.gov/pubmed/33670179 http://dx.doi.org/10.3390/ijms22041789 |
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