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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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