Abstract
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.
Highlights
A deficiency in human Fumarylacetoacetate hydrolase (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
Tyrosinemia type I (HT1) is a rare autosomal recessive genetic disease caused by a deficiency in fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2), the last enzyme in the tyrosine catabolism pathway [1]
Pharmacological chaperones usually target the binding site of the enzyme acting as reversible inhibitors, but this is not always the case and we recently demonstrated that the off-patent synthetic antimicrobial ciclopirox acts as an allosteric pharmacological chaperone, targeting variants of the enzyme uroporphyrinogen III synthase with impaired homeostasis [14]
Summary
Tyrosinemia type I (HT1) is a rare autosomal recessive genetic disease caused by a deficiency in fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2), the last enzyme in the tyrosine catabolism pathway [1]. Impaired protein homeostasis is exacerbated in many of the missense mutations, providing a molecular mechanism for HT1 disease In this context, an attractive alternative way to regulate tyrosine catabolism is by means of pharmacological chaperones, which are chemical substrates or modulators that usually bind to the partially folded intermediate, stabilize the protein, and allow it to complete the folding process to yield a functional protein [12]. An attractive alternative way to regulate tyrosine catabolism is by means of pharmacological chaperones, which are chemical substrates or modulators that usually bind to the partially folded intermediate, stabilize the protein, and allow it to complete the folding process to yield a functional protein [12] These chemical entities have successfully reduced clinical symptoms of disease by slowing down or inhibiting the tendency of different proteins to aggregate, resulting in detectable enzyme levels in the cell (see Table 1 in the review by Loo [13]). These molecules do not just act as in vitro inhibitors, but they are capable of partially restoring the nonpathogenic phenotype in a newly developed cellular model of HT1
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