Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.

ABSTRACT: More than 100 mutations in the gene encoding fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1), a metabolic disorder characterized by elevated blood levels of tyrosine. Some of these mutations are known to decrease FAH catalytic activity, but the mechanisms of FAH mutation-induced pathogenicity remain poorly understood. Here, using diffusion ordered NMR spectroscopy, cryo-EM, and CD analyses, along with site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations, we investigated the putative role of thermodynamic and kinetic stability in WT FAH and a representative set of 19 missense mutations identified in individuals with HT1. We found that at physiological temperatures and concentrations, WT FAH is in equilibrium between a catalytically ac

SUBMITTER: Macias I 

PROVIDER: S-EPMC6721957 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature