Disease relevance of C01036

• Hepatocyte injury in tyrosinemia type 1 is induced by fumarylacetoacetate and is inhibited by caspase inhibitors [1].

High impact information on C01036

• Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1 [1].
• In a cell-free system, the addition of fumarylacetoacetate induced the release of cytochrome c from the mitochondria [1].
• Transient expression of this FAH cDNA in transfected CV-1 mammalian cells resulted in the synthesis of an immunoreactive protein comigrating with purified human liver FAH on SDS-PAGE and having enzymatic activity as shown by the hydrolysis of the natural substrate fumarylacetoacetate [2].
• Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability [3].
• M. Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis [4].

Biological context of C01036

• Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate-induced apoptosis [4].
• GSTZ1-1 catalyzes the cis-trans isomerization of maleylacetoacetate to fumarylacetoacetate and the biotransformation of a range of alpha-haloalkanoic acids [5].
• Our results suggest that the availability of thiol groups may modify the phenotype of tyrosinaemia type 1 and that liver 4-fumarylacetoacetate hydrolase deficiency may be a secondary complicating factor in some forms of glutathione synthetase deficiency [6].
• Characterization and substrate specificity of fumarylacetoacetate fumarylhydrolase [7].

Anatomical context of C01036

• Herein, we demonstrate that FAA also causes a cellular insult leading to the endoplasmic reticulum (ER) stress signaling [8].
• Deficient fumarylacetoacetate fumarylhydrolase activity in lymphocytes and fibroblasts from patients with hereditary tyrosinemia [9].

Associations of C01036 with other chemical compounds

• The cis-trans isomerisation of maleylacetoacetate to fumarylacetoacetate is the penultimate step in the tyrosine/phenylalanine catabolic pathway and has recently been shown to be catalysed by glutathione S-transferase enzymes belonging to the zeta class [10].
• Glutathione transferase zeta (GSTZ1-1) catalyzes the cis-trans isomerization of maleylacetoacetate or maleylacetone (MA) to fumarylacetoacetate or fumarylacetone (FA), respectively [11].
• BACKGROUND: Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of tyrosine and phenylalanine catabolism, the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate, to yield fumarate and acetoacetate [12].
• Fumarylacetoacetate hydrolase cleaves fumarylacetoacetate to fumarate and acetoacetate using a water molecule, activated by a catalytic His/Asp dyad, aided by a calcium ion that both chelates the enol acid form of the substrate and indirectly positions the water for nucleophilic attack at a carbonyl group [13].

Gene context of C01036

• FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12 [8].
• Tyrosinaemia type 1 and glutathione synthetase deficiency: two disorders with reduced hepatic thiol group concentrations and a liver 4-fumarylacetoacetate hydrolase deficiency [6].

Analytical, diagnostic and therapeutic context of C01036

• The molecular weight of fumarylacetoacetate fumarylhydrolase (EC 3.7.1.2) is 86 000 +/- 10 000, as determined by gel filtration [7].

References