Fumarylacetoacetate hydrolase (FAH)

Fumarylacetoacetate hydrolase (FAH) is an essential enzyme encoded by the FAH gene, predominantly expressed in the liver and kidneys[1][3]. It catalyzes the final step in the catabolic pathway of the amino acids phenylalanine and tyrosine, hydrolyzing fumarylacetoacetate into fumarate and acetoacetate, which are then fed into energy production and biosynthetic pathways[1][2][3][6]. FAH deficiency results in accumulation of toxic intermediates, especially fumarylacetoacetate and succinylacetone, leading to hereditary tyrosinemia type I—a life-threatening disorder that primarily affects the liver and kidneys, often causing liver failure, renal dysfunction, neurological crises, and heightened risk for hepatocellular carcinoma[3][4][5]. Treatment often involves substrate reduction therapy using nitisinone to block an upstream enzyme, thereby preventing toxic buildup. Monitoring blood and urine levels of tyrosine and succinylacetone serves as a key biomarker for efficacy and safety of treatment.

Other names

FumarylacetoacetaseBeta-diketonaseFAAFAAA_HUMAN

Inhibition of tyrosine catabolic pathway (for nitisinone: inhibits 4-hydroxyphenylpyruvate dioxygenase upstream, thus limiting substrate for FAH and preventing toxic metabolite accumulation)[3]