Fumarylacetoacetate

Fumarylacetoacetate is a metabolic intermediate in the catabolism of the amino acid tyrosine. It is formed from maleylacetoacetate by the enzyme maleylacetoacetate isomerase and is subsequently hydrolyzed by fumarylacetoacetate hydrolase to yield fumarate and acetoacetate, which feed into the citric acid cycle and ketone body metabolism, respectively.

In humans, tyrosine degradation largely occurs in the liver. The conversion sequence proceeds from p-hydroxyphenylpyruvate to homogentisate, then to maleylacetoacetate, fumarylacetoacetate, and finally to fumarate and acetoacetate. Fumarylacetoacetate is a relatively reactive dicarbonyl intermediate, and its proper turnover is essential to prevent accumulation of toxic metabolites.

Clinical relevance centers on deficiency of fumarylacetoacetate hydrolase (FAH), which causes tyrosinemia type I. FAH deficiency leads to the accumulation of fumarylacetoacetate and other upstream intermediates, resulting in progressive liver and kidney dysfunction, coagulopathy, and life-threatening complications if untreated. Treatment approaches include inhibition of upstream tyrosine degradation with nitisinone (NTBC) to reduce formation of toxic intermediates, along with dietary restriction of tyrosine and phenylalanine. Newborn screening for tyrosinemia type I often detects elevated levels of succinylacetone, a biomarker associated with FAH deficiency and fumarylacetoacetate accumulation.

Fumarylacetoacetate serves primarily as a biochemical intermediate rather than a stored substance, with its proper metabolism essential for normal amino acid catabolism and energy production.