InterPro domain: IPR036663

Fumarylacetoacetase ( 3.7.1.2 ; also known as fumarylacetoacetate hydrolase or FAH) catalyses the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step in phenylalanine and tyrosine degradation [ 1 ]. This is an essential metabolic function in humans, the lack of FAH causing type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders [ 2 , 3 ]. The enzyme mechanism involves a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole [ 4 ]. FAH folds into two domains: an N-terminal domain SH3-like beta-barrel, and a C-terminal with an unusual fold consisting of three layers of beta-sheet structures [ 5 ].

This superfamily represents the C-terminal domain of fumarylacetoacetase, as well as other domains that share a homologous alpha/beta structure, including:

• 5-carboxymethyl-2-hydroxymuconate delta-isomerase (CHM isomerase; 5.3.3.10 ), which catalyses the conversion of 5-carboxymethyl-2-hydroxymuconate to 5-carboxy-2-oxohept-3-enedioate [ 5 ].
• 5-oxopent-3-ene-1,2,5-tricarboxylate decarboxylase (OPET decarboxylase; 4.1.1.68 ), which catalyses the conversion of 5-oxopent-3-ene-1,2,5-tricarboxylate to 2-oxohept-3-enedioate and carbon dioxide.
• Bifunctional enzyme HpcE (OPET decarboxylase 4.1.1.68 /HHDD isomerase 5.3.3.10 ), which is a duplication consisting of a tandem repeat of two FAH C-terminal-like domains. This enzyme is responsible for the degradation of 4-hydroxyphenylacetate, a product of tyrosine and phenylalanine metabolism also released by lignin catabolism [ 6 ].
• 2-keto-4-pentenoate hydratase MhpD ( 4.2.1.80 ; also known as 2-oxopent-4-enoate hydratase), which converts 4-hydroxy-2-oxopentanoate to 2-oxopent-4-enoate [ 7 ].
• 4-oxalocrotonate decarboxylase (4-OD; 4.1.1.77 ), which catalyses the conversion of 4-oxalocrotonate to 2-oxopent-4-enoate and carbon dioxide [ 8 ].
• 2-oxo-hepta-3-ene-1,7-dioic acid hydratase, which hydrates the double bond of 2-oxo-hepta-3-ene-1,7-dioic acid to form 4-hydroxy-2-oxo-heptane-1,7-dioic acid in the catabolism of 4-hydroxyphenylacetic acid.

1. Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor. J. Biol. Chem. 276, 15284-91
2. Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. Hum. Mutat. 9, 291-9
3. The genetic tyrosinemias. FEBS Lett. 142C, 121-6
4. Crystal structure and mechanism of a carbon-carbon bond hydrolase. Structure 7, 1023-33
5. Purification, some properties and nucleotide sequence of 5-carboxymethyl-2-hydroxymuconate isomerase of Escherichia coli C. Microbiology (Reading, Engl.) 266, 63-6
6. The crystal structure of HpcE, a bifunctional decarboxylase/isomerase with a multifunctional fold. Biochemistry 41, 2982-9
7. Genetic organization and characteristics of the 3-(3-hydroxyphenyl)propionic acid degradation pathway of Comamonas testosteroni TA441. Biochemistry 145 ( Pt 10), 2813-20
8. Expression and stereochemical and isotope effect studies of active 4-oxalocrotonate decarboxylase. null 39, 718-26