1HYO is an EC 3.7.1.2 hydrolase involved in the final step of the Phe/Tyr catabolic pathway, and producing [Fumarate and Acetoacetate].
The mechanism is not well understood, but is hypothesized that His-133 activates a nucleophilic water, which attacks the δ carbon, leading to cleavage. The resultant tetrahedral alkoxy transition state is thought to be stabazlied by Arg-237, Gln-240, and Lys-253 residues.
Disease and Treatment
Mutations in 1HYO are responsible for hereditary tyrosemia Type I, a serious metabolic disease resulting in chronic inflammation of the liver and neuronal damage. It is in the same metabolic pathway as Phenylketonuria (PKU) in infants, and is treated similarly with strict dietary control and pharmacological inhibition of Phenylalanine hydroxylase, the key first enzyme in the degradation pathway.
In very serious acute cases, double liver/kidney transplant may be considered as an option as well.
Relevance
Structural highlights
FAH is a homodimer made up of two 46 kDa subunits.[1] The subunits form a cavity . The binding is coordinated by Ca2+, Arg and two Tyr(INSERT IMAGE LINK). The active residues in are His-133, acting as a base to activate a water, and Arg-237, Gln-240 and Lys-253 (INSERT IMAGE LINK)acting to stabilize the tetrahedral alkoxy transition state.
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