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[1]. The resultant tetrahedral alkoxy transition state is thought to be stabilized by Arg-237, Gln-240, and Lys-253 residues. As with all of the EC 3.7.1 class enzymes, the key to the C-C cleavage is the metal ion that lines up with the carbon to be cleaved.
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[2]. It is in the same metabolic pathway as Phenylketonuria (PKU) in infants, and is treated similarly with strict lifelong 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. The subunits form a cavity [3]. The binding is coordinated by Ca2+, Arg and two Tyr. The active residues in are His-133, acting as a base to activate a water, and Arg-237, Gln-240 and Lys-253 acting to stabilize the tetrahedral alkoxy transition state.
References
- ↑ Bateman, R.L., Bhanumoorthy, P., Witte, J.F., McClard, R.W., Grompe, M., Timm, D.E. (2001) Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound
Phosphorus-based Inhibitor. Journal of Biological Chemistry, 207(18) 15284-15291
- ↑ Grompe, M. (2001)The Pathophysiology and Treatment of Hereditary Tyrosinemia Type 1. Liver Diease, 21(4):563-572 DOI:10.1055/s-2001-19035
- ↑ Bateman, R.L., Bhanumoorthy, P., Witte, J.F., McClard, R.W., Grompe, M., Timm, D.E. (2001) Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound
Phosphorus-based Inhibitor. Journal of Biological Chemistry, 207(18) 15284-15291
