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 The mechanism is not well understood, but is hypothesized that His-133 activates a nucleophilic water, which attacks the δ carbon, leading to cleavage<ref name=”1”> 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
-</ref>. The resultant tetrahedral alkoxy transition state is thought to be stabazlied 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.
+</ref>. 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<ref name="2"> Grompe, M. (2001)The Pathophysiology and Treatment of Hereditary Tyrosinemia Type 1. Liver Diease, 21(4):563-572  DOI:10.1055/s-2001-19035</ref>.  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.
+Mutations in 1HYO are responsible for hereditary tyrosemia Type I, a serious metabolic disease resulting in chronic inflammation of the liver and neuronal damage<ref name="2"> Grompe, M. (2001)The Pathophysiology and Treatment of Hereditary Tyrosinemia Type 1. Liver Diease, 21(4):563-572  DOI:10.1055/s-2001-19035</ref>.  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 [[http://ec.asm.org/content/6/3/514/F1.large.jpg 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.

Revision as of 05:11, 1 April 2014

Structure of Fumarylacetoacetate Hydrolase with Phosphorus-based Inhibitor

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Fumarylacetoacetate Hydrolase

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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.

1 Disease and Treatment
2 Relevance
3 Structural highlights
4 References

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 damageCite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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 Cite error: Invalid <ref> tag; name cannot be a simple integer. Use a descriptive title. 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