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User:James Bahng/sandbox 1
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1HYO is an [http://www.ebi.ac.uk/intenz/query?cmd=SearchEC&ec=3.7.1 EC 3.7.1.2] hydrolase involved in the final step of the Phe/Tyr catabolic pathway, and <scene name='58/581360/Ligand_bound/1'>binds to Fumarylacetoacetate</scene> producing [[http://ec.asm.org/content/6/3/514/F1.large.jpg Fumarate and Acetoacetate]]. | 1HYO is an [http://www.ebi.ac.uk/intenz/query?cmd=SearchEC&ec=3.7.1 EC 3.7.1.2] hydrolase involved in the final step of the Phe/Tyr catabolic pathway, and <scene name='58/581360/Ligand_bound/1'>binds to Fumarylacetoacetate</scene> producing [[http://ec.asm.org/content/6/3/514/F1.large.jpg 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<ref name= | + | 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=”main paper”> 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 | Phosphorus-based Inhibitor. Journal of Biological Chemistry, 207(18) 15284-15291 | ||
</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. | </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. | ||
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== Disease and Treatment == | == 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=" | + | 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="disease"> 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. | In very serious acute cases, double liver/kidney transplant may be considered as an option as well. | ||
Revision as of 06:32, 1 April 2014
Structure of Fumarylacetoacetate Hydrolase with Phosphorus-based Inhibitor
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