User:James Bahng/sandbox 1

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== Structure of Fumarylacetoacetate Hydrolase with Phosphorus-based Inhibitor ==
== Structure of Fumarylacetoacetate Hydrolase with Phosphorus-based Inhibitor ==
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<StructureSection load='1hyo' size='340' side='right' caption='Caption for this structure' scene=''>
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<StructureSection load='1hyo' size='340' side='right' caption='Fumarylacetoacetate Hydrolase' scene=''>
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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 <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]].
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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]].
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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. The resultant tetrahedral alkoxy transition state are stabilized by
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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=”1hyo”> 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
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Phosphorus-based Inhibitor. Journal of Biological Chemistry, 207(18) 15284-15291
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</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 ==
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== Disease and Treatment ==
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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.
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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.
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== Relevance ==
== Relevance ==
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== Structural highlights ==
== Structural highlights ==
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FAH is a homodimer made up of two 46 kDa subunits. The subunits form a cavity complementary in shape and charge to fumarylacetoacetate. 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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FAH is a homodimer made up of two 46 kDa subunits. The subunits form a cavity <scene name='58/581360/Close_up_showing_metal_ions/2'>complementary in shape and charge to fumarylacetoacetate</scene><ref name=”1hyo”> 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
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Phosphorus-based Inhibitor. Journal of Biological Chemistry, 207(18) 15284-15291
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</ref>. 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.
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
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</StructureSection>
 
== References ==
== References ==
<references/>
<references/>

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Structure of Fumarylacetoacetate Hydrolase with Phosphorus-based Inhibitor

Fumarylacetoacetate Hydrolase

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James Bahng

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