1hyo
From Proteopedia
(New page: 200px<br /><applet load="1hyo" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hyo, resolution 1.3Å" /> '''CRYSTAL STRUCTURE OF ...) |
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| - | [[Image:1hyo.jpg|left|200px]]<br /><applet load="1hyo" size=" | + | [[Image:1hyo.jpg|left|200px]]<br /><applet load="1hyo" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1hyo, resolution 1.3Å" /> | caption="1hyo, resolution 1.3Å" /> | ||
'''CRYSTAL STRUCTURE OF FUMARYLACETOACETATE HYDROLASE COMPLEXED WITH 4-(HYDROXYMETHYLPHOSPHINOYL)-3-OXO-BUTANOIC ACID'''<br /> | '''CRYSTAL STRUCTURE OF FUMARYLACETOACETATE HYDROLASE COMPLEXED WITH 4-(HYDROXYMETHYLPHOSPHINOYL)-3-OXO-BUTANOIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Fumarylacetoacetate hydrolase (FAH) catalyzes the hydrolytic cleavage of a | + | Fumarylacetoacetate hydrolase (FAH) catalyzes the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step of Phe and Tyr degradation. This unusual reaction is an essential human metabolic function, with loss of FAH activity causing the fatal metabolic disease hereditary tyrosinemia type I (HT1). An enzymatic mechanism involving a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole was previously proposed based on recently determined FAH crystal structures. Here we report the development and characterization of an FAH inhibitor, 4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid (HMPOBA), that competes with the physiological substrate with a K(i) of 85 microM. The crystal structure of FAH complexed with HMPOBA refined at 1.3-A resolution reveals the molecular basis for the competitive inhibition, supports the proposed formation of a tetrahedral alkoxy transition state intermediate during the FAH catalyzed reaction, and reveals a Mg(2+) bound in the enzyme's active site. The analysis of FAH structures corresponding to different catalytic states reveals significant active site side-chain motions that may also be related to catalytic function. Thus, these results advance the understanding of an essential catabolic reaction associated with a fatal metabolic disease and provide insight into the structure-based development of FAH inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 1HYO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with MG, CA, NI, ACT and HBU as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Fumarylacetoacetase Fumarylacetoacetase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.7.1.2 3.7.1.2] Full crystallographic information is available from [http:// | + | 1HYO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=NI:'>NI</scene>, <scene name='pdbligand=ACT:'>ACT</scene> and <scene name='pdbligand=HBU:'>HBU</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Fumarylacetoacetase Fumarylacetoacetase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.7.1.2 3.7.1.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HYO OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bateman, R | + | [[Category: Bateman, R L.]] |
[[Category: Bhanumoorthy, P.]] | [[Category: Bhanumoorthy, P.]] | ||
[[Category: Grompe, M.]] | [[Category: Grompe, M.]] | ||
| - | [[Category: McClard, R | + | [[Category: McClard, R W.]] |
| - | [[Category: Timm, D | + | [[Category: Timm, D E.]] |
| - | [[Category: Witte, J | + | [[Category: Witte, J F.]] |
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: CA]] | [[Category: CA]] | ||
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[[Category: beta-sandwich roll]] | [[Category: beta-sandwich roll]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:06:10 2008'' |
Revision as of 11:06, 21 February 2008
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CRYSTAL STRUCTURE OF FUMARYLACETOACETATE HYDROLASE COMPLEXED WITH 4-(HYDROXYMETHYLPHOSPHINOYL)-3-OXO-BUTANOIC ACID
Overview
Fumarylacetoacetate hydrolase (FAH) catalyzes the hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to yield fumarate and acetoacetate as the final step of Phe and Tyr degradation. This unusual reaction is an essential human metabolic function, with loss of FAH activity causing the fatal metabolic disease hereditary tyrosinemia type I (HT1). An enzymatic mechanism involving a catalytic metal ion, a Glu/His catalytic dyad, and a charged oxyanion hole was previously proposed based on recently determined FAH crystal structures. Here we report the development and characterization of an FAH inhibitor, 4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid (HMPOBA), that competes with the physiological substrate with a K(i) of 85 microM. The crystal structure of FAH complexed with HMPOBA refined at 1.3-A resolution reveals the molecular basis for the competitive inhibition, supports the proposed formation of a tetrahedral alkoxy transition state intermediate during the FAH catalyzed reaction, and reveals a Mg(2+) bound in the enzyme's active site. The analysis of FAH structures corresponding to different catalytic states reveals significant active site side-chain motions that may also be related to catalytic function. Thus, these results advance the understanding of an essential catabolic reaction associated with a fatal metabolic disease and provide insight into the structure-based development of FAH inhibitors.
About this Structure
1HYO is a Single protein structure of sequence from Mus musculus with , , , and as ligands. Active as Fumarylacetoacetase, with EC number 3.7.1.2 Full crystallographic information is available from OCA.
Reference
Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor., Bateman RL, Bhanumoorthy P, Witte JF, McClard RW, Grompe M, Timm DE, J Biol Chem. 2001 May 4;276(18):15284-91. Epub 2001 Jan 11. PMID:11154690
Page seeded by OCA on Thu Feb 21 13:06:10 2008
Categories: Fumarylacetoacetase | Mus musculus | Single protein | Bateman, R L. | Bhanumoorthy, P. | Grompe, M. | McClard, R W. | Timm, D E. | Witte, J F. | ACT | CA | HBU | MG | NI | Beta-sandwich roll
