1hyo

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spinqualitylabelsall models 1hyo, resolution 1.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 MG, CA, NI, ACT and HBU 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

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