2hzy

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Revision as of 09:57, 21 November 2007

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spinqualitylabelsall models 2hzy, resolution 1.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Mouse fumarylacetoacetate hydrolase complexes with a transition-state mimic of the complete substrate

Overview

FAH (fumarylacetoacetate hydrolase) catalyses the final step of tyrosine, catabolism to produce fumarate and acetoacetate. HT1 (hereditary, tyrosinaemia type 1) results from deficiency of this enzyme. Previously, we prepared a partial mimic of the putative tetrahedral intermediate in, the reaction catalysed by FAH co-crystallized with the enzyme to reveal, details of the mechanism [Bateman, Bhanumoorthy, Witte, McClard, Grompe, and Timm (2001) J. Biol. Chem. 276, 15284-15291]. We have now successfully, synthesized complete mimics CEHPOBA, {4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate} and COPHPAA, {3-[(3-carboxy-2-oxopropyl)hydroxyphosphinyl]acrylate}, which inhibit FAH, in slow-onset tight-binding mode with K(i) values of 41 and 12 nM, respectively. A high-resolution (1.35 A; 1 A=0.1 nm) crystal structure of, the FAH.CEHPOBA complex was solved to reveal the affinity determinants for, these compounds and to provide further insight into the mechanism of FAH, catalysis. These compounds are active in vivo, and CEHPOBA demonstrated a, notable dose-dependent increase in SA (succinylacetone; a metabolite seen, in patients with HT1) in mouse serum after repeated injections, and, following a single injection (1 mumol/g; intraperitoneal), only a modest, regain of FAH enzyme activity was detected in liver protein isolates after, 24 h. These potent inhibitors provide a means to chemically phenocopy the, metabolic defects of either HT1 or FAH knockout mice and promise future, pharmacological utility for hepatocyte transplantation.

About this Structure

2HZY is a Single protein structure of sequence from Mus musculus with NA, MN, NI, CA and DHJ as ligands. Active as Fumarylacetoacetase, with EC number 3.7.1.2 Full crystallographic information is available from OCA.

Reference

Slow-onset inhibition of fumarylacetoacetate hydrolase by phosphinate mimics of the tetrahedral intermediate: kinetics, crystal structure and pharmacokinetics., Bateman RL, Ashworth J, Witte JF, Baker LJ, Bhanumoorthy P, Timm DE, Hurley TD, Grompe M, McClard RW, Biochem J. 2007 Mar 1;402(2):251-60. PMID:17064256

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