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J. Biol. Chem., Vol. 277, Issue 10, 8466-8473, March 8, 2002
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From the Laboratory of Physiological Chemistry, University of
Louvain and Christian de Duve Institute of Cellular Pathology,
B-1200 Brussels, Belgium
Glucokinase is inhibited in the liver by a
regulatory protein (GKRP) whose effects are increased by Fru-6-P and
suppressed by Fru-1-P. To identify the binding site of these phosphate
esters, we took advantage of the homology of GKRP to the isomerase
domain of GlmS (glucosamine-6-phosphate
synthase) and created 12 different mutants of rat GKRP.
Mutations of three residues predicted to bind to Fru-6-P resulted in
proteins that were ~5-fold (S110A) and 50-fold (S179A and K514A) less
potent as inhibitors of glucokinase and had an at least 100-fold
reduced affinity for the effectors. Mutation of another residue of the
putative binding site (T109A) resulted in a 10-fold decrease in the
inhibitory power and an inversion of the effect of sorbitol-6-P, a
Fru-6-P analog. The replacement of Gly107, a residue
close to the binding site, by cysteine (as in GlmS and
Xenopus GKRP) resulted in a protein that had 20 times more affinity for Fru-6-P and 30 times less affinity for Fru-1-P. These results are consistent with GKRP having one single binding site for
phosphate esters. They also show that a missense mutation of GKRP can
lead to a gain of function.
Identification of Fructose 6-Phosphate- and Fructose
1-Phosphate-binding Residues in the Regulatory Protein of
Glucokinase*
and
*
This work was supported by the Actions de Recherche
Concertées; the Belgian Federal Service for Scientific,
Technical, and Cultural Affairs; the Fonds National de la Recherche
Scientifique; and the Juvenile Diabetes Foundation International.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
"Chercheur qualifié" of the Fonds National de la
Recherche Scientifique. To whom correspondence should be addressed:
Lab. Physiological Chemistry, Christian de Duve Inst. of Cellular
Pathology, 75, Av. Hippocrate, B-1200 Brussels, Belgium. Tel.:
32-2764-7559; Fax: 32-2764-7598; E-mail:
veigadacunha@bchm.ucl.ac.be.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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