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J. Biol. Chem., Vol. 281, Issue 45, 33892-33899, November 10, 2006

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Inhibition of Fructose-1,6-bisphosphatase by Aminoimidazole Carboxamide Ribotide Prevents Growth of Salmonella enterica purH Mutants on Glycerol^*

From the Department of Bacteriology, University of Wisconsin, Madison, Wisconsin 53706

The enzyme fructose-1,6-bisphosphatase (FBP) is key regulatory point in gluconeogenesis. Mutants of Salmonella enterica lacking purH accumulate 5-amino-4-imidazole carboxamide ribotide (AICAR) and are unable to utilize glycerol as sole carbon and energy sources. The work described here demonstrates this lack of growth is due to inhibition of FBP by AICAR. Mutant alleles of fbp that restore growth on glycerol encode proteins resistant to inhibition by AICAR and the allosteric regulator AMP. This is the first report of biochemical characterization of substitutions causing AMP resistance in a bacterial FBP. Inhibition of FBP activity by AICAR occurs at physiologically relevant concentrations and may represent a form of regulation of gluconeogenic flux in Salmonella enterica.

Received for publication, May 9, 2006 , and in revised form, September 20, 2006.

^* This work was supported in part by competitive Grant GM47296 from the National Institutes of Health and funds from a 21st Century Scientist Scholars Award from the J. S. McDonnell Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Biotechnology Traineeship Grant T32 GM08349 from the National Institutes of Health, a Louis and Elsa Thomsen Wisconsin Distinguished Fellowship Award, and the William H. Peterson Predoctoral Fellowship from the Department of Bacteriology. Present address: Div. of Chemistry and Chemical Engineering, 210-41, California Institute of Technology, Pasadena, CA 91125.

² To whom correspondence should be addressed: 420 Henry Mall, Madison, WI 53706. Tel.: 608-265-4630; Fax: 608-262-9865; E-mail: downs{at}bact.wisc.edu.

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