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Originally published as Genetics Published Articles Ahead of Print on March 2, 2005.
Genetics, Vol. 170, 61-70, May 2005, Copyright © 2005
doi:10.1534/genetics.104.039396
Revisiting Purine-Histidine Cross-Pathway Regulation in Saccharomyces cerevisiae
A Central Role for a Small Molecule
Karine Rébora, Benoît Laloo and Bertrand Daignan-Fornier1
Institut de Biochimie et Génétique Cellulaires, Université Bordeaux 2, CNRS UMR 5095, 33077 Bordeaux Cedex, France
1 Corresponding author: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France.
E-mail: b.daignan-fornier{at}ibgc.u-bordeaux2.fr
Because some metabolic intermediates are involved in more than one pathway, crosstalk between pathways is crucial to maintaining homeostasis. AMP and histidine biosynthesis pathways are coregulated at the transcriptional level in response to adenine availability. 5'-Phosphoribosyl-4-carboxamide-5-aminoimidazole (AICAR), a metabolic intermediate at the crossroads between these two pathways, is shown here to be critical for activation of the transcriptional response in the absence of adenine. In this study, we show that both AMP and histidine pathways significantly contribute to AICAR synthesis. Furthermore, we show that upregulation of the histidine pathway clearly interferes with regulation of the AMP pathway, thus providing an explanation for the regulatory crosstalk between these pathways. Finally, we revisit the histidine auxotrophy of ade3 or ade16 ade17 mutants. Interestingly, overexpression of PMU1, encoding a potential phosphomutase, partially suppresses the histidine requirement of an ade3 ade16 ade17 triple mutant, most probably by reducing the level of AICAR in this mutant. Together our data clearly establish that AICAR is not just a metabolic intermediate but also acts as a true regulatory molecule.
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