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Papers In Press, published online ahead of print October 16, 2000
J. Biol. Chem, 10.1074/jbc.M007926200
Submitted on August 30, 2000
Revised on October 12, 2000
Accepted on October 16, 2000
IBGC CNRS, Bordeaux, cedex 33077
Corresponding Author: B.Daignan-Fornier{at}ibgc.u-bordeaux2.fr
AMP and GMP are synthesized from IMP by specific conserved pathways. In yeast, while IMP and AMP synthesis are coregulated, we found that the GMP synthesis pathway is specifically regulated. Transcription of the IMD genes, encoding the yeast homologs of IMP dehydrogenase (IMPDH), was repressed by extracellular guanine. Only this first step of GDP synthesis pathway is regulated, since the latter steps, encoded by the GUA1 and GUK1 genes, are guanine-insensitive. Use of mutants affecting GDP metabolism revealed that guanine had to be transformed into GDP to allow repression of the IMD genes. IMD genes transcription was also strongly activated by mycophenolic acid (MPA), a specific inhibitor of IMPDH activity. Serial deletions of the IMD2 gene promoter revealed the presence of a negative cis element, required for guanine regulation. Point mutations in this guanine response element (GRE) strongly enhanced IMD2 expression, also making it insensitive to guanine and MPA. From these data, we propose that the GRE sequence mediates a repression process, which is enhanced by guanine addition, through GDP or a GDP derivative, and abolished in the presence of MPA.
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