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J. Biol. Chem., Vol. 276, Issue 2, 1523-1530, January 12, 2001
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From the Institut de Biochimie et Génétique
Cellulaires, CNRS UMR 5095, 1 Rue Camille Saint-Saëns,
F-33077 Bordeaux Cedex, France
AMP and GMP are synthesized from IMP by specific
conserved pathways. In yeast, whereas 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, 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 gene transcription was also strongly activated by
mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenase
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 strongly enhanced IMD2 expression, also making it
insensitive to guanine and MPA. From these data, we propose that the
guanine response element sequence mediates a repression process, which
is enhanced by guanine addition, through GDP or a GDP derivative, and
abolished in the presence of MPA.
To whom correspondence should be addressed. Tel.: 33 5 56 99 90 55; Fax: 33 5 56 99 90 59; E-mail: B. Daignan-Fornier@
ibgc.u-bordeaux2.fr.
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