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J Biol Chem, Vol. 273, Issue 30, 18992-19001, July 24, 1998
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From the CTP synthetase (EC 6.3.4.2, UTP:ammonia ligase
(ADP-forming)) activity in Saccharomyces cerevisiae is
allosterically regulated by CTP product inhibition. Amino acid residue
Glu161 in the URA7-encoded and
URA8-encoded CTP synthetases was identified as being
involved in the regulation of these enzymes by CTP product inhibition.
The specific activities of the URA7-encoded and
URA8-encoded enzymes with a Glu161 Department of Food Science, Cook College,
New Jersey Agricultural Experiment Station, Rutgers University,
New Brunswick, New Jersey 08901 and the § Department of
Microbial Molecular Biology, Pharmaceutical Research Institute,
Bristol-Myers Squibb, Princeton, New Jersey 08543
Lys
(E161K) mutation were 2-fold greater when compared with the wild-type
enzymes. The E161K mutant URA7-encoded and
URA8-encoded CTP synthetases were less sensitive to CTP
product inhibition with inhibitor constants for CTP of 8.4- and 5-fold
greater, respectively, than those of their wild-type counterparts.
Cells expressing the E161K mutant enzymes on a multicopy plasmid
exhibited an increase in resistance to the pyrimidine poison and cancer
therapeutic drug cyclopentenylcytosine and accumulated elevated
(6-15-fold) levels of CTP when compared with cells expressing the
wild-type enzymes. Cells expressing the E161K mutation in the
URA7-encoded CTP synthetase exhibited an increase
(1.5-fold) in the utilization of the Kennedy pathway for
phosphatidylcholine synthesis when compared with control cells. Cells
bearing the mutation also exhibited an increase in the synthesis of
phosphatidylcholine (1.5-fold), phosphatidylethanolamine (1.3-fold),
and phosphatidate (2-fold) and a decrease in the synthesis of
phosphatidylserine (1.7-fold). These alterations were accompanied by an
inositol excretion phenotype due to the misregulation of the
INO1 gene. Moreover, cells bearing the E161K mutation
exhibited an increase (1.6-fold) in the ratio of total neutral lipids
to phospholipids, an increase in triacylglycerol (1.4-fold), free fatty
acids (1.7-fold), and ergosterol ester (1.8-fold), and a decrease in
diacylglycerol (1.3-fold) when compared with control cells. These data
indicated that the regulation of CTP synthetase activity by CTP plays
an important role in the regulation of phospholipid synthesis.
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