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J. Biol. Chem., Vol. 276, Issue 22, 19094-19101, June 1, 2001
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From the Department of Bacteriology, University of Wisconsin,
Madison, Wisconsin 53706-1567
Salmonella enterica serovar
Typhimurium LT2 showed increased sensitivity to propionate when the
2-methylcitric acid cycle was blocked. A derivative of a
prpC mutant (which lacked 2-methylcitrate synthase
activity) resistant to propionate was isolated, and the mutation
responsible for the newly acquired resistance to propionate was mapped
to the citrate synthase (gltA) gene. These results suggested that citrate synthase activity was the source of the increased sensitivity to propionate observed in the absence of the
2-methylcitric acid cycle. DNA sequencing of the wild-type and mutant
gltA alleles revealed that the ATG start codon of the wild-type gene was converted to the rare GTG start codon in the revertant strain. This result suggested that lower levels of this enzyme were present in the mutant. Consistent with this change, cell-free extracts of the propionate-resistant strain contained 12-fold
less citrate synthase activity. This was interpreted to mean that, in
the wild-type strain, high levels of citrate synthase activity were the
source of a toxic metabolite. In vitro experiments performed with homogeneous citrate synthase enzyme indicated that this
enzyme was capable of synthesizing 2-methylcitrate from propionyl-CoA and oxaloacetate. This result lent further support to the in
vivo data, which suggested that citrate synthase was the source
of a toxic metabolite.
Studies of Propionate Toxicity in Salmonella
enterica Identify 2-Methylcitrate as a Potent Inhibitor of
Cell Growth*
,
*
This work was supported in part by National Institutes of
Health Grant GM62203 (to J. C. E.-S.)The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a National Science Foundation predoctoral fellowship
and by National Institutes of Health Biotechnology Training Grant GM08349.
§
To whom correspondence should be addressed: Dept. of Bacteriology,
1550 Linden Dr., Madison, WI 53706-1567. Tel.: 608-262-7379; Fax: 608-262-9865; E-mail: jcescala@facstaff.wisc.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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