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J. Biol. Chem., Vol. 277, Issue 50, 48205-48209, December 13, 2002
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From the Department of Chemistry and Chemical Biology, Baker
Laboratory, Cornell University, Ithaca, New York, 14853
Pantothenic acid (vitamin B5)
is the natural precursor of coenzyme A (CoA), an essential cofactor in
all organisms. The pantothenic acid antimetabolite
N-pentylpantothenamide inhibits the growth of
Escherichia coli with a minimum inhibitory concentration of 2 µM. In this study, we examine the mechanism of this
inhibition. Using the last five enzymes of the CoA biosynthetic pathway
in E. coli we demonstrate that
N-pentylpantothenamide does not inhibit the CoA
biosynthetic enzymes but instead acts as an alternative substrate,
forming the CoA analog ethyldethia-CoA. We show that N-pentylpantothenamide is converted to ethyldethia-CoA 10.5 times faster than CoA is biosynthesized from pantothenic acid,
demonstrating that ethyldethia-CoA biosynthesis can effectively compete
with CoA biosynthesis in the cell. We conclude that the mechanism of toxicity of N-pentylpantothenamide is most likely due to
its biosynthetic conversion to the CoA analog ethyldethia-CoA, which
may act as an inhibitor of CoA- and acetyl-CoA-utilizing enzymes.
The Antibiotic Activity of N-Pentylpantothenamide
Results from Its Conversion to Ethyldethia-Coenzyme A, a Coenzyme A
Antimetabolite*
*
This work was funded by grants from the Petroleum Research
Foundation and from GlaxoSmithKline.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.
To whom correspondence should be addressed: Dept. of Chemistry and
Chemical Biology, 120 Baker Laboratory, Cornell University, Ithaca, NY
14853-1401. Tel.: 607-255-7133; Fax: 607-255-4137; E-mail:
tpb2@cornell.edu.
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