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J. Biol. Chem., Vol. 280, Issue 5, 3314-3322, February 4, 2005

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A Pantothenate Kinase from Staphylococcus aureus Refractory to Feedback Regulation by Coenzyme A^*

Roberta Leonardi, Shigeru Chohnan, Yong-Mei Zhang, Kristopher G. Virga¶, Richard E. Lee¶, Charles O. Rock, and Suzanne Jackowski||

From the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 and ^¶Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163

The key regulatory step in CoA biosynthesis in bacteria and mammals is pantothenate kinase (CoaA), which governs the intracellular concentration of CoA through feedback regulation by CoA and its thioesters. CoaA from Staphylococcus aureus (SaCoaA) has a distinct primary sequence that is more similar to the mammalian pantothenate kinases than the prototypical bacterial CoaA of Escherichia coli. In contrast to all known pantothenate kinases, SaCoaA activity is not feedback-regulated by CoA or CoA thioesters. Metabolic labeling of S. aureus confirms that CoA levels are not controlled by CoaA or at steps downstream from CoaA. The pantothenic acid antimetabolite N-heptylpantothenamide (N7-Pan) possesses potent antimicrobial activity against S. aureus and has multiple cellular targets. N7-Pan is a substrate for SaCoaA and is converted to the inactive butyldethia-CoA analog by the downstream pathway enzymes. The analog is also incorporated into acyl carrier protein and D-alanyl carrier protein, the prosthetic groups of which are derived from CoA. The inactivation of acyl carrier protein and the cessation of fatty acid synthesis are the most critical causes of growth inhibition by N7-Pan because the toxicity of the drug is ameliorated by supplementing the growth medium with fatty acids. The absence of feedback regulation at the pantothenate kinase step allows the accumulation of high concentrations of intracellular CoA, consistent with the physiology of S. aureus, which lacks glutathione and relies on the CoA/CoA disulfide reductase redox system for protection from oxidative damage.

Received for publication, October 12, 2004 , and in revised form, November 8, 2004.

^* This work was supported by National Institutes of Health Grants GM 62896 (to S. J.) and GM 34496 (to C. O. R.), Cancer Center (CORE) Support Grant CA 21765, and the American Lebanese Syrian Associated Charities. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Bioresource Science, College of Agriculture, Ibaraki University, 3-21-1 Chu-ou, Ami, Ibaraki 300-0393, Japan.

^|| To whom correspondence should be addressed: St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Tel.: 901-495-3494; Fax: 901-495-3099; E-mail: Suzanne.jackowski{at}stjude.org.

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