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J. Biol. Chem., Vol. 280, Issue 38, 32594-32601, September 23, 2005

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Feedback Regulation of Murine Pantothenate Kinase 3 by Coenzyme A and Coenzyme A Thioesters^*

From the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Pantothenate kinase catalyzes a key regulatory step in coenzyme A biosynthesis, and there are four mammalian genes that encode isoforms of this enzyme. Pantothenate kinase isoform PanK3 is highly related to the previously characterized PanK1 isoform (79% identical, 91% similar), and these two almost identical proteins are expressed most highly in the same tissues. PanK1 and PanK3 had very similar molecular sizes, oligomeric form, cytoplasmic cellular location, and kinetic constants for ATP and pantothenate. However, these two PanK isoforms possessed distinct regulatory properties. PanK3 was significantly more sensitive to feedback regulation by acetyl-CoA (IC₅₀ = 1 µM) than PanK1 (IC₅₀ = 10 µM), and PanK3 was stringently regulated by long-chain acyl-CoA (IC₅₀ = 2 µM), whereas PanK1 was not. Domain swapping experiments localized the difference in the two proteins to a 48-amino-acid domain, where they are the most divergent. Consistent with these more stringent regulatory properties, metabolic labeling experiments showed that coenzyme A (CoA) levels in cells overexpressing PanK3 were lower than in cells overexpressing an equivalent amount of PanK1. Thus, the distinct regulatory properties exhibited by the family of the pantothenate kinases allowed the rate of CoA biosynthesis to be controlled by regulatory signals from CoA thioesters involved in different branches of intermediary metabolism.

Received for publication, June 8, 2005 , and in revised form, July 8, 2005.

^* This work was supported by National Institutes of Health Grant GM62896, Cancer Center (CORE) Support Grant CA 21765, and a grant from 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.

¹ To whom correspondence should be addressed: Dept. of Infectious Diseases, 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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