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Journal of Bacteriology, June 2003, p. 3410-3415, Vol. 185, No. 11
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.11.3410-3415.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Feedback Regulation of Pantothenate Kinase (CoaA) in Control of Coenzyme A Levels in Escherichia coli

Charles O. Rock,1,2 Hee-Won Park,2,3 and Suzanne Jackowski1,2*

Protein Science Division, Department of Infectious Diseases,1 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,3 Department of Molecular Biosciences, University of Tennessee Health Science Center, Memphis, Tennessee 381632

Received 10 December 2002/ Accepted 12 March 2003

Pantothenate kinase (CoaA) is a key regulator of coenzyme A (CoA) biosynthesis in Escherichia coli, and its activity is controlled by feedback inhibition by CoA and its thioesters. The importance of feedback inhibition in the control of the intracellular CoA levels was tested by constructing three site-directed mutants of CoaA that were predicted to be feedback resistant based on the crystal structure of the CoaA-CoA binary complex. CoaA[R106A], CoaA[H177Q], and CoaA[F247V] were purified and shown to retain significant catalytic activity and be refractory to inhibition by CoA. CoaA[R106A] retained 50% of the catalytic activity of CoaA, whereas the CoaA[H177Q] and CoaA[F247V] mutants were less active. The importance of feedback control of CoaA to the intracellular CoA levels was assessed by expressing either CoaA or CoaA[R106A] in strain ANS3 [coaA15(Ts) panD2]. Cells expressing CoaA[R106A] had significantly higher levels of phosphorylated pantothenate-derived metabolites and CoA in vivo and excreted significantly more 4'-phosphopantetheine into the medium compared to cells expressing the wild-type protein. These data illustrate the key role of feedback regulation of pantothenate kinase in the control of intracellular CoA levels.

* Corresponding author. Mailing address: Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3494. Fax: (901) 495-3099. E-mail: suzanne.jackowski{at}stjude.org.

Journal of Bacteriology, June 2003, p. 3410-3415, Vol. 185, No. 11
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.11.3410-3415.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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