Feedback regulation of murine pantothenate kinase 3 by coenzyme A and coenzyme A thioesters

doi:10.1074/jbc.M506275200

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Papers In Press, published online ahead of print July 22, 2005
J. Biol. Chem, 10.1074/jbc.M506275200
Submitted on June 8, 2005
Revised on July 8, 2005
Accepted on July 22, 2005

Feedback regulation of murine pantothenate kinase 3 by coenzyme A and coenzyme A thioesters

Yong-Mei Zhang, Charles O. Rock, and Suzanne Jackowski

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794

Corresponding Author: suzanne.jackowski{at}stjude.org

Pantothenate kinase catalyzes a key regulatory step in coenzyme A biosynthesis and there are four mammalian genes that encode isoforms of this enzyme. 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 have very similar molecular sizes, oligomeric form, cytoplasmic cellular location and kinetic constants for ATP and pantothenate. However, these two PanK isoforms possess distinct regulatory properties. PanK3 is significantly more sensitive to feedback regulation by acetyl-CoA (IC50 = 1 M) than PanK1 (IC50 = 20 M), and PanK3 is stringently regulated by long-chain acyl-CoA (IC50 = 2 M), whereas PanK1 is not. Domain swapping experiments localize 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 show that 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 allow the rate of CoA biosynthesis to be controlled by regulatory signals from CoA thioesters involved in different branches of intermediary metabolism.

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