Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.

Abstract	Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.
Authors	Yong-Mei Zhang, Shigeru Chohnan, Kristopher G Virga, Robert D Stevens, Olga R Ilkayeva, Brett R Wenner, James R Bain, Christopher B Newgard, Richard E Lee, Charles O Rock, Suzanne Jackowski
Journal	Chemistry & biology (Chem Biol) Vol. 14 Issue 3 Pg. 291-302 (Mar 2007) ISSN: 1074-5521 [Print] United States
PMID	17379144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Nootropic Agents pantogab Pantothenic Acid gamma-Aminobutyric Acid Phosphotransferases (Alcohol Group Acceptor) pantothenate kinase Carnitine Coenzyme A
Topics	Animals Carnitine (metabolism) Coenzyme A (metabolism) Female Gene Deletion Gene Expression Profiling Gene Expression Regulation, Enzymologic (drug effects) Homeostasis Liver (enzymology, metabolism) Mice Mice, Inbred C57BL Mice, Knockout Nootropic Agents (pharmacology) Pantothenic Acid (analogs & derivatives, chemical synthesis, pharmacology) Phosphotransferases (Alcohol Group Acceptor) (genetics) gamma-Aminobutyric Acid (analogs & derivatives, chemical synthesis, pharmacology)

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