Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.
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.
Zhang
Yong-Mei
YM
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Chohnan
Shigeru
S
Virga
Kristopher G
KG
Stevens
Robert D
RD
Ilkayeva
Olga R
OR
Wenner
Brett R
BR
Bain
James R
JR
Newgard
Christopher B
CB
Lee
Richard E
RE
Rock
Charles O
CO
Jackowski
Suzanne
S
D000818:Animals; D002331:Carnitine / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006706:Homeostasis; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018697:Nootropic Agents / Q000494:pharmacology; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D018697:Nootropic Agents; C016030:pantogab; D010205:Pantothenic Acid; D005680:gamma-Aminobutyric Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D002331:Carnitine; D003065:Coenzyme A